Molecule Information

General Information of the Molecule (ID: Mol04095)

• Name: B-cell lymphoma 2 (BCL2) ,Homo sapiens
• Molecule Type: Protein
• Gene Name: BCL2
• Gene ID: 596
• Location: chr18:63123346-63320128[-]
• Sequence:
  MAHAGRTGYDNREIVMKYIHYKLSQRGYEWDAGDVGAAPPGAAPAPGIFSSQPGHTPHPA
  ASRDPVARTSPLQTPAAPGAAAGPALSPVPPVVHLTLRQAGDDFSRRYRRDFAEMSSQLH
  LTPFTARGRFATVVEELFRDGVNWGRIVAFFEFGGVMCVESVNREMSPLVDNIALWMTEY
  LNRHLHTWIQDNGGWDAFVELYGPSMRPLFDFSWLSLKTLLSLALVGACITLGAYLGHK
• 3D-structure: PDB ID: 5JSN; Classification: Viral protein/inhibitor; Method: X-ray diffraction; Resolution: 2.10 Å
• Function: Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells (PubMed:1508712, PubMed:8183370). Regulates cell death by controlling the mitochondrial membrane permeability (PubMed:11368354). Appears to function in a feedback loop system with caspases (PubMed:11368354). Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1) (PubMed:11368354). Also acts as an inhibitor of autophagy: interacts with BECN1 and AMBRA1 during non-starvation conditions and inhibits their autophagy function (PubMed:18570871, PubMed:20889974, PubMed:21358617). May attenuate inflammation by impairing NLRP1- inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785). .
• Uniprot ID: BCL2_HUMAN
• Ensembl ID: ENSG00000171791
• HGNC ID: HGNC:990

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  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 Drug

Approved Drug(s) 2 drug(s) in total

Arsenic trioxide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute promyelocytic leukemia [ICD-11: 2A60.2] [1]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Arsenic trioxide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: NB4 cells; Bone marrow; Homo sapiens (Human); CVCL_0005
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: ATO-resistant APL cells showed upregulation of?APAF1,?BCL2,?BIRC3, and?NOL3?genes, while?CD70?and?IL10?genes were downregulated, compared to ATO-sensitive cells.

Venetoclax

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [2]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Venetoclax
• Molecule Alteration: Missense mutation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SU-DHL-2 cells; N.A.; Homo sapiens (Human); CVCL_9950
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL5 cells; Blood; Homo sapiens (Human); CVCL_1735
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL8 cells; Blood; Homo sapiens (Human); CVCL_2207
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL16 cells; Blood; Homo sapiens (Human); CVCL_1890
• In Vitro Model: Toledo cells; Peripheral blood; Homo sapiens (Human); CVCL_3611
• Experiment for Molecule Alteration: Western blot assay; RNA Sequencing assay; Flow cytometry
• Experiment for Drug Resistance: Cell survival and synergy assay; Caspase-3/7 apoptosis assay; Live/Dead assay
• Mechanism Description: Our findings demonstrate that multiple, complex mechanisms of venetoclax resistance can emerge in DLBCL. However, our elucidation of the increased vulnerability of venetoclax-resistant DLBCL to ETC complex I and IDH2 inhibition revealed potential new treatment approaches to overcome venetoclax resistance. Although there is still interest in adding venetoclax to decrease the threshold of apoptosis in the therapeutic armamentarium for DLBCL as a combination therapy, targeting other BCL2 family members, such as BCLW and BFL1, for which there are currently no specific targeted agents, could also be an option.

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Diffuse large B-cell lymphoma [ICD-11: 2A81.0] [3]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Venetoclax
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: OCI-LY10 cells; Blood; Homo sapiens (Human); CVCL_8795
• In Vitro Model: OCI-LY3 cells; Blood; Homo sapiens (Human); CVCL_8800
• In Vitro Model: SUDHL10 cells; Blood; Homo sapiens (Human); CVCL_1889
• In Vitro Model: SUDHL16 cells; Blood; Homo sapiens (Human); CVCL_1890
• In Vitro Model: SUDHL2 cells; Blood; Homo sapiens (Human); CVCL_9550
• In Vitro Model: SUDHL4 cells; Blood; Homo sapiens (Human); CVCL_0539
• In Vitro Model: SUDHL5 cells; Blood; Homo sapiens (Human); CVCL_1735
• In Vitro Model: SUDHL6 cells; Blood; Homo sapiens (Human); CVCL_2206
• In Vitro Model: SUDHL8 cells; Blood; Homo sapiens (Human); CVCL_2207
• In Vitro Model: Toledo cells; Peripheral blood; Homo sapiens (Human); CVCL_3611
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Caspase-3/7 apoptosis assay
• Mechanism Description: We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation.

Preclinical Drug(s) 1 drug(s) in total

JNK1 inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Chronic lymphocytic leukemia [ICD-11: 2A82.0] [4]

• Sensitive Disease: Chronic lymphocytic leukemia [ICD-11: 2A82.0]
• Sensitive Drug: JNK1 inhibitors
• Molecule Alteration: Phosphorylation; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: B cell receptor signaling pathway; Inhibition; hsa04662
• In Vitro Model: 3T3-msCD40L cells; Embryo; Homo sapiens (Human); CVCL_1H10
• In Vitro Model: M2-10B4 cells; Bone marrow; Homo sapiens (Human); CVCL_5794
• In Vivo Model: NOG mice; Eu-TCL1-tg mice; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: JNK1 inhibition affects BCL2 and MCL1 expression in CLL;JNK1 inhibition reduces CLL cell viability preferentially in IGHV unmutated CLLs and overcomes stromal protective effects;JNK1 is a crucial downstream mediator of BCR signaling in CLL.

References

• Ref 1: Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors. Pharmaceuticals (Basel). 2024 Nov 14;17(11):1529.
• Ref 2: Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma. Cancers (Basel). 2024 Jun 3;16(11):2130.
• Ref 3: Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma. Cancers (Basel). 2024 Jun 3;16(11):2130.
• Ref 4: JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL. J Exp Med. 2025 Jan 6;222(1):e20230681.