BCL-2

Overview

B-cell lymphoma 2 (BCL-2) is an anti-apoptotic, pro-survival member of the BCL-2 family of proteins that function to regulate the intrinsic pathway of apoptosis, or programmed cell death, and help maintain cellular homeostasis.1,2

BCL-2 family proteins are key regulators of the intrinsic apoptotic pathway and include both pro-survival (anti-apoptotic) and pro-death (pro-apoptotic) proteins with opposing functions. Apoptosis is regulated by the balance of these BCL-2 family proteins.1

  • Anti-apoptotic proteins: BCL-2, BCL-XL, BFL-1/A1, BCL-W and MCL-12-4
  • Pro-apoptotic multi-domain effector proteins: BAX, BAK, BOK2-4
  • Pro-apoptotic BH3-only proteins: BIM, BID, BAD, PUMA and NOXA2-4

The BH3-only proteins are further subdivided into two groups based on function: the "activators" (such as BIM and PUMA) and the "sensitizers" (such as NOXA and BAD).4,6

The BCL-2 family of proteins controls cell death primarily by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP), a process leading to the irreversible release of intermembrane space proteins, subsequent caspase activation and apoptosis.7

  • The affinities and relative abundance of the BCL-2 family proteins dictate interactions between anti-apoptotic and pro-apoptotic BCL-2 family proteins that regulate MOMP.7

Implications in cancer

Cytotoxic stresses (e.g. DNA damage or oxidative stress) may activate pro-death BH3-only proteins, which can initiate apoptosis in two ways:

  • The "activators" are often bound and sequestered by pro-survival proteins. When unbound, they can directly interact with pro-death "effectors" BAX and BAK, leading to oligomerization and insertion into the mitochondrial outer membrane. BAX and BAK then assemble to form pores, leading to mitochondrial outer membrane permeabilization (MOMP), the release of cytochrome c into the cytosol, the formation of the apoptosome, and caspase activation, which eventually result in apoptosis2,6,8
  • The "sensitizers" can only bind to the pro-survival proteins, which neutralizes them and allows for the release of the "activator" and "effector" proteins to drive the initiation of apoptosis2,6,8,9

Malignant cells often evade apoptosis by upregulating BCL-2 and other pro-survival proteins (such as MCL-1 and BCL-XL).3,4,6,8,9

Some malignant cells lie close to the apoptotic threshold but are held back from death by the pro-survival BCL-2 family proteins. In such cells, the increased expression of these pro-survival proteins (BCL-2, MCL-1, and/or BCL-XL) allows them to sequester and inactivate pro–death proteins, thereby resisting cytotoxic stress-induced apoptosis.3,4,6,8,9

  • Pro-survival proteins have been shown to be expressed at high levels in many hematologic malignancies, where they can sequester pro–death proteins, resulting in malignant cell survival.3,4,6,8,9

Cells with a large pool of bound and inactivated pro-death proteins are said to be "primed for death," meaning they are on the verge of freeing sufficient pro-death proteins to initiate apoptosis.3,4,9

Agents that inhibit pro-survival proteins (e.g., BCL-2, BCL-XL, or MCL-1 inhibitors) can also promote apoptosis in malignant cells.3-5, 10

Oncogenic Expression

The majority of tumors have defects in the p53 pathway and many overexpress BCL-2 or a close relative, such as BCL-XL.2

  • Most CLLs, FLs, and MCLs were found to have moderate to high expression of BCL-2 and BCL-XL.11
  • BCL-2, frequently overexpressed in follicular lymphomas bearing the t(14;18) chromosomal translocation, is also widely expressed in myeloma cell lines.12

As a pro-survival oncoprotein which can be overexpressed as a result of cancer-specific mutations or gene amplifications, BCL-2 clearly deserves consideration for therapeutic inhibition.13

Chronic Lymphocytic Leukemia (CLL)

  • Relatively high levels of BCL-2 expression are documented in 95% of CLL cases compared to normal peripheral blood lymphocytes.14
  • Impaired apoptosis caused by BCL-2 overexpression results in the accumulation of mature neoplastic lymphocytes in the blood and other lymphoid organs.15

Acute Myeloid Leukemia (AML) / Myelodysplastic Syndromes (MDS)

  • The BCL-2 protein is overexpressed in up to 70% of AML cases.16-17
  • Elevated levels of BCL-2 correlate with poor prognosis and chemoresistance.18-21
  • A high number of BCL-2-addicted cell lines and patient samples are sensitive to selective BCL-2 inhibition.22
  • Sensitivity to BCL-2 inhibition can be promoted by directly or indirectly downregulating or neutralizing other pro-survival proteins (e.g., with proteasome inhibitors, hypomethylating agents, or LDAC).4

Non-Hodgkin Lymphoma (NHL)

Mantle Cell Lymphoma (MCL)

  • The BCL-2 pathway is commonly deregulated in MCL cases and the BCL2 gene is often amplified.23,24
  • The BCL-2 protein is overexpressed in up to 97% of AML cases.11,25
  • Chromosome 18q21 amplification leading to high BCL-2 protein levels has been reported in a subset of patients with MCL.25,26

Follicular Lymphoma (FL)

  • Approximately 85% of patients with FL have t(14;18), a translocation between chromosomes 14 (Ig) and 18 (BCL2).28
  • Of those FL patients with t(14;18) translocation, up to 90% overexpress BCL-2 protein.29,30
  • The vast majority of patients with BCL-2 protein overexpression develop chemoresistance and experience higher relapse rates compared with BCL-2-negative patients.31
  • Mutations in the BCL-2 coding sequence are associated with shorter times to transformation to a more aggressive lymphoma and earlier death.32

Diffuse Large B-Cell Lymphoma (DLBCL)

  • BCL-2 protein overexpression is detected in up to 40% of DLBCL cases.18,33
  • DLBCL may also be classified as "double-hit" lymphoma or "double-expression" lymphoma based on MYC and BCL2 gene characteristics.34,35
    • "Double expression", where MYC and BCL-2 are overexpressed at the protein level, may be present in as many as one-third of patients with DLBCL and correlates with an aggressive clinical course and a poor outcome.33,34
    • "Double hit", the presence of both the MYC and BCL2 rearrangements, occurs in approximately 5% to 7% of patients with DLBCL and is associated with highly proliferative and drug-resistant disease leading to a poor prognosis.34

Multiple Myeloma (MM)

  • BCL-2 is highly expressed in a subset of myeloma cells, including those with a t(11;14) translocation.36-38
  • Preclinical evidence suggests that inhibition of BCL-2 and downmodulation of MCL-1 induce synthetic lethality, resulting in a more durable response to therapy relative to proteasome inhibitors alone.35,39,40
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  12. Trudel S, Stewart AK, Li Z, et al. The Bcl-2 family protein inhibitor, ABT-737, has substantial antimyeloma activity and shows synergistic effect with dexamethasone and melphalan. Clin Cancer Res. 2007;13(2):621-629.
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  16. Campos L, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood. 1993;81(11):3091-3096.
  17. Mehta SV, et al. Overexpression of Bcl2 protein predicts chemoresistance in acute myeloid leukemia: its correlation with FLT3. Neoplasma. 2013;60(6):666-675.
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  22. Pan R, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362-375.
  23. Perez-Galan P, et al. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2011;117(1):26-38.
  24. Parekh S, et al. New molecular targets in mantle cell lymphoma. Semin Cancer Biol. 2011;21(5):335-346.
  25. Tracey L, et al. Expression of the NF-nB targets BCL2 and BIRC5/survivin characterizes small B-cell and aggressive B-cell lymphomas, respectively. JPathol. 2005;206:123–134.
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  27. Bentz M, et al. t(11;14)-positive mantle cell lymphomas exhibit complex karyotypes and share similarities with B-cell chronic lymphocytic leukemia. Genes Chromosomes Cancer. 2000;27(3):285-294.
  28. Freedman A. Follicular lymphoma: 2018 update on diagnosis and management. Am J Hematol. 2018;93(2):296-305.
  29. Vaandrager et al. Interphase FISH detection of BCL2 rearrangement in follicular lymphoma using breakpoint-flanking probes. Genes Chromosomes Cancer. 2000, 27:85-94.
  30. Skinnider BF. et al. Bcl-6 and Bcl-2 protein expression in diffuse large B-cell lymphoma and follicular lymphoma: correlation with 3q27 and 18q21 chromosomal abnormalities. Human Pathology. 1999. 30(7):803-808.
  31. Kang MH, Reynolds CP. Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy. Clinical Cancer Research. 2009;15(4):1126-1132.
  32. Correia C, et al. BCL2 mutations are associated with increased risk of transformation and shortened survival in follicular lymphoma. Blood. 2015;125(4):658-667.
  33. Wang J, et al. Combination of BCL-2 and MYC protein expression improves high-risk stratification in diffuse large B-cell lymphoma. Onco Targets Ther. 2015;8:2645-2650.
  34. Smith SM, et al. Aggressive B-cell lymphoma: the double-hit and double-expressor phenotypes. Clin Adv Hematol Oncol. 2017;15(1):40-42.
  35. Punnoose EA, et al. Expression Profile of BCL-2, BCL-XL, and MCL-1 Predicts Pharmacological Response to the BCL-2 Selective Antagonist Venetoclax in Multiple Myeloma Models. Mol Cancer Ther. 2016;15(5):1132-1144.
  36. Bodet L, et al. ABT-737 is highly effective against molecular subgroups of multiple myeloma. Blood. 2011;118(14):3901-3910.
  37. Kumar S, et al. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017;130(22):2401-2409.
  38. Touzeau C, et al. The Bcl-2 specific BH3 mimetic ABT-199: a promising targeted therapy for t(11;14) multiple myeloma. Leukemia. 2014;28:210-212.
  39. Czabotar PE, et al. Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc Natl Acad Sci USA. 2007;104(15):6217-6222.
  40. Qin J-Z, et al. Proteasome Inhibitors Trigger NOXA-Mediated Apoptosis in Melanoma and Myeloma Cells. Cancer Res. 2005;65(14):6282-6293.

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