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.
Highlights
Apoptosis is an active form of programmed cell death, in which a controlled sequence of events leads to the elimination of aged, damaged and unnecessary cells [1]
We focus on the mitochondrial apoptotic pathway, which plays a critical role in pathogenesis and drug resistance of distinct hematologic malignancies and has been extensively studied and targeted therapeutically
Another anti-apoptotic protein, BCL-W has been shown to be overexpressed in the majority of aggressive and indolent lymphoma, including Diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), mantle cell lymphoma (MCL), Follicular lymphoma (FL), and marginal zone lymphoma (MZL), making it a potential therapeutic target in B-cell non-Hodgkin lymphomas (B-non-Hodgkin lymphomas (NHL)) [52]
Summary
Apoptosis is an active form of programmed cell death, in which a controlled sequence of events leads to the elimination of aged, damaged and unnecessary cells [1]. Activated caspases possess proteolytic activity and can cleave proteins at aspartic acid residues and target cytoskeletal or nuclear proteins resulting in highly controlled cell disintegration Another apoptotic pathway has been described, which is mediated by cytotoxic T cells and natural killer (NK) cells (Figure 1). Granzyme B triggers caspase activation indirectly by activation of pro-apoptotic BH3-only proteins, such as BH3-interacting domain death agonist (BID) which results in the activation of the mitochondrial apoptotic pathway (in detail described below) [6]. These morphological features are visible via light microscopy and typically include cell shrinkage and nuclear pyknosis caused by chromatin condensation Another characteristic feature of apoptosis is plasma membrane blebbing with subsequent formation of apoptotic bodies consisting of cytoplasm, intact organelles and nuclear fragments [8]. The apoptotic bodies are cleared via phagocytes without releasing pro-inflammatory cell contents into the surrounding area
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