Targeting the Bcl-2 Family in B Cell Lymphoma

Abstract

Although lymphoma is a very heterogeneous group of biologically complex malignancies, tumor cells across all B cell lymphoma subtypes share a set of underlying traits that promote the development and sustain malignant B cells. One of these traits, the ability to evade apoptosis, is essential for lymphoma development. Alterations in the Bcl-2 family of proteins, the key regulators of apoptosis, is a hallmark of B cell lymphoma. Significant efforts have been made over the last 30 years to advance knowledge of the biology, molecular mechanisms, and therapeutic potential of targeting Bcl-2 family members. In this review, we will highlight the complexities of the Bcl-2 family, including our recent discovery of overexpression of the anti-apoptotic Bcl-2 family member Bcl-w in lymphomas, and describe recent advances in the field that include the development of inhibitors of anti-apoptotic Bcl-2 family members for the treatment of B cell lymphomas and their performance in clinical trials.

Keywords: B cell lymphoma; BCL-2; BCL-W; BH-3 mimetic; CLL; apoptosis; navitoclax; venetoclax.

Figure 1

Bcl-2 family members regulate apoptosis. (A) Various cellular stressors induce apoptosis through the intrinsic, mitochondrial pathway, which is regulated by the Bcl-2 family of proteins. These stress signals activate pro-apoptotic BH-3 only initiators (red), which inhibit the anti-apoptotic proteins (green). This, in turn, allows the pro-apoptotic effectors (blue) to be activated. Activation of the effector proteins results in their oligomerization and subsequent mitochondrial outer membrane permeabilization (MOMP), enabling the release of apoptotic factors that initiate the caspase cascade and final stages of cellular destruction. (B) Pro-apoptotic BH-3 only proteins bind to anti-apoptotic Bcl-2 family members with different affinities. BIM, PUMA, and BID bind strongly to all anti-apoptotic Bcl-2 proteins, whereas BAD binds preferentially to BCL-2, BCL-X, and BCL-W, and NOXA binds preferentially to MCL-1 and A1/BFL-1.

Figure 2

MicroRNA mediate a novel mechanism of Myc-induced apoptosis that is inactivated in malignant cells, but re-activated by HDAC inhibition. In normal B cells (top), MYC transcriptionally upregulates the miR-15 family and let-7a to target and reduce BCL-2, BCL-W, and BCL-X levels, thereby promoting apoptosis. However, in lymphoma cells (bottom), MYC, in complex with histone deacetylases (HDAC), transcriptionally repress the same miRNA, causing increased levels of anti-apoptotic proteins and reduced apoptosis. This mechanism can be re-activated in lymphoma cells by inhibiting HDACs (purple arrow).

Figure 3

Targeting anti-apoptotic BCL-2 family members for therapy. Therapeutic strategies directed at targeting single or multiple anti-apoptotic BCL-2 family members include the use of antisense oligonucleotides and small molecule inhibitors or mimetics. Like the pro-apoptotic BH-3 only proteins, these small molecules display varying affinities for anti-apoptotic BCL-2 family members as indicated.