Drug Information

Drug (ID: DG00241) and It's Reported Resistant Information

• Name: Lenalidomide
• Synonyms: Revamid; Revimid; Revlimid; Celgene brand of lenalidomide; Lenalidomide [USAN]; CC 5013; CC5013; CDC 501; IMiD3; IMiD3cpd; ALBB-015321; CC-5013; CDC-501; CDC-5013; ENMD-0997; IMID-5013; Revlimid (Celgene); Revlimid (TN); Thalidomide analog CC-5013; Lenalidomide (USAN/INN); CC-5013, Revlimid, Lenalidomide; 3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione; 3-(4-Amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione; 3-(7-Amino-3-oxo-1H-isoindol-2-yl)-piperidine-2,6-dione; 3-(7-amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione; Lenalidomide (Immunomodulator)
• Indication:
  In total 1 Indication(s)
  Multiple myeloma [ICD-11: 2A83]; Approved; [1], [2]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]; [3]
  Multiple myeloma [ICD-11: 2A83]; [1], [2]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Multiple myeloma [ICD-11: 2A83]; [4]
• Target: Tumor necrosis factor (TNF); TNFA_HUMAN; [1]
• Formula: C13H13N3O3
• IsoSMILES: C1CC(=O)NC(=O)C1N2CC3=C(C2=O)C=CC=C3N
• InChI: 1S/C13H13N3O3/c14-9-3-1-2-7-8(9)6-16(13(7)19)10-4-5-11(17)15-12(10)18/h1-3,10H,4-6,14H2,(H,15,17,18)
• InChIKey: GOTYRUGSSMKFNF-UHFFFAOYSA-N
• PubChem CID: 216326
• ChEBI ID: CHEBI:63791
• TTD Drug ID: D0Q5NX
• VARIDT ID: DR00261
• DrugBank ID: DB00480

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Multiple myeloma [ICD-11: 2A83]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Double-stranded RNA-specific adenosine deaminase (ADAR) [5]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Down-regulation
• 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)

Key Molecule: Nuclear receptor binding SET domain protein 2 (NSD2) [4]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• 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)

Key Molecule: Zinc finger protein Aiolos (IKZF3) [1], [2]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Missense mutation; p.Q147H
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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) [6]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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) [6]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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) [6]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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) [6]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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) [6]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Mutation; .
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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) [6]

• Resistant Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Truncating mutation; p.Q99*
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: 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)

Key Molecule: Lys-63-specific deubiquitinase BRCC36 (BRCC3) [7]

• Sensitive Disease: Multiple myeloma [ICD-11: 2A83.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEK 293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: RPMI 8226 cells; Peripheral blood; Homo sapiens (Human); CVCL_7353
• In Vitro Model: LP1 cells; Blood; Homo sapiens (Human); CVCL_E2V5
• In Vitro Model: U266 cells; Bone marrow; Homo sapiens (Human); N.A.
• In Vitro Model: 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.

Mature B-cell neoplasms/lymphoma [ICD-11: 2A85]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [3]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.Y361C
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [3]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.G123S
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [3]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.D357E
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [3]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Missense mutation; p.D230N
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Whole-exome sequencing assay
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

Key Molecule: Caspase recruitment domain-containing protein 11 (CARD11) [3]

• Resistant Disease: Mantle cell lymphoma [ICD-11: 2A85.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BCR/NF-kB signaling pathway; Activation; hsa05200
• In Vitro Model: JVM2 cells; Peripheral blood; Homo sapiens (Human); CVCL_1319
• In Vitro Model: Mino cells; Peripheral blood; Homo sapiens (Human); CVCL_UW35
• In Vitro Model: Z138 cells; Peripheral blood; Homo sapiens (Human); CVCL_B077
• In Vitro Model: Jeko-1 cells; Blood; Homo sapiens (Human); CVCL_1865
• In Vitro Model: Granta-519 cells; Blood; Homo sapiens (Human); CVCL_1818
• In Vitro Model: Rec-1 cells; Lymph; Homo sapiens (Human); CVCL_1884
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Drug inhibition assay
• Mechanism Description: Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-kB-inhibitor lenalidomide.

References

• Ref 1: Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science. 2014 Jan 17;343(6168):301-5. doi: 10.1126/science.1244851. Epub 2013 Nov 29.
• Ref 2: Clonal rat parathyroid cell line expresses a parathyroid hormone-related peptide but not parathyroid hormone itself. Biochem Biophys Res Commun. 1989 Jul 14;162(1):108-15. doi: 10.1016/0006-291x(89)91969-4.
• Ref 3: Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations. Oncotarget. 2016 Jun 21;7(25):38180-38190. doi: 10.18632/oncotarget.9500.
• Ref 4: Histone Methyltransferase NSD2 Activates PKCalpha to Drive Metabolic Reprogramming and Lenalidomide Resistance in Multiple Myeloma. Cancer Res. 2023 Oct 13;83(20):3414-3427.
• Ref 5: The ADAR1-regulated cytoplasmic dsRNA-sensing pathway is a novel mechanism of lenalidomide resistance in multiple myeloma. Blood. 2025 Mar 13;145(11):1164-1181.
• Ref 6: Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood. 2016 Sep 29;128(13):1735-44. doi: 10.1182/blood-2016-06-723007. Epub 2016 Aug 11.
• Ref 7: Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon. Cell Mol Life Sci. 2024 Aug 13;81(1):349.