Targeting BCL-2 in Hematologic Malignancies

Published: Friday, Jan 11, 2019
The BCL-2 family of proteins are central regulators of apoptosis, programmed cell death, which can occur in response to intrinsic stress signals or environmental cues. During the life span of any organism, proliferation must be balanced with apoptosis, to ensure both appropriate development and proper, mature physiologic cell and organ function. This balance between proliferation and apoptosis is particularly important in such highly proliferative tissues as the bone marrow.1 Deregulation of apoptotic pathways can lead to cancer, with resistance to apoptosis having been identified as a hallmark of human cancer nearly 20 years ago.2 Over the past 2 decades, considerable efforts have focused on the development of therapies that can restore apoptosis in malignant cells.3 

Members of the BCL-2 family of proteins can either inhibit or activate apoptosis. Antiapoptotic family members include BCL-2, BCL-XL, BCL-W, BCL-B, BFL1, and myeloid cell leukemia 1. Proapoptotic family members can be subdivided into 2 subfamilies: (1) the multidomain effector proteins BAX and BAK and (2) the BH3-only proteins BID, BIK, NOXA, PUMA, BAD, and BIM.1 Under normal circumstances, the antiapoptotic and proapoptotic family members bind to each other in various combinations to mutually inhibit their individual functions.1 The antiapoptotic proteins BCL-2 and BCL-XL inhibit the proapoptotic effector proteins BAX and BAK. BH3-only proteins sequester and inhibit BCL-2 and BCL-XL, however, freeing BAX and BAK to initiate the cascade of events that leads to cell death.1 Therefore, strategies to develop inhibitors of antiapoptotic BCL-2 family proteins have focused on agents that can interfere with these interactions and promote the activity of the proapoptotic proteins. Recent advances in agents that can inhibit the antiapoptotic BCL-2 proteins have begun to validate the potential of this approach and provide new treatment options for patients with aggressive disease.

BCL-2 Deregulation in Hematologic Malignancies

In normal, healthy lymphoid cells, prosurvival members of the BCL2 family restrain BAX and BAK in order to maintain cell viability.3 BCL-2 overexpression is one of the most common alterations in lymphoid malignancies, however, which disrupts the balance between the proapoptotic and antiapoptotic proteins.3 Cells that overexpress BCL-2 survive despite exposure to cell death stimuli, and the inappropriate survival of BCL-2–overexpressing cells contributes to the pathogenesis of a variety of malignancies.

Although BCL-2 overexpression is characteristic of multiple hematologic malignancies, the mechanisms leading to overexpression differ among tumor types.3 BCL-2 was first identified as a result of cloning of the t(14;18)(q32;q21) chromosomal translocation in patients with follicular lymphoma (FL).4 This translocation places the immunoglobulin heavy chain gene enhancer in 14q32 in the region of the BCL-2 promoter, leading to upregulation of BCL-2 expression.Elevated BCL-2 expression contributes to survival in multiple hematologic malignancies. Approximately 70% to 90% of cases of FL, 20% to 30% of cases of diffuse large B-cell lymphoma (DLBCL), and 5% to 10% of cases of other less common subtypes of non-Hodgkin lymphoma (NHL) harbor this translocation.

BCL-2 overexpression and impaired apoptosis are also hallmarks of chronic lymphocytic leukemia (CLL).1 Unlike FL and other NHL malignancies, deletion of 13q14 is the most frequently reported genetic lesion in patients with CLL, occurring in 50% to 60% of cases.1,5 The minimal deleted region in this lesion contains the micro-RNAs (miRNAs) miR-15a and miR-16, which normally inhibit BCL-2 transcription.6 Deletion of these miRNAs, which have also been observed in up to 70% of cases of mantle cell lymphoma (MCL), leads to elevated BCL2 expression and constitutive survival of tumor B cells.1,7 

Epigenetic silencing due to high histone deacetylase activity in patients with CLL can also cause decreased expression of miR-15a/16.1 In addition to chromosomal deletion and epigenetic silencing, these miRNAs can be regulated by TP53. Under normal circumstances, TP53 can enhance miR-15a/16 transcription.1 TP53 is often altered in hematologic malignancies, however, including CLL.Loss of TP53 function in CLL and other hematologic cancers impairs miR-15a/16 transcription and promotes elevated BCL-2 expression. In addition, TP53 normally upregulates expression of the proapoptotic BH3-only proteins NOXA and PUMA.9 Therefore, loss of TP53 can also decrease the levels of the proapoptotic proteins, thus shifting the balance between the apoptotic regulators and resulting in aberrant cell survival.


View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Cancer Summaries and Commentaries™: Update from Atlanta: Advances in the Treatment of Chronic Lymphocytic LeukemiaFeb 28, 20190.5
Year in Review™: Reflecting on Recent Evidence for the Treatment of Hematologic MalignanciesFeb 28, 20192.0
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