Disease Information

General Information of the Disease (ID: DIS00056)

Name	Multiple myeloma
ICD	ICD-11: 2A83
Resistance Map

Type(s) of Resistant Mechanism of This Disease

ADTT: Aberration of the Drug's Therapeutic Target

EADR: Epigenetic Alteration of DNA, RNA or Protein

MRAP: Metabolic Reprogramming via Altered Pathways

RTDM: Regulation by the Disease Microenvironment

UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s)

12 drug(s) in total

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Dexamethasone

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B)				[1]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Dexamethasone			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Multiple myeloma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.30E-09 Fold-change: -7.72E-01 Z-score: -7.50E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	JNk/SAPk signaling pathway		Regulation	N.A.
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	WST assay
Mechanism Description	miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.
Key Molecule: Microphthalmia-associated transcription factor (MITF)				[8]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Dexamethasone			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.25E-01 Fold-change: -4.23E-02 Z-score: -1.06E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT signaling pathway		Regulation	N.A.
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-137 can improve the dexamethasone sensitivity in multiple myeloma cells by reducing the c-MET expression and further decreasing the AkT phosphorylation via targeting MITF.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-193a				[4]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Dexamethasone			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	miR193a/MCL1 signaling pathway		Activation	hsa05206
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	ANBL6 cells	Peripheral blood	Homo sapiens (Human)	CVCL_5425
	JJN-3 cells	Bone marrow	Homo sapiens (Human)	CVCL_2078
	MM1R cells	Peripheral blood	Homo sapiens (Human)	CVCL_8794
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR193a/MCL1 pathway.
Key Molecule: hsa-mir-137				[8]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Dexamethasone			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
	PI3K/AKT signaling pathway		Regulation	N.A.
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
In Vivo Model	BALB/c nu/nu nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Real Time RT-PCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-137 can improve the dexamethasone sensitivity in multiple myeloma cells by reducing the c-MET expression and further decreasing the AkT phosphorylation via targeting MITF.
Key Molecule: hsa-mir-202				[1]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Dexamethasone			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	JNk/SAPk signaling pathway		Regulation	N.A.
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	WST assay
Mechanism Description	miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)				[4]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Dexamethasone			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 2.65E-02 Fold-change: 8.45E-02 Z-score: 2.76E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	ANBL6 cells	Peripheral blood	Homo sapiens (Human)	CVCL_5425
	JJN-3 cells	Bone marrow	Homo sapiens (Human)	CVCL_2078
	MM1R cells	Peripheral blood	Homo sapiens (Human)	CVCL_8794
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	Western blot analysis; Luciferase reporter assay
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR193a/MCL1 pathway. NEAT1 promotes MM cell DEX resistance by competitively binding miR193a.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1)				[4]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Dexamethasone			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	ANBL6 cells	Peripheral blood	Homo sapiens (Human)	CVCL_5425
	JJN-3 cells	Bone marrow	Homo sapiens (Human)	CVCL_2078
	MM1R cells	Peripheral blood	Homo sapiens (Human)	CVCL_8794
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay; Flow cytometric analysis
Mechanism Description	LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR193a/MCL1 pathway. NEAT1 promotes MM cell DEX resistance by competitively binding miR193a.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: hsa-mir-15				[23]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Dexamethasone			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	microRNA-15a and -16 expressions tightly correlated with proliferation and drug sensitivity of MM cells. miRNA-15a/-16 expression in MM cells was significantly increased after treatment with cytotoxic agents. The interaction of bone marrow stromal cells (BMSC) with MM cells resulted in decreased miRNA-15a/-16 expression and promoted the survival of the MM cells.
Key Molecule: hsa-mir-16				[23]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Dexamethasone			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	Flow cytometry assay
Mechanism Description	microRNA-15a and -16 expressions tightly correlated with proliferation and drug sensitivity of MM cells. miRNA-15a/-16 expression in MM cells was significantly increased after treatment with cytotoxic agents. The interaction of bone marrow stromal cells (BMSC) with MM cells resulted in decreased miRNA-15a/-16 expression and promoted the survival of the MM cells.

Thalidomide

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B)				[1]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Thalidomide			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Multiple myeloma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.30E-09 Fold-change: -7.72E-01 Z-score: -7.50E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	JNk/SAPk signaling pathway		Regulation	N.A.
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	WST assay
Mechanism Description	miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-202				[1]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Thalidomide			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	JNk/SAPk signaling pathway		Regulation	N.A.
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	WST assay
Mechanism Description	miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Zinc finger protein Aiolos (IKZF3)				[27], [28]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Thalidomide			Drug Info
Molecule Alteration	Missense mutation		p.Q147H	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: Zinc finger protein Helios (IKZF2)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Thalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: DNA-binding protein Ikaros (IKZF1)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Thalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: DNA damage-binding protein 1 (DDB1)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Thalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: Cullin-4B (CUL4B)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Thalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: Cullin-4A (CUL4A)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Thalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: Protein cereblon (CRBN)				[20], [21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Thalidomide			Drug Info
Molecule Alteration	Truncating mutation		p.R283K	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Bortezomib

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B)				[1]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Multiple myeloma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.30E-09 Fold-change: -7.72E-01 Z-score: -7.50E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	JNk/SAPk signaling pathway		Regulation	N.A.
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	WST assay
Mechanism Description	miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[7]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Peripheral blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 6.24E-01 Fold-change: -1.27E-02 Z-score: -4.96E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell colony		Inhibition	hsa05200
	Cell proliferation		Inhibition	hsa05200
	Cell viability		Inhibition	hsa05200
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	microRNA-497 inhibits multiple myeloma growth and increases susceptibility to bortezomib by targeting Bcl-2.
Key Molecule: Ubiquitin-conjugating enzyme E2 C (UBE2C)				[9]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Peripheral blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.19E-01 Fold-change: -9.76E-02 Z-score: -6.55E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	miR631/UbcH10/MDR1 signaling pathway		Regulation	N.A.
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226/BTZ cells	Pancreas	Homo sapiens (Human)	CVCL_XK17
Experiment for Molecule Alteration	RT-PCR; Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Hsa-miR631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10.
Key Molecule: Aurora kinase A (AURKA)				[10]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
	KMS11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2989
In Vivo Model	Mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Epigenetic silencing of miR137 induces drug resistance and chromosomal instability by targeting AURkA in multiple myeloma.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Tumor necrosis factor ligand superfamily member 13B (TNFSF13B)				[2]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Multiple myeloma
The Studied Tissue	Blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.30E-09 Fold-change: -7.72E-01 Z-score: -7.50E+00
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	JNk/SAPk signaling pathway		Activation	hsa05161
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	WST-1 assay; Annexin V-FLUOS assay
Mechanism Description	miR202 contributes to sensitizing MM cells to drug significantly via activing JNk/SAPk signaling pathway. miR202 mimics combined with Bort could inhibit proliferation and induce apoptosis of U266 cells through negative regulating target gene BAFF, which further inhibited the JNk/SAPk signaling pathway.
Key Molecule: hsa-miR-324-5p				[22]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Hedgehog signaling pathway		Inhibition	hsa04340
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
	ARH-77 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1072
In Vivo Model	Mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometric analysis; Colony formation assay
Mechanism Description	Overexpression of miR324-5p significantly decreased Hh signaling components Smo and Gli1, and functionally reduced cell growth, survival as well as stem cell compartment in MM. miR324-5p potentiated the anti-MM efficacy of bortezomib through regulating the activities of multidrug-resistance proteins and the expression of Bcl-2 family genes. Down-regulation of miR324-5p is a novel mechanism of Hh signaling activation in MM.
Key Molecule: hsa-miR-631				[9]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	miR631/UbcH10/MDR1 signaling pathway		Regulation	N.A.
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226/BTZ cells	Pancreas	Homo sapiens (Human)	CVCL_XK17
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Hsa-miR631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10.
Key Molecule: hsa-mir-202				[2]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	JNk/SAPk signaling pathway		Activation	hsa05161
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	WST-1 assay; Annexin V-FLUOS assay
Mechanism Description	miR202 contributes to sensitizing MM cells to drug significantly via activing JNk/SAPk signaling pathway. miR202 mimics combined with Bort could inhibit proliferation and induce apoptosis of U266 cells through negative regulating target gene BAFF, which further inhibited the JNk/SAPk signaling pathway.
Key Molecule: hsa-mir-137				[10]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
	KMS11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2989
In Vivo Model	Mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Epigenetic silencing of miR137 induces drug resistance and chromosomal instability by targeting AURkA in multiple myeloma.
Key Molecule: hsa-mir-497				[7]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Activation	hsa05200
	Cell viability		Inhibition	hsa05200
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	microRNA-497 inhibits multiple myeloma growth and increases susceptibility to bortezomib by targeting Bcl-2.
Key Molecule: hsa-mir-202				[1]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell invasion		Inhibition	hsa05200
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
	JNk/SAPk signaling pathway		Regulation	N.A.
In Vitro Model	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	WST assay
Mechanism Description	miR-202 was functioned as a modulator of BAFF expression. miR-202 over-expression sensitized MM cells to bortezomib (Bort) but less to Thalidomide (Thal) and dexamethasone (Dex). miR-202 mimics in combination with Bort inhibited MM cell survival more effectively as compared with Bort treatment alone. Our study also provided experimental evidence that JNk/SAPk signaling pathway was involved in the regulatory effect of miR-202 on drug resistance of MM cells.

Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Glucose-6-phosphate dehydrogenase (G6PD)				[6]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.85E-04 Fold-change: 1.21E-01 Z-score: 6.68E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	Pentose phosphate signaling pathway		Activation	hsa00030
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226/BTZ cells	Pancreas	Homo sapiens (Human)	CVCL_XK17
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	PDIA3P interacts with c-Myc to enhance its transactivation activity and binding to G6PD promoter, leading to increase of G6PD expression and PPP flux, promoting cell proliferation and drug resistance.
Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)				[12]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	8226 cells	Bone marrow	Homo sapiens (Human)	CVCL_0014
	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis; RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via downregulating miR-29b-3p.
Key Molecule: Early growth response protein 1 (EGR1)				[19]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK signaling pathway		Activation	hsa04010
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Exome sequencing assay; High-resolution copy-number array assay; Cytogenetics exome sequencing assay
Mechanism Description	Knockdown of EGR1 in myeloma cells enhanced their resistance to bortezomib, and the clustered point mutation of key residues that we observed may have similar effects.
Key Molecule: Proteasome assembly chaperone 2 (PSMG2)				[20], [21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Missense mutation		p.E171K	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: Proteasome subunit beta type-5 (PSMB5)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-29b-3p				[12]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Inhibition	hsa05200
In Vitro Model	8226 cells	Bone marrow	Homo sapiens (Human)	CVCL_0014
	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via downregulating miR-29b-3p.
Key Molecule: H19, imprinted maternally expressed transcript (H19)				[12]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	8226 cells	Bone marrow	Homo sapiens (Human)	CVCL_0014
	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via miR-29b-3p.
Key Molecule: Protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P1)				[6]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	Pentose phosphate signaling pathway		Activation	hsa00030
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226/BTZ cells	Pancreas	Homo sapiens (Human)	CVCL_XK17
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	PDIA3P interacts with c-Myc to enhance its transactivation activity and binding to G6PD promoter, leading to increase of G6PD expression and PPP flux, promoting cell proliferation and drug resistance.
Key Molecule: Apoptosis regulator Bcl-2 (BCL2)				[13]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Mechanism Description	Our findings demonstrate miR-34c-5p is differentially expressed between bortezomib-sensitive and -resistant MM cells. Inhibiting miR-34c-5p re-sensitized resistant cells to bortezomib by modulating Bax/Bcl-2 expression, suggesting this miRNA regulates apoptosis and drug resistance and may be a promising therapeutic target for overcoming proteasome inhibitor resistance in MM.
Key Molecule: BCL2 associated X protein (BAX)				[13]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		S1148A	Molecule Info
Mechanism Description	Our findings demonstrate miR-34c-5p is differentially expressed between bortezomib-sensitive and -resistant MM cells. Inhibiting miR-34c-5p re-sensitized resistant cells to bortezomib by modulating Bax/Bcl-2 expression, suggesting this miRNA regulates apoptosis and drug resistance and may be a promising therapeutic target for overcoming proteasome inhibitor resistance in MM.
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Tripartite motif containing 44 (TRIM44)				[14]
Metabolic Type	Redox metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030
	RPMI cells	Blood	Homo sapiens (Human)	N.A.
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Apoptosis assay
Mechanism Description	This analysis further identified high TRIM44 expression as predictive of lower responsiveness to proteasome inhibitor (PI) treatments, underscoring its critical function in the unfolded protein response (UPR) in TRIM44-high MM cells. Our findings also demonstrate that TRIM44 facilitates SQSTM1 oligomerization under oxidative stress, essential for its phosphorylation and subsequent autophagic degradation. This process supports the survival of PI-resistant MM cells by activating the NRF2 pathway, which is crucial for oxidative stress response and, potentially, other chemotherapy-induced stressors. Additionally, TRIM44 counters the TRIM21-mediated suppression of the antioxidant response, enhancing MM cell survival under oxidative stress.
Key Molecule: Ubiquinone (Q10)				[15]
Metabolic Type	Lipid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	AMO-1 cells	Blood	Homo sapiens (Human)	CVCL_1806
	ARH-77 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1072
	MM RPMI-8226 cells	Blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	Proteomics
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Mechanistically, BTZ-resistant cells show increased activity of glutamine-driven TCA cycle and oxidative phosphorylation, together with an increased vulnerability towards ETC inhibition. Moreover, BTZ resistance is accompanied by high levels of the mitochondrial electron carrier CoQ, while the mevalonate pathway inhibitor simvastatin increases cell death and decreases CoQ levels, specifically in BTZ-resistant cells. Both in vitro and in vivo, simvastatin enhances the effect of bortezomib treatment. Our study links CoQ synthesis to drug resistance in MM and provides a novel avenue for improving BTZ responses through statin-induced inhibition of mitochondrial metabolism.
Key Molecule: Pyrroline-5-carboxylate reductase 1 (PYCR1)				[16]
Metabolic Type	Glutamine metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	ANBL-6 cells	Blood	Homo sapiens (Human)	CVCL_5425
	JJN-3 cells	Bone marrow	Homo sapiens (Human)	CVCL_2078
	LP-1 cells	Blood	Homo sapiens (Human)	CVCL_0012
	OPM2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI 8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_7353
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis.
Key Molecule: Pyrroline-5-carboxylate reductase 2 (PYCR2)				[16]
Metabolic Type	Glutamine metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	ANBL-6 cells	Blood	Homo sapiens (Human)	CVCL_5425
	JJN-3 cells	Bone marrow	Homo sapiens (Human)	CVCL_2078
	LP-1 cells	Blood	Homo sapiens (Human)	CVCL_0012
	OPM2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI 8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_7353
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis.
Key Molecule: Proline-rich Akt substrate 40 kDa (PRAS40)				[16]
Metabolic Type	Glutamine metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	ANBL-6 cells	Blood	Homo sapiens (Human)	CVCL_5425
	JJN-3 cells	Bone marrow	Homo sapiens (Human)	CVCL_2078
	LP-1 cells	Blood	Homo sapiens (Human)	CVCL_0012
	OPM2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI 8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_7353
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	We found that PYCR1 and PYCR2 mRNA expression correlated with an inferior overall survival. MM cells from relapsed/refractory patients express significantly higher levels of PYCR1 mRNA. In line with the strong expression of PYCR1, we performed a tracer study in RPMI-8226 cells, which revealed an increased conversion of 13C-glutamine to proline in hypoxia. PYCR1 inhibition reduced MM viability and proliferation and increased apoptosis. Mechanistically, we found that PYCR1 silencing reduced protein levels of p-PRAS40, p-mTOR, p-p70, p-S6, p-4EBP1 and p-eIF4E levels, suggesting a decrease in protein synthesis, which we also confirmed in vitro. Pargyline and siPYCR1 increased bortezomib-mediated apoptosis.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[17]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	293 T cells	Blood	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS10 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[17]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS6 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[17]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MM1 S cells	Blood	Homo sapiens (Human)	CVCL_8792
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS7 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[17]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	U266B1 cells	Blood	Homo sapiens (Human)	CVCL_0566
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS8 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[17]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	RPMI 8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_7353
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS9 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Suppressor of cytokine signaling 6 (SOCS6)				[18]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Protein kinase C (PKC)				[18]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		.	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Tumor necrosis factor receptor superfamily member 10B (TNFRSF10B)				[18]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A)				[18]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Tumor necrosis factor receptor superfamily member 6 (FAS)				[18]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Tumor necrosis factor receptor superfamily member 3 (LTBR)				[18]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Interleukin-1 receptor-associated kinase 1 (IRAK1)				[18]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.
Key Molecule: Stimulator of interferon genes protein (STING1)				[18]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Bortezomib			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	Western blot assay
Experiment for Drug Resistance	MTT assay
Mechanism Description	In particular, the dynamic interaction between BM mesenchymal stem cells (BM-MSC) and MM cells has shown great relevance. Here we showed that inhibiting both PKC and NF-kappaB signalling pathways in BM-MSC reduced cell survival in the MM cell line H929 and increased its susceptibility to the proteasome inhibitor bortezomib. PKC-mediated cell survival inhibition and bortezomib susceptibility induction were better performed by the chimeric peptide HKPS than by the classical enzastaurin inhibitor, probably due to its greatest ability to inhibit cell adhesion and its increased capability to counteract the NF-kappaB-related signalling molecules increased by the co-cultivation of BM-MSC with H929 cells. Thus, inhibiting two coupled signalling molecules in BM-MSC was more effective in blocking the supportive cues emerging from the mesenchymal stroma.

Doxorubicin

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Forkhead box protein O3 (FOXO3)				[3]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 1.29E-02 Fold-change: 8.93E-02 Z-score: 3.29E+00
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	RPMI8226/Dox cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
	RPMI8226/S cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Targeting inhibition of miR155 expression could restore chemotherapy sensitivity by increasing FOXO3a expression in drug-resistant myeloma cells.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-155				[3]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Doxorubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	RPMI8226/Dox cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
	RPMI8226/S cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Targeting inhibition of miR155 expression could restore chemotherapy sensitivity by increasing FOXO3a expression in drug-resistant myeloma cells.

Melphalan

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Beclin 1-associated autophagy-related key regulator (ATG14)				[5]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Melphalan			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 4.37E-01 Fold-change: 1.75E-02 Z-score: 8.21E-01
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell autophagy		Activation	hsa04140
	Cell viability		Activation	hsa05200
In Vitro Model	KMS11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2989
	LP1 cells	Bone marrow	Homo sapiens (Human)	CVCL_0012
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.
Key Molecule: Bcl-2-binding component 3 (BBC3)				[30]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Melphalan			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226/BTZ cells	Pancreas	Homo sapiens (Human)	CVCL_XK17
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	miR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.
Key Molecule: Bcl-2-binding component 3 (BBC3)				[30]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Melphalan			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226/BTZ cells	Pancreas	Homo sapiens (Human)	CVCL_XK17
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	miR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Long non-protein coding RNA (LINC00515)				[5]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Melphalan			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	KMS11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2989
	LP1 cells	Bone marrow	Homo sapiens (Human)	CVCL_0012
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.
Key Molecule: hsa-miR-140-5p				[5]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Melphalan			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell autophagy		Activation	hsa04140
	Cell viability		Activation	hsa05200
In Vitro Model	KMS11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2989
	LP1 cells	Bone marrow	Homo sapiens (Human)	CVCL_0012
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.
Key Molecule: hsa-mir-221				[30]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Melphalan			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	RPMI-8226/BTZ cells	Pancreas	Homo sapiens (Human)	CVCL_XK17
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay; Flow cytometry assay
Mechanism Description	miR-221/222 expression inversely correlated with melphalan-sensitivity of MM cells. Inhibition of miR-221/222 overcame melphalan-resistance and triggered apoptosis of MM cells in vitro, in the presence or absence of human bone marrow stromal cells. Decreased MM cell growth induced by inhibition of miR-221/222 plus melphalan was associated with a marked upregulation of pro-apoptotic BBC3/PUMA protein, a miR-221/222 target, as well as with modulation of drug influx-efflux transporters SLC7A5/LAT1 and the ATP-binding cassette (ABC) transporter ABCC1/MRP1. Finally, in vivo treatment of SCID/NOD mice bearing human melphalan-refractory MM xenografts with systemic LNA-i-miR-221 plus melphalan overcame drug-resistance, evidenced by growth inhibition with significant antitumor effects together with modulation of PUMA and ABCC1 in tumors retrieved from treated mice.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-140-5p				[5]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Melphalan			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell autophagy		Activation	hsa04140
	Cell viability		Activation	hsa05200
In Vitro Model	KMS11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2989
	LP1 cells	Bone marrow	Homo sapiens (Human)	CVCL_0012
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Beclin 1-associated autophagy-related key regulator (ATG14)				[5]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Melphalan			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell autophagy		Activation	hsa04140
	Cell viability		Activation	hsa05200
In Vitro Model	KMS11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2989
	LP1 cells	Bone marrow	Homo sapiens (Human)	CVCL_0012
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	MTT assay; Flow cytometry assay
Mechanism Description	Linc00515 enhanced autophagy and chemoresistance of melphalan-resistant myeloma by directly inhibiting miR-140-5p, which elevated ATG14 level.

Epirubicin

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Aurora kinase A (AURKA)				[10]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Epirubicin			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Peripheral blood
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 5.27E-01 Fold-change: -1.02E-01 Z-score: -6.42E-01
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
	KMS11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2989
In Vivo Model	Mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Ectopic expression of miR137 strongly reduced the expression of AURkA and p-ATM/Chk2 in MM cells, and increased the expression of p53, and p21, overexpression of miR137 could reduce drug resistance and overcome chromosomal instability of the MM cells via affecting the apoptosis and RNA damage pathways.
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-137				[10]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Epirubicin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
	U266 cells	Bone marrow	Homo sapiens (Human)	CVCL_0566
	MM1S cells	Peripheral blood	Homo sapiens (Human)	CVCL_8792
	OPM-2 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1625
	RPMI-8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_0014
	KMS11 cells	Peripheral blood	Homo sapiens (Human)	CVCL_2989
In Vivo Model	Mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	Ectopic expression of miR137 strongly reduced the expression of AURkA and p-ATM/Chk2 in MM cells, and increased the expression of p53, and p21, overexpression of miR137 could reduce drug resistance and overcome chromosomal instability of the MM cells via affecting the apoptosis and RNA damage pathways.

Trifluoperazine

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Nuclear protein 1, transcriptional regulator (NUPR1)				[11]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Trifluoperazine			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Differential expression of the molecule in resistant disease
Classification of Disease	Multiple myeloma [ICD-11: 2A83]
The Specified Disease	Myeloma
The Studied Tissue	Bone marrow
The Expression Level of Disease Section Compare with the Healthy Individual Tissue	p-value: 3.83E-03 Fold-change: -1.04E-01 Z-score: -4.20E+00
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell autophagy		Activation	hsa04140
	Cell apoptosis		Activation	hsa04210
In Vitro Model	HSC3 cells	Tongue	Homo sapiens (Human)	CVCL_1288
	OVCAR3 cells	Ovary	Homo sapiens (Human)	CVCL_0465
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	There was statistical difference in the expression of the aforementioned proteins between the TFptreated group and TFptreated NC-LV group, but the autophagy level was upregulated and apoptosis was downregulated in the TFptreated NUPR1-LV group compared with the TFptreated NC-LV group. NUPR1 overexpression reversed the autophagic suppression and cellular apoptosis induction caused by TFP in U266 and RPMI 8226 cells. Thus, we concluded that TFP targeted NUPR1 in MM cells and subsequently induced apoptosis by inhibiting autophagy.

Iopamidol

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: Solute carrier family 2, facilitated glucose transporter member 1 (Glucose transporter type 1, erythrocyte/brain) (GLUT-1) (GT1)				[24]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Iopamidol			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Discovered Using In-vivo Testing Model
In Vitro Model	NCI-H508 cells	Colon	Homo sapiens (Human)	CVCL_1564
In Vivo Model	Orthotopic BM engrafted MM xenograft model			Mus musculus
Experiment for Molecule Alteration	Immunohistochemistry and histologic analysis
Experiment for Drug Resistance	Micro-Computed Tomography; Positron emission tomography; Magnetic resonance spectroscopy; Magnetic resonance imaging (MRI)
Mechanism Description	Adaptive responses to hypoxia may be an essential element in MM progression and drug resistance. This metabolic adaptation involves a decrease in extracellular pH (pHe), and it depends on the upregulation of glucose transporters (GLUTs) that is common in hypoxia and in cancer cells.

Lenalidomide

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Aberration of the Drug's Therapeutic Target (ADTT)			Click to Show/Hide
Key Molecule: Double-stranded RNA-specific adenosine deaminase (ADAR)				[25]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Lenalidomide			Drug Info
Molecule Alteration	Expression		Down-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	KMS-11 cells	Pleural effusion	Homo sapiens (Human)	CVCL_2989

In Vivo Model	NSG female mice model			Mus musculus
Experiment for Molecule Alteration	RNA sequencing assay; Whole-exome sequencing assay; qRT-PCR; Western blot assay; ELISA assay
Experiment for Drug Resistance	Cell viability assay; Colony formation assay; Cell cycle assay; Apoptosis assay
Mechanism Description	Here, we identified adenosine deaminase acting on RNA1 (ADAR1) as a novel driver of lenalidomide resistance in MM. We showed that lenalidomide activates the MDA5-mediated double-stranded RNA (dsRNA)-sensing pathway in MM cells, leading to interferon (IFN)-mediated apoptosis, with ADAR1 as the key regulator. Mechanistically, ADAR1 loss increased lenalidomide sensitivity through endogenous dsRNA accumulation, which in turn triggered dsRNA-sensing pathways and enhanced IFN responses. Conversely, ADAR1 overexpression reduced lenalidomide sensitivity, attributed to increased RNA editing frequency, reduced dsRNA accumulation, and suppression of the dsRNA-sensing pathways. In summary, we report the involvement of ADAR1-regulated dsRNA sensing in modulating lenalidomide sensitivity in MM. These findings highlight a novel RNA-related mechanism underlying lenalidomide resistance and underscore the potential of targeting ADAR1 as a novel therapeutic strategy.
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Nuclear receptor binding SET domain protein 2 (NSD2)				[26]
Metabolic Type	Glucose metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Lenalidomide			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vivo Model	6-week-old female NOD/SCID mice, with KMS11 cells			Mice
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Tumor volume assay
Mechanism Description	Here, we identified PKCalpha as an epigenetic target that contributes to the oncogenic potential of NSD2. RNA sequencing of t(4;14) multiple myeloma cell lines revealed a significant enrichment in the regulation of metabolic processes by PKCalpha, and the glycolytic gene, hexokinase 2 (HK2), was transcriptionally regulated by PKCalpha in a PI3K/Akt-dependent manner. Loss of PKCalpha displaced mitochondria-bound HK2 and reversed sensitivity to the glycolytic inhibitor 3-bromopyruvate. In addition, the perturbation of glycolytic flux led to a metabolic shift to a less energetic state and decreased ATP production.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Zinc finger protein Aiolos (IKZF3)				[27], [28]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Lenalidomide			Drug Info
Molecule Alteration	Missense mutation		p.Q147H	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: Zinc finger protein Helios (IKZF2)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Lenalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: DNA-binding protein Ikaros (IKZF1)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Lenalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: DNA damage-binding protein 1 (DDB1)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Lenalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: Cullin-4B (CUL4B)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Lenalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: Cullin-4A (CUL4A)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Lenalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: Protein cereblon (CRBN)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Lenalidomide			Drug Info
Molecule Alteration	Truncating mutation		p.Q99*	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Aberration of the Drug's Therapeutic Target (ADTT)			Click to Show/Hide
Key Molecule: Lys-63-specific deubiquitinase BRCC36 (BRCC3)				[29]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Lenalidomide			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	HEK 293T cells	Kidney	Homo sapiens (Human)	CVCL_0063
	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030

	RPMI 8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_7353
	LP1 cells	Blood	Homo sapiens (Human)	CVCL_E2V5
	U266 cells	Bone marrow	Homo sapiens (Human)	N.A.
	ARH-77 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1072
In Vivo Model	BALB/c male nude mice model			Mus musculus
Experiment for Molecule Alteration	qPCR; Protein degradation assay; Proteasome inhibition assay; Western blot assay; Proximity-labeling assay; MS analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	In this study, we used the proximity labeling technique TurboID and quantitative proteomics to identify Lys-63-specific deubiquitinase BRCC36 as a CRBN-interacting protein. Biochemical experiments demonstrated that BRCC36 in the BRISC complex protects CRBN from lysosomal degradation by specifically cleaving the K63-linked polyubiquitin chain on CRBN. Further studies found that a small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can upregulate CRBN by elevating BRCC36. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM.

Pomalidomide

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Aberration of the Drug's Therapeutic Target (ADTT)			Click to Show/Hide
Key Molecule: Protein cereblon (CRBN)				[31]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Pomalidomide			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	AsPC-1 cells	Pancreas	Homo sapiens (Human)	CVCL_0152
Experiment for Molecule Alteration	Whole-genome sequencing assay
Mechanism Description	Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma.

Simvastatin

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Ubiquinone (Q10)				[15]
Metabolic Type	Lipid metabolism
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	Simvastatin			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	AMO-1 cells	Blood	Homo sapiens (Human)	CVCL_1806
	ARH-77 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1072
	MM RPMI-8226 cells	Blood	Homo sapiens (Human)	CVCL_0014
Experiment for Molecule Alteration	Proteomics
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Mechanistically, BTZ-resistant cells show increased activity of glutamine-driven TCA cycle and oxidative phosphorylation, together with an increased vulnerability towards ETC inhibition. Moreover, BTZ resistance is accompanied by high levels of the mitochondrial electron carrier CoQ, while the mevalonate pathway inhibitor simvastatin increases cell death and decreases CoQ levels, specifically in BTZ-resistant cells. Both in vitro and in vivo, simvastatin enhances the effect of bortezomib treatment. Our study links CoQ synthesis to drug resistance in MM and provides a novel avenue for improving BTZ responses through statin-induced inhibition of mitochondrial metabolism.

Vemurafenib

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Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

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Key Molecule: GTPase Nras (NRAS)

[32]

Resistant Disease

Multiple myeloma [ICD-11: 2A83.0]

Resistant Drug

Vemurafenib

Drug Info

Molecule Alteration

Missense mutation

p.Q61H

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 1.31 Å

PDB: 6T5V

Mutant Type Structure

Method: X-ray diffraction

Resolution: 2.20 Å

PDB: 6MNX

Download The Information of Sequence

Download The Structure File

Click to Show/Hide the Structure

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Ion Torrent semiconductor-based targeted resequencing assay

Experiment for
Drug Resistance

Whole-body magnetic resonance imaging (MRI) assay

Mechanism Description

Although all 5 reference lesions biopsied in month 10 still harbored a BRAFV600E mutation in all MM cells, an additio.l monoallelic NRAS mutation was detectable in each of the 3 lesions resistant to the full dose of vemurafenib. Of note, each lesion harbored a unique, independent, yet clo.l NRAS mutation (NRAS G13R, NRAS G12A, and NRAS Q61H, respectively).

Key Molecule: GTPase Nras (NRAS)

[32]

Resistant Disease

Multiple myeloma [ICD-11: 2A83.0]

Resistant Drug

Vemurafenib

Drug Info

Molecule Alteration

Missense mutation

p.G12A

Molecule Info

Wild Type Structure

Method: X-ray diffraction

Resolution: 1.40 Å

PDB: 6VJJ

Mutant Type Structure

Method: X-ray diffraction

Resolution: 1.45 Å

PDB: 8TBJ

Download The Information of Sequence

Download The Structure File

Click to Show/Hide the Structure

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Ion Torrent semiconductor-based targeted resequencing assay

Experiment for
Drug Resistance

Whole-body magnetic resonance imaging (MRI) assay

Mechanism Description

Key Molecule: GTPase Nras (NRAS)

[32]

Resistant Disease

Multiple myeloma [ICD-11: 2A83.0]

Resistant Drug

Vemurafenib

Drug Info

Molecule Alteration

Missense mutation

p.G13R

Molecule Info

Experimental Note

Identified from the Human Clinical Data

In Vivo Model

A retrospective survey in conducting clinical studies

Homo sapiens

Experiment for
Molecule Alteration

Ion Torrent semiconductor-based targeted resequencing assay

Experiment for
Drug Resistance

Whole-body magnetic resonance imaging (MRI) assay

Mechanism Description

Clinical Trial Drug(s)

1 drug(s) in total

Click to Show/Hide the Full List of Drugs

Selinexor

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Metabolic Reprogramming via Altered Pathways (MRAP)			Click to Show/Hide
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[17]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Selinexor			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	NCI-H929 cells	Bone marrow	Homo sapiens (Human)	CVCL_1600
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS1 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[17]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Selinexor			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MM1 S cells	Blood	Homo sapiens (Human)	CVCL_8792
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS2 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[17]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Selinexor			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	U266B1 cells	Blood	Homo sapiens (Human)	CVCL_0566
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS3 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[17]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Selinexor			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	RPMI 8226 cells	Peripheral blood	Homo sapiens (Human)	CVCL_7353
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS4 is mainly involved in cytidine metabolism and nucleic acids metabolism.
Key Molecule: Cytidine triphosphate synthase 1 (CTPS1)				[17]
Metabolic Type	Nucleic acid metabolism
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Selinexor			Drug Info
Molecule Alteration	Expression		Up-regulation	Molecule Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	293 T cells	Blood	Homo sapiens (Human)	N.A.
Experiment for Molecule Alteration	qRT-PCR; Western blot analysis
Experiment for Drug Resistance	Cell viability assay
Mechanism Description	Among these, upregulation of CTPS1 was associated with poor prognosis in MM and drug resistance recurrence. CTPS5 is mainly involved in cytidine metabolism and nucleic acids metabolism.

Preclinical Drug(s)

1 drug(s) in total

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E7090

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Aberration of the Drug's Therapeutic Target (ADTT)		Click to Show/Hide
Key Molecule: Fibroblast growth factor receptor 3 (FGFR3)			[33]
Sensitive Disease	Multiple myeloma [ICD-11: 2A83.0]
Sensitive Drug	E7090		Drug Info
Molecule Alteration	Missense mutation	p.Y373C (c.1118A>G)	Molecule Info
Experimental Note	Identified from the Human Clinical Data

Investigative Drug(s)

1 drug(s) in total

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Cortiosteroids

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Proteasome assembly chaperone 2 (PSMG2)				[20], [21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Cortiosteroids			Drug Info
Molecule Alteration	Missense mutation		p.E171K	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.
Key Molecule: Proteasome subunit beta type-5 (PSMB5)				[21]
Resistant Disease	Multiple myeloma [ICD-11: 2A83.0]
Resistant Drug	Cortiosteroids			Drug Info
Molecule Alteration	Mutation		.	Molecule Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell proliferation		Activation	hsa05200
	PI3K/RAS signaling pathway		Regulation	N.A.
In Vitro Model	Bone marrow	Blood	Homo sapiens (Human)	N.A.
In Vivo Model	A retrospective survey in conducting clinical studies			Homo sapiens
Experiment for Molecule Alteration	Gene expression profiling assay; High-resolution copy number arrays assay; Whole-exome sequencing assay
Experiment for Drug Resistance	Longitudinal copy number aberration (CNA) analysis
Mechanism Description	Resistance to immunomodulatory drugs (IMiD) and proteasome inhibitors was recently associated with mutations in IMiD response genes IRF4, CRBN, DDB1, CUL4A, CUL4B, IkZF1, IkZF2, and IkZF3 or in the proteasome inhibitor response genes PSMB5 and PSMG2, respectively. Mechanistically, bi-allelic loss of tumor-suppressor genes is a crucial mechanism, allowing units of selection to evade treatment-induced apoptosis with the acquisition of subsequent proliferative advantage leading to their outgrowth.

References

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Ref 2	[miR-202 contributes to sensitizing MM cells to drug significantly via activing JNK/SAPK signaling pathway]. Zhonghua Xue Ye Xue Za Zhi. 2016 Nov 14;37(11):987-992. doi: 10.3760/cma.j.issn.0253-2727.2016.11.012.
Ref 3	[Targeting miR155 restores chemotherapy sensitivity in drug-resistant myeloma cell-line RPMI8226/DOX cells]. Zhonghua Xue Ye Xue Za Zhi. 2017 Jan 14;38(1):55-59. doi: 10.3760/cma.j.issn.0253-2727.2017.01.012.
Ref 4	LncRNA NEAT1 promotes dexamethasone resistance in multiple myeloma by targeting miR-193a/MCL1 pathway. J Biochem Mol Toxicol. 2018 Jan;32(1). doi: 10.1002/jbt.22008. Epub 2017 Dec 4.
Ref 5	Knockdown of Linc00515 Inhibits Multiple Myeloma Autophagy and Chemoresistance by Upregulating miR-140-5p and Downregulating ATG14. Cell Physiol Biochem. 2018;48(6):2517-2527. doi: 10.1159/000492690. Epub 2018 Aug 17.
Ref 6	LncRNA PDIA3P interacts with c-Myc to regulate cell proliferation via induction of pentose phosphate pathway in multiple myeloma. Biochem Biophys Res Commun. 2018 Mar 25;498(1):207-213. doi: 10.1016/j.bbrc.2018.02.211. Epub 2018 Mar 1.
Ref 7	MicroRNA-497 inhibits multiple myeloma growth and increases susceptibility to bortezomib by targeting Bcl-2. Int J Mol Med. 2019 Feb;43(2):1058-1066. doi: 10.3892/ijmm.2018.4019. Epub 2018 Dec 7.
Ref 8	miR-137 Suppresses the Phosphorylation of AKT and Improves the Dexamethasone Sensitivity in Multiple Myeloma Cells Via Targeting MITF. Curr Cancer Drug Targets. 2016;16(9):807-817. doi: 10.2174/1568009616666160203114140.
Ref 9	hsa-miR-631 resensitizes bortezomib-resistant multiple myeloma cell lines by inhibiting UbcH10. Oncol Rep. 2017 Feb;37(2):961-968. doi: 10.3892/or.2016.5318. Epub 2016 Dec 14.
Ref 10	Epigenetic silencing of miR-137 induces drug resistance and chromosomal instability by targeting AURKA in multiple myeloma. Leukemia. 2017 May;31(5):1123-1135. doi: 10.1038/leu.2016.325. Epub 2016 Nov 18.
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Prof. Feng ZHU (zhufeng@zju.edu.cn)