Disease Information

General Information of the Disease (ID: DIS00054)

Name	Diffuse large B-cell lymphoma
ICD	ICD-11: 2A81
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

RTDM: Regulation by the Disease Microenvironment

UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s)

9 drug(s) in total

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Alectinib

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Zinc finger C3HC-type containing 1 (ZC3HC1)				[1]
Resistant Disease	NPM-ALK-Positive anaplastic large cell lymphoma [ICD-11: 2A81.8]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Alectinib			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SUP-M2 cells	Colon	Homo sapiens (Human)	CVCL_2209
	KARPAS-299 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1324
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	Proliferation assay
Mechanism Description	For KARPAS-299-derived cell lines, we observed oncogene overexpression as the main resistance mechanism, whereas in SUP-M2-derived cell lines, we identified several point mutations located within the NPM-ALK kinase domain, which could explain drug resistance.
Key Molecule: Zinc finger C3HC-type containing 1 (ZC3HC1)				[1]
Resistant Disease	NPM-ALK-Positive anaplastic large cell lymphoma [ICD-11: 2A81.8]
Molecule Alteration	Mutation		p.L1122V+p.F1174V+p.L1196M+p.L1198F+p.S1206C+p.L1122V+p.L1196M+p.F1174V+p.L1198F+p.L1196M+p.D1203N	Molecule Info
Resistant Drug	Alectinib			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SUP-M2 cells	Colon	Homo sapiens (Human)	CVCL_2209
	KARPAS-299 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1324
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	Proliferation assay
Mechanism Description	For KARPAS-299-derived cell lines, we observed oncogene overexpression as the main resistance mechanism, whereas in SUP-M2-derived cell lines, we identified several point mutations located within the NPM-ALK kinase domain, which could explain drug resistance.

Ceritinib

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Zinc finger C3HC-type containing 1 (ZC3HC1)				[1]
Resistant Disease	NPM-ALK-Positive anaplastic large cell lymphoma [ICD-11: 2A81.8]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Ceritinib			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SUP-M2 cells	Colon	Homo sapiens (Human)	CVCL_2209
	KARPAS-299 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1324
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	Proliferation assay
Mechanism Description	For KARPAS-299-derived cell lines, we observed oncogene overexpression as the main resistance mechanism, whereas in SUP-M2-derived cell lines, we identified several point mutations located within the NPM-ALK kinase domain, which could explain drug resistance.
Key Molecule: Zinc finger C3HC-type containing 1 (ZC3HC1)				[1]
Resistant Disease	NPM-ALK-Positive anaplastic large cell lymphoma [ICD-11: 2A81.8]
Molecule Alteration	Mutation		p.L1122V+p.139S+p.L1198F+p.S1206C+p.L1122V+p.L1196M+p.F1174V+p.L1198F+p.L1196M+p.D1203N	Molecule Info
Resistant Drug	Ceritinib			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SUP-M2 cells	Colon	Homo sapiens (Human)	CVCL_2209
	KARPAS-299 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1324
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	Proliferation assay
Mechanism Description	For KARPAS-299-derived cell lines, we observed oncogene overexpression as the main resistance mechanism, whereas in SUP-M2-derived cell lines, we identified several point mutations located within the NPM-ALK kinase domain, which could explain drug resistance.

Cyclophosphamide

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-148b				[2]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Acetylation		Down-regulation	Molecule Info
Resistant Drug	Cyclophosphamide			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell viability		Activation	hsa05200
	HDAC6/miR148b/Ezrin signaling pathway		Regulation	hsa05206
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
	CRL2631/CHOP cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: hsa-miR-125b-5p				[3]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Cyclophosphamide			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SU-DHL-2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_9550
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.
Key Molecule: hsa-miR-99a-5p				[3]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Cyclophosphamide			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SU-DHL-2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_9550
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Ezrin (EZR)				[2]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Cyclophosphamide			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	HDAC6/miR148b/Ezrin signaling pathway		Regulation	hsa05206
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
	CRL2631/CHOP cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-21				[4]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Cyclophosphamide			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 impacts the PI3k/AkT signaling pathway through the regulation of PTEN, thereby affecting cellular sensitivity to the CHOP chemotherapeutic regimen.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Phosphatase and tensin homolog (PTEN)				[4]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Cyclophosphamide			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 impacts the PI3k/AkT signaling pathway through the regulation of PTEN, thereby affecting cellular sensitivity to the CHOP chemotherapeutic regimen.

Doxorubicin

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-148b				[2]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Acetylation		Down-regulation	Molecule Info
Resistant Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	HDAC6/miR148b/Ezrin signaling pathway		Regulation	hsa05206
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
	CRL2631/CHOP cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: hsa-miR-125b-5p				[3]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SU-DHL-2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_9550
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.
Key Molecule: hsa-miR-99a-5p				[3]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SU-DHL-2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_9550
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Ezrin (EZR)				[2]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	HDAC6/miR148b/Ezrin signaling pathway		Regulation	hsa05206
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
	CRL2631/CHOP cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.
Key Molecule: Sirtuin 6 (SIRT6)				[5]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MET/PI3K/AKT/mTOR signaling pathway		Activation	hsa04150
In Vitro Model	Val cells	Bone marrow	Homo sapiens (Human)	CVCL_1819
	LY1 cells	Ovary	Homo sapiens (Human)	CVCL_ZU83
	DLBCL cells	Lymph node	Homo sapiens (Human)	N.A.
	LY8 cells	Lymph node	Homo sapiens (Human)	CVCL_8803
	LY3 cells	Bone marrow	Homo sapiens (Human)	CVCL_8800
In Vivo Model	Beige mice xenografts model			Mus musculus
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	CCK-8 assay
Mechanism Description	Sirt6 expression was raised in DLBCL, with its high levels corresponding to poor patient outcomes. Sirt6 was also found to promote tumorigenesis by regulating the PI3K/Akt/mTOR pathway. Targeting Sirt6 exerted anti-lymphoma activity and enhanced chemo-sensitivity. OSS_128167 may prove to be a useful component in further development of novel chemotherapy regimens in DLBCL.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-370-3p				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: hsa-miR-381-3p				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: hsa-miR-409-3p				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: hsa-mir-199a				[7]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
	Karpas-422 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1325
	RI-1 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1885
	U2932 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1896
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	High expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. Overexpression of the individual miRNAs did not result in any difference in cell viability, cell growth or apoptosis.
Key Molecule: hsa-mir-497				[7]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
	Karpas-422 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1325
	RI-1 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1885
	U2932 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1896
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	High expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. Overexpression of the individual miRNAs did not result in any difference in cell viability, cell growth or apoptosis.
Key Molecule: hsa-mir-21				[4]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 impacts the PI3k/AkT signaling pathway through the regulation of PTEN, thereby affecting cellular sensitivity to the CHOP chemotherapeutic regimen.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Inositol monophosphatase 1 (IMPA1)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: Mitogen-activated protein kinase kinase kinase 8 (MAP3K8)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: Mitogen-activated protein kinase 1 (MAPK1)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: PI3-kinase delta (PIK3CD)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: PI3-kinase gamma (PIK3CG)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: PI3-kinase regulatory subunit alpha (PIK3R1)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: Phosphatase and tensin homolog (PTEN)				[4]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 impacts the PI3k/AkT signaling pathway through the regulation of PTEN, thereby affecting cellular sensitivity to the CHOP chemotherapeutic regimen.
Key Molecule: Sirtuin 6 (SIRT6)				[5]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MET/PI3K/AKT/mTOR signaling pathway		Activation	hsa04150
In Vitro Model	Val cells	Bone marrow	Homo sapiens (Human)	CVCL_1819
	LY1 cells	Ovary	Homo sapiens (Human)	CVCL_ZU83
	DLBCL cells	Lymph node	Homo sapiens (Human)	N.A.
	LY8 cells	Lymph node	Homo sapiens (Human)	CVCL_8803
	LY3 cells	Bone marrow	Homo sapiens (Human)	CVCL_8800
In Vivo Model	Beige mice xenografts model			Mus musculus
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	CCK-8 assay
Mechanism Description	Sirt6 expression was raised in DLBCL, with its high levels corresponding to poor patient outcomes. Sirt6 was also found to promote tumorigenesis by regulating the PI3K/Akt/mTOR pathway. Targeting Sirt6 exerted anti-lymphoma activity and enhanced chemo-sensitivity. OSS_128167 may prove to be a useful component in further development of novel chemotherapy regimens in DLBCL.

Ibrutinib

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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: Myeloid differentiation primary response protein MyD88 (MYD88)			[8]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation	p.L265P	Molecule Info
Resistant Drug	Ibrutinib		Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Mechanism Description	Furthermore, within ABC DLBCL, responses were significantly different depending on the specific genetic lesions. Ibrutinib-resistant tumours carry mutant MYD88 and WT CD79A/B whereas all other genotypic combinations (CD79A/BWT + MYD88WT, CD79A/Bmutant + MYD88WT and CD79A/Bmutant + MYD88mutant) were responsive to ibrutinib therapy. It is foreseeable why ibrutinib therapy is less effective in MYD88-mutated ABC-DLBCL patients because MYD88 activates NFkappa-B through a parallel pathway independent of BTK. However, it is unclear why MYD88 mutations alone are associated with ibrutinib resistance whereas the MYD88 mutations in conjunction with CD79A/B mutations appears to render ABC DLBCL ibrutinib-sensitive.

Loncastuximab tesirine

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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: B-lymphocyte antigen CD19 (CD19)				[9]
Sensitive Disease	Relapsed/refractory large B-cell lymphoma [ICD-11: 2A81.1]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Loncastuximab tesirine			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell invasion		Activation	hsa05200
	Cell viability		Activation	hsa05200
In Vitro Model	VL51 cells	Lymph	Homo sapiens (Human)	CVCL_3169
Experiment for Molecule Alteration	Flow Cytometry and protein analyses
Experiment for Drug Resistance	MTT assay
Mechanism Description	The resistant cells had higher CD19 expression on their cell surface, which gave a much higher activity to the CD19 targeting antibody drug conjugate loncastuximab tesirine.

Prednisone

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-148b				[2]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Acetylation		Down-regulation	Molecule Info
Resistant Drug	Prednisone			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	HDAC6/miR148b/Ezrin signaling pathway		Regulation	hsa05206
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
	CRL2631/CHOP cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: hsa-miR-125b-5p				[3]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Prednisone			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SU-DHL-2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_9550
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.
Key Molecule: hsa-miR-99a-5p				[3]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Prednisone			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SU-DHL-2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_9550
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Ezrin (EZR)				[2]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Prednisone			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	HDAC6/miR148b/Ezrin signaling pathway		Regulation	hsa05206
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
	CRL2631/CHOP cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-21				[4]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Prednisone			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 impacts the PI3k/AkT signaling pathway through the regulation of PTEN, thereby affecting cellular sensitivity to the CHOP chemotherapeutic regimen.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Phosphatase and tensin homolog (PTEN)				[4]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Prednisone			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 impacts the PI3k/AkT signaling pathway through the regulation of PTEN, thereby affecting cellular sensitivity to the CHOP chemotherapeutic regimen.

Rituximab

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: hsa-miR-125b-5p				[3]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SU-DHL-2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_9550
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.
Key Molecule: hsa-miR-99a-5p				[3]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SU-DHL-2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_9550
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-370-3p				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: hsa-miR-381-3p				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: hsa-miR-409-3p				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: hsa-mir-199a				[7]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
	Karpas-422 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1325
	RI-1 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1885
	U2932 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1896
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	High expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. Overexpression of the individual miRNAs did not result in any difference in cell viability, cell growth or apoptosis.
Key Molecule: hsa-mir-497				[7]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
	Karpas-422 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1325
	RI-1 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1885
	U2932 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1896
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	High expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. Overexpression of the individual miRNAs did not result in any difference in cell viability, cell growth or apoptosis.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Inositol monophosphatase 1 (IMPA1)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: Mitogen-activated protein kinase kinase kinase 8 (MAP3K8)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell apoptosis		Inhibition	hsa04210
	Cell proliferation		Activation	hsa05200
	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: Mitogen-activated protein kinase 1 (MAPK1)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: PI3-kinase delta (PIK3CD)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: PI3-kinase gamma (PIK3CG)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: PI3-kinase regulatory subunit alpha (PIK3R1)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: PI3-kinase regulatory subunit alpha (PIK3R1)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Rituximab			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

Vincristine

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-155				[10]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Resistant Drug	Vincristine			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	OCI-Ly7 cells	N.A.	Homo sapiens (Human)	CVCL_1881
	SU-DHL-5 cells	N.A.	Homo sapiens (Human)	CVCL_1735
Experiment for Molecule Alteration	RT-qPCR
Experiment for Drug Resistance	Dose-response assays
Mechanism Description	Down-regulation of miR-155 promotes vincristine resistance via upregulating Week1.
Key Molecule: hsa-mir-148b				[2]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Acetylation		Down-regulation	Molecule Info
Resistant Drug	Vincristine			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	HDAC6/miR148b/Ezrin signaling pathway		Regulation	hsa05206
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
	CRL2631/CHOP cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.
Regulation by the Disease Microenvironment (RTDM)			Click to Show/Hide
Key Molecule: hsa-miR-125b-5p				[3]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Vincristine			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SU-DHL-2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_9550
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.
Key Molecule: hsa-miR-99a-5p				[3]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Vincristine			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	SU-DHL-2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_9550
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	Expression levels of exosomal miR-99a-5p/miR-125b-5p & their correlation with clinicopathological features in DLBCL patients, the expression levels of miR-99a-5p and miR-125b-5p were significantly higher in the chemoresistant group than in the chemosensitive group.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Wee1-like protein kinase (WEE1)				[10]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Vincristine			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	OCI-Ly7 cells	N.A.	Homo sapiens (Human)	CVCL_1881
	SU-DHL-5 cells	N.A.	Homo sapiens (Human)	CVCL_1735
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	Dose-response assays
Mechanism Description	Down-regulation of miR-155 promotes vincristine resistance via upregulating Week1.
Key Molecule: Ezrin (EZR)				[2]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Vincristine			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	Cell viability		Activation	hsa05200
	HDAC6/miR148b/Ezrin signaling pathway		Regulation	hsa05206
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
	CRL2631/CHOP cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	Western blot analysis
Experiment for Drug Resistance	CCK8 assay
Mechanism Description	The high level of HDAC6 inhibited miR-148b via maintaining the low acetylation of histones H3 and H4 in the miR-148b promoter, thus rescuing Ezrin expression and promoting CHOP resistance in DLBCL.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-mir-199a				[7]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Vincristine			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
	Karpas-422 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1325
	RI-1 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1885
	U2932 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1896
In Vivo Model	Nude mouse xenograft model			Mus musculus
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	High expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. Overexpression of the individual miRNAs did not result in any difference in cell viability, cell growth or apoptosis.
Key Molecule: hsa-mir-497				[7]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Vincristine			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	Cell apoptosis		Activation	hsa04210
	Cell migration		Inhibition	hsa04670
	Cell proliferation		Inhibition	hsa05200
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
	Karpas-422 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1325
	RI-1 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1885
	U2932 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_1896
Experiment for Molecule Alteration	RT-PCR
Experiment for Drug Resistance	MTS assay
Mechanism Description	High expression of miR-497 or miR-199a was associated with better overall survival (p = 0.042 and p = 0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in aggressive lymphoma patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment of patients with DLBCL. Overexpression of the individual miRNAs did not result in any difference in cell viability, cell growth or apoptosis.
Key Molecule: hsa-mir-21				[4]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Vincristine			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
Experiment for Molecule Alteration	qPCR
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 impacts the PI3k/AkT signaling pathway through the regulation of PTEN, thereby affecting cellular sensitivity to the CHOP chemotherapeutic regimen.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Phosphatase and tensin homolog (PTEN)				[4]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Vincristine			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
Cell Pathway Regulation	PI3K/AKT signaling pathway		Inhibition	hsa04151
In Vitro Model	CRL2631 cells	Bone marrow	Homo sapiens (Human)	CVCL_3611
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	MTT assay
Mechanism Description	miR-21 impacts the PI3k/AkT signaling pathway through the regulation of PTEN, thereby affecting cellular sensitivity to the CHOP chemotherapeutic regimen.

Clinical Trial Drug(s)

2 drug(s) in total

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AP26113

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Zinc finger C3HC-type containing 1 (ZC3HC1)				[1]
Resistant Disease	NPM-ALK-Positive anaplastic large cell lymphoma [ICD-11: 2A81.8]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	AP26113			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SUP-M2 cells	Colon	Homo sapiens (Human)	CVCL_2209
	KARPAS-299 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1324
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	Proliferation assay
Mechanism Description	For KARPAS-299-derived cell lines, we observed oncogene overexpression as the main resistance mechanism, whereas in SUP-M2-derived cell lines, we identified several point mutations located within the NPM-ALK kinase domain, which could explain drug resistance.
Key Molecule: Zinc finger C3HC-type containing 1 (ZC3HC1)				[1]
Resistant Disease	NPM-ALK-Positive anaplastic large cell lymphoma [ICD-11: 2A81.8]
Molecule Alteration	Mutation		p.L1122V+p.139S+p.F1174V+p.L1196M+p.L1198F+p.S1206C+p.L1122V+p.L1196M+p.F1174V+p.L1198F+p.L1196M+p.D1203N	Molecule Info
Resistant Drug	AP26113			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SUP-M2 cells	Colon	Homo sapiens (Human)	CVCL_2209
	KARPAS-299 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1324
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	Proliferation assay
Mechanism Description	For KARPAS-299-derived cell lines, we observed oncogene overexpression as the main resistance mechanism, whereas in SUP-M2-derived cell lines, we identified several point mutations located within the NPM-ALK kinase domain, which could explain drug resistance.

GSK126

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[11]
Resistant Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation		p.Y641S (c.1922A>C)	Molecule Info
Resistant Drug	GSK126			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030
Experiment for Molecule Alteration	Chromatin Immunoprecipitation assay; Western blotting analysis
Experiment for Drug Resistance	Propidium-iodide cell cycle analysis; BrdU-PI cell cycle analysis

Preclinical Drug(s)

4 drug(s) in total

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ACY-957/DZNEP

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[11]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation		p.Y641S (c.1922A>C)	Molecule Info
Sensitive Drug	ACY-957/DZNEP			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030
Experiment for Molecule Alteration	Chromatin Immunoprecipitation assay; Western blotting analysis
Experiment for Drug Resistance	Propidium-iodide cell cycle analysis; BrdU-PI cell cycle analysis

ACY-957/GSK126

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[11]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation		p.Y641N (c.1921T>A)	Molecule Info
Sensitive Drug	ACY-957/GSK126			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030
Experiment for Molecule Alteration	Chromatin Immunoprecipitation assay; Western blotting analysis
Experiment for Drug Resistance	Propidium-iodide cell cycle analysis; BrdU-PI cell cycle analysis
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[11]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation		p.Y641N (c.1921T>A)	Molecule Info
Sensitive Drug	ACY-957/GSK126			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030
Experiment for Molecule Alteration	Chromatin Immunoprecipitation assay; Western blotting analysis
Experiment for Drug Resistance	Propidium-iodide cell cycle analysis; BrdU-PI cell cycle analysis

EED226

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[12]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation		p.Y646F (c.1937A>T)	Molecule Info
Sensitive Drug	EED226			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	WSU-DLCL2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_1902
	Toledo cells	Peripheral blood	Homo sapiens (Human)	CVCL_3611
	SU-DHL6 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_2206
	SU-DHL4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
	OCI-LY19 cells	Bone marrow	Homo sapiens (Human)	CVCL_1878
	Karpas422 cells	Pleural effusion	Homo sapiens (Human)	CVCL_1325
	GA10 cells	Brain	Homo sapiens (Human)	CVCL_1222
	DB cells	Ascites	Homo sapiens (Human)	CVCL_1168
	AZ_521 cells	Small intestine	Homo sapiens (Human)	CVCL_2862
In Vivo Model	Female athymic balb/c nude mouse PDX model			Mus musculus
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	LC-MS assay; Vi-CELL assay
Mechanism Description	In contrast to SAM-competitive inhibitors, EED226 acts through a distinct allosteric mechanism via direct binding to the H3K27me3 pocket of EED. We further demonstrated that EED226 regulates histone H3K27 methylation and PRC2 target gene expression in cells. EED226 effectively induced tumor regression in a mouse xenograft model. Our work demonstrates that allosteric inhibition of PRC2 by targeting EED is a promising approach for developing effective cancer therapy.
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[12]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation		p.Y641N (c.1921T>A)	Molecule Info
Sensitive Drug	EED226			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	WSU-DLCL2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_1902
	Toledo cells	Peripheral blood	Homo sapiens (Human)	CVCL_3611
	SU-DHL6 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_2206
	SU-DHL4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
	OCI-LY19 cells	Bone marrow	Homo sapiens (Human)	CVCL_1878
	Karpas422 cells	Pleural effusion	Homo sapiens (Human)	CVCL_1325
	GA10 cells	Brain	Homo sapiens (Human)	CVCL_1222
	DB cells	Ascites	Homo sapiens (Human)	CVCL_1168
	AZ_521 cells	Small intestine	Homo sapiens (Human)	CVCL_2862
In Vivo Model	Female athymic balb/c nude mouse PDX model			Mus musculus
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	LC-MS assay; Vi-CELL assay
Mechanism Description	In contrast to SAM-competitive inhibitors, EED226 acts through a distinct allosteric mechanism via direct binding to the H3K27me3 pocket of EED. We further demonstrated that EED226 regulates histone H3K27 methylation and PRC2 target gene expression in cells. EED226 effectively induced tumor regression in a mouse xenograft model. Our work demonstrates that allosteric inhibition of PRC2 by targeting EED is a promising approach for developing effective cancer therapy.
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[12]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation		p.Y646N (c.1936T>A)	Molecule Info
Sensitive Drug	EED226			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	WSU-DLCL2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_1902
	Toledo cells	Peripheral blood	Homo sapiens (Human)	CVCL_3611
	SU-DHL6 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_2206
	SU-DHL4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
	OCI-LY19 cells	Bone marrow	Homo sapiens (Human)	CVCL_1878
	Karpas422 cells	Pleural effusion	Homo sapiens (Human)	CVCL_1325
	GA10 cells	Brain	Homo sapiens (Human)	CVCL_1222
	DB cells	Ascites	Homo sapiens (Human)	CVCL_1168
	AZ_521 cells	Small intestine	Homo sapiens (Human)	CVCL_2862
In Vivo Model	Female athymic balb/c nude mouse PDX model			Mus musculus
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	LC-MS assay; Vi-CELL assay
Mechanism Description	In contrast to SAM-competitive inhibitors, EED226 acts through a distinct allosteric mechanism via direct binding to the H3K27me3 pocket of EED. We further demonstrated that EED226 regulates histone H3K27 methylation and PRC2 target gene expression in cells. EED226 effectively induced tumor regression in a mouse xenograft model. Our work demonstrates that allosteric inhibition of PRC2 by targeting EED is a promising approach for developing effective cancer therapy.
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[12]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation		p.Y646S (c.1937A>C)	Molecule Info
Sensitive Drug	EED226			Drug Info
Experimental Note	Identified from the Human Clinical Data
In Vitro Model	WSU-DLCL2 cells	Pleural effusion	Homo sapiens (Human)	CVCL_1902
	Toledo cells	Peripheral blood	Homo sapiens (Human)	CVCL_3611
	SU-DHL6 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_2206
	SU-DHL4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
	OCI-LY19 cells	Bone marrow	Homo sapiens (Human)	CVCL_1878
	Karpas422 cells	Pleural effusion	Homo sapiens (Human)	CVCL_1325
	GA10 cells	Brain	Homo sapiens (Human)	CVCL_1222
	DB cells	Ascites	Homo sapiens (Human)	CVCL_1168
	AZ_521 cells	Small intestine	Homo sapiens (Human)	CVCL_2862
In Vivo Model	Female athymic balb/c nude mouse PDX model			Mus musculus
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	LC-MS assay; Vi-CELL assay
Mechanism Description	In contrast to SAM-competitive inhibitors, EED226 acts through a distinct allosteric mechanism via direct binding to the H3K27me3 pocket of EED. We further demonstrated that EED226 regulates histone H3K27 methylation and PRC2 target gene expression in cells. EED226 effectively induced tumor regression in a mouse xenograft model. Our work demonstrates that allosteric inhibition of PRC2 by targeting EED is a promising approach for developing effective cancer therapy.

UNC1999

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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: Histone-lysine N-methyltransferase EZH2 (EZH2)				[13]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation		p.Y641N (c.1921T>A)	Molecule Info
Sensitive Drug	UNC1999			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	MCF10A cells	Breast	Homo sapiens (Human)	CVCL_0598
Mechanism Description	The missense mutation p.Y641N (c.1921T>A) in gene EZH2 cause the sensitivity of UNC1999 by aberration of the drug's therapeutic target

Investigative Drug(s)

4 drug(s) in total

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3-Deazaneplanocin

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Histone-lysine N-methyltransferase EZH2 (EZH2)				[11]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Missense mutation		p.Y641N (c.1921T>A)	Molecule Info
Sensitive Drug	3-Deazaneplanocin			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	Hela cells	Cervix uteri	Homo sapiens (Human)	CVCL_0030
Experiment for Molecule Alteration	Chromatin Immunoprecipitation assay; Western blotting analysis
Experiment for Drug Resistance	Propidium-iodide cell cycle analysis; BrdU-PI cell cycle analysis

ASP3026

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Zinc finger C3HC-type containing 1 (ZC3HC1)				[1]
Resistant Disease	NPM-ALK-Positive anaplastic large cell lymphoma [ICD-11: 2A81.8]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	ASP3026			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SUP-M2 cells	Colon	Homo sapiens (Human)	CVCL_2209
	KARPAS-299 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1324
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	Proliferation assay
Mechanism Description	For KARPAS-299-derived cell lines, we observed oncogene overexpression as the main resistance mechanism, whereas in SUP-M2-derived cell lines, we identified several point mutations located within the NPM-ALK kinase domain, which could explain drug resistance.
Key Molecule: Zinc finger C3HC-type containing 1 (ZC3HC1)				[1]
Resistant Disease	NPM-ALK-Positive anaplastic large cell lymphoma [ICD-11: 2A81.8]
Molecule Alteration	Mutation		p.L1122V+p.139S+p.F1174V+p.L1196M+p.L1198F+p.S1206C+p.L1122V+p.L1196M+p.F1174V+p.L1198F+p.L1196M+p.D1203N	Molecule Info
Resistant Drug	ASP3026			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SUP-M2 cells	Colon	Homo sapiens (Human)	CVCL_2209
	KARPAS-299 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1324
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	Proliferation assay
Mechanism Description	For KARPAS-299-derived cell lines, we observed oncogene overexpression as the main resistance mechanism, whereas in SUP-M2-derived cell lines, we identified several point mutations located within the NPM-ALK kinase domain, which could explain drug resistance.

Clozatinib

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: Zinc finger C3HC-type containing 1 (ZC3HC1)				[1]
Resistant Disease	NPM-ALK-Positive anaplastic large cell lymphoma [ICD-11: 2A81.8]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Resistant Drug	Clozatinib			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SUP-M2 cells	Colon	Homo sapiens (Human)	CVCL_2209
	KARPAS-299 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1324
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	Proliferation assay
Mechanism Description	For KARPAS-299-derived cell lines, we observed oncogene overexpression as the main resistance mechanism, whereas in SUP-M2-derived cell lines, we identified several point mutations located within the NPM-ALK kinase domain, which could explain drug resistance.
Key Molecule: Zinc finger C3HC-type containing 1 (ZC3HC1)				[1]
Resistant Disease	NPM-ALK-Positive anaplastic large cell lymphoma [ICD-11: 2A81.8]
Molecule Alteration	Mutation		p.L1122V+p.139S+p.L1196M+p.S1206C+p.L1122V+p.L1196M+p.L1196M+p.D1203N	Molecule Info
Resistant Drug	Clozatinib			Drug Info
Experimental Note	Revealed Based on the Cell Line Data
In Vitro Model	SUP-M2 cells	Colon	Homo sapiens (Human)	CVCL_2209
	KARPAS-299 cells	Peripheral blood	Homo sapiens (Human)	CVCL_1324
Experiment for Molecule Alteration	Western blotting analysis
Experiment for Drug Resistance	Proliferation assay
Mechanism Description	For KARPAS-299-derived cell lines, we observed oncogene overexpression as the main resistance mechanism, whereas in SUP-M2-derived cell lines, we identified several point mutations located within the NPM-ALK kinase domain, which could explain drug resistance.

Rituximab/Doxorubicin

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Drug Sensitivity Data Categorized by Their Corresponding Mechanisms
Epigenetic Alteration of DNA, RNA or Protein (EADR)			Click to Show/Hide
Key Molecule: hsa-miR-370-3p				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Rituximab/Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: hsa-miR-381-3p				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Rituximab/Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: hsa-miR-409-3p				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Up-regulation	Molecule Info
Sensitive Drug	Rituximab/Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	qRT-PCR
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Unusual Activation of Pro-survival Pathway (UAPP)			Click to Show/Hide
Key Molecule: Mitogen-activated protein kinase 1 (MAPK1)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Rituximab/Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	Immunoblotting assay
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.
Key Molecule: PI3-kinase gamma (PIK3CG)				[6]
Sensitive Disease	Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
Molecule Alteration	Expression		Down-regulation	Molecule Info
Sensitive Drug	Rituximab/Doxorubicin			Drug Info
Experimental Note	Identified from the Human Clinical Data
Cell Pathway Regulation	MAPK/BCR/PI signaling pathway		Regulation	hsa04662
In Vitro Model	SUDHL-4 cells	Peritoneal effusion	Homo sapiens (Human)	CVCL_0539
Experiment for Molecule Alteration	Immunoblotting assay
Experiment for Drug Resistance	CellTiter-Blue Cell Viability assay
Mechanism Description	miR370-3p, miR381-3p, and miR409-3p miRNAs appear to be the most potent regulators of the MAPk, BCR, and PI signaling system. Overexpression of miR370-3p, miR381-3p, and miR409-3p increases sensitivity to rituximab and doxorubicin.

References

Ref 1	Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK-Positive Anaplastic Large Cell Lymphoma .Mol Cancer Res. 2015 Apr;13(4):775-83. doi: 10.1158/1541-7786.MCR-14-0157. Epub 2014 Nov 24. 10.1158/1541-7786.MCR-14-0157
Ref 2	Down-regulated miR-148b increases resistance to CHOP in diffuse large B-cell lymphoma cells by rescuing Ezrin. Biomed Pharmacother. 2018 Oct;106:267-274. doi: 10.1016/j.biopha.2018.06.093. Epub 2018 Jun 28.
Ref 3	Exosome-derived miRNAs as predictive biomarkers for diffuse large B-cell lymphoma chemotherapy resistance. Epigenomics. 2019 Jan;11(1):35-51. doi: 10.2217/epi-2018-0123. Epub 2018 Sep 13.
Ref 4	MicroRNA-21 regulates the sensitivity of diffuse large B-cell lymphoma cells to the CHOP chemotherapy regimen. Int J Hematol. 2013 Feb;97(2):223-31. doi: 10.1007/s12185-012-1256-x. Epub 2012 Dec 30.
Ref 5	Sirt6 promotes tumorigenesis and drug resistance of diffuse large B-cell lymphoma by mediating PI3K/Akt signaling .J Exp Clin Cancer Res. 2020 Jul 25;39(1):142. doi: 10.1186/s13046-020-01623-w. 10.1186/s13046-020-01623-w
Ref 6	MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma. Blood Cancer J. 2017 Dec 15;7(12):654. doi: 10.1038/s41408-017-0033-8.
Ref 7	miR-199a and miR-497 Are Associated with Better Overall Survival due to Increased Chemosensitivity in Diffuse Large B-Cell Lymphoma Patients. Int J Mol Sci. 2015 Aug 5;16(8):18077-95. doi: 10.3390/ijms160818077.
Ref 8	Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma .Br J Haematol. 2015 Aug;170(4):445-56. doi: 10.1111/bjh.13427. Epub 2015 Apr 9. 10.1111/bjh.13427
Ref 9	Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia Leukemia. 2019 Apr;33(4):884-892. doi: 10.1038/s41375-018-0265-z. Epub 2018 Sep 28.
Ref 10	MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma. Blood Adv. 2019 Apr 9;3(7):1185-1196. doi: 10.1182/bloodadvances.2018029660.
Ref 11	HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphomaOncotarget. 2015 Mar 10;6(7):4863-87. doi: 10.18632/oncotarget.3120.
Ref 12	An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EEDNat Chem Biol. 2017 Apr;13(4):381-388. doi: 10.1038/nchembio.2304. Epub 2017 Jan 30.
Ref 13	An orally bioavailable chemical probe of the Lysine Methyltransferases EZH2 and EZH1ACS Chem Biol. 2013;8(6):1324-34. doi: 10.1021/cb400133j. Epub 2013 Apr 24.

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Correspondence

Prof. Feng ZHU (zhufeng@zju.edu.cn)