BCL-2 Proteins in Pathogenesis and Therapy of B-Cell Non-Hodgkin Lymphomas

Abstract

The ability to inhibit mitochondrial apoptosis is a hallmark of B-cell non-Hodgkin lymphomas (B-NHL). Activation of mitochondrial apoptosis is tightly controlled by members of B-cell leukemia/lymphoma-2 (BCL-2) family proteins via protein-protein interactions. Altering the balance between anti-apoptotic and pro-apoptotic BCL-2 proteins leads to apoptosis evasion and extended survival of malignant cells. The pro-survival BCL-2 proteins: B-cell leukemia/lymphoma-2 (BCL-2/BCL2), myeloid cell leukemia-1 (MCL-1/MCL1) and B-cell lymphoma-extra large (BCL-XL/BCL2L1) are frequently (over)expressed in B-NHL, which plays a crucial role in lymphoma pathogenesis, disease progression, and drug resistance. The efforts to develop inhibitors of anti-apoptotic BCL-2 proteins have been underway for several decades and molecules targeting anti-apoptotic BCL-2 proteins are in various stages of clinical testing. Venetoclax is a highly specific BCL-2 inhibitor, which has been approved by the US Food and Drug Agency (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL) and is in advanced clinical testing in other types of B-NHL. In this review, we summarize the biology of BCL-2 proteins and the mechanisms of how these proteins are deregulated in distinct B-NHL subtypes. We describe the mechanism of action of BH3-mimetics and the status of their clinical development in B-NHL. Finally, we summarize the mechanisms of sensitivity/resistance to venetoclax.

Keywords: B-cell leukemia/lymphoma-2 (BCL-2); apoptosis; non-Hodgkin lymphomas (NHL); venetoclax.

Figure 1

The perforin-granzyme, intrinsic (mitochondrial) and extrinsic apoptotic pathway. The extrinsic pathway is triggered via ligation of cell surface death receptors from the tumor necrosis factor (TNF) receptor family with death ligands (e.g., FAS ligand or TNFα) on the outside of the cell membrane. Subsequently, a multiprotein complex: death-inducing signaling complex (DISC) is created on the cytosolic side of the cell membrane resulting in activation of pro-caspase 8. The initiator caspase 8 subsequently activates the effector caspases (caspase-3 and 7), that cleave cellular proteins and promotes the apoptotic machinery. The perforin-granzyme and intrinsic apoptotic pathways are described in the text.

Figure 2

Binding profile of pro-apoptotic BH3 domain-only proteins and multi-domain effector proteins to pro-survival proteins. BH3 domain-only proteins are depicted in orange (direct activators) and pink (sensitizers).

Figure 3

Pathogenesis of B-cell non-Hodgkin lymphomas. Simplified scheme of B cell development showing distinct types of B-NHLs arising from different non-malignant lymphoid counterparts. Reprinted with permission. ^© (2020) American Society of Clinical Oncology. All rights reserved. Nogai, H. et al.: J. Clin. Oncol. 29, 2011: 1803–1811 [20].

Figure 4

(A) Mechanism of action of venetoclax. Venetoclax binds to the BH3 domain of BCL-2 protein with subsequent release of proapoptotic proteins, activation of BAX/BAK1 and apoptosis induction. (B) Mechanisms of resistance to venetoclax. Four different mechanisms of inherited or acquired resistance to venetoclax include: 1. Lack of BCL-2 protein expression, 2. Overexpression of other anti-apoptotic BCL-2 proteins that sequester pro-apoptotic BH3-only proteins displaced from BCL-2 protein following its pharmacological inhibition by venetoclax, 3. Acquired mutations within the BH3 domain of BCL-2 abrogating venetoclax binding, 4. Acquired mutations of BAX preventing BAX activation and apoptosis induction.