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

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 primarily controls cell death by direct binding interactions that regulate mitochondrial outer membrane permeabilization (MOMP), a process that leads 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


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; 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


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 chronic lymphocytic leukemias (CLLs), follicular lymphomas (FLs), and mantle cell lymphomas (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 that 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 MCL cases.11,25
  • Chromosome 18q21 amplification leading to high BCL-2 protein levels has been reported in a subset of patients with MCL.25,26,27

Follicular Lymphoma (FL)

  • BCL-2 protein overexpression is detected in over 60% of FL cases.18
  • Approximately 85% of patients with FL have t(14;18), a translocation between chromosomes 14 (Ig) and 18 (BCL2). Of those FL patients with t(14;18) translocation, up to 90% overexpress BCL-2 protein.28-30
  • The vast majority of patients with BCL-2 protein overexpression develop chemoresistance and experience higher relapse rates comparedwith BCL-2–negative/normal 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," in which 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)

  • Multiple myeloma is a heterogenous disease, and the rate of progression may be influenced by the underlying cytogenetic type of disease. Primary cytogenetic abnormalities like translocations involving the IgH locus can influence disease course, response to therapy, and prognosis. IgH translocations such as t(11;14), t(4;14), t(6;14), t(14;16), and t(14;20) are identified in approximately 40% of MM patients. The most common IgH translocation in MM is t(11;14) and is present in approximately 20% of patients.36
  • Multiple myeloma harboring t(11;14) represents a unique disease subset as t(11;14)-positive myeloma cells exhibit biological features that are distinct from t(11;14)-negative myeloma cells.37
    • t(11;14) MM cells often lack traditional plasma cell markers that are detected on other MM cell types and exhibit remnants of B-cell biology. Expression of the B-cell lineage membrane protein CD20 and higher levels of the B-cell receptor component CD79a have been detected in t(11;14) MM cells.
    • MM cells carrying t(11;14) have been shown to express a higher degree of anti-apoptotic BCL-2 relative to MCL-1. Both normal plasma cells and most MM cells without t(11;14) primarily depend on the anti-apoptotic protein MCL-1 for survival.
    • t(11;14) MM cells have been confirmed to retain features of B-cell biology, including lower mitochondrial metabolism and significantly lower Mito signature scores detected in t(11;14)-positive versus t(11;14)-negative R/R MM patients39
  • Preclinical data shows that the combination of dexamethasone and venetoclax enhances the dependency on BCL-2 for survival.38  Co-treatment of human myeloma cell lines and primary patient samples with dexamethasone and venetoclax significantly increased cell death over venetoclax alone. This occurs because the addition of dexamethasone increases the expression of both BCL-2 and BIM, which shifts BIM binding towards BCL-2 and results in increased venetoclax sensitivity
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