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.

Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells

“…In this study, BCL2 expression was significantly reduced in surviving cells at T2 and T3 compared to baseline. This is consistent with recent observations suggesting that high BCL2 expression is associated with greater sensitivity to BCL2 inhibitors in preclinical, in vitro and in vivo models of lymphomas [ 39 ]. We confirmed upregulation of Mcl-1, a previously identified navitoclax resistance gene, in the drug-resistant cells detected by both single-cell analysis and also in the bulk RNAseq in on-treatment T2 samples (FDR = 0.038).…”

Recent advances in aptamer applications for analytical biochemistry

“…4 ) that has been PEGylated for clinical studies [ 28 ]. Through binding to cell surface nucleolin, AS1411 is internalized and may prevent nucleolin from binding to and stabilizing mRNA of anti-apoptotic BCL2 [ 29 ] protein, thereby destabilizing BCL2 mRNA, leading to a reduction in BCL2 protein synthesis. This can then lead to the induction of apoptosis.…”

Histone Deacetylase 6 as a Therapeutic Target in B cell-associated Hematological Malignancies

“…B-NHL is a general term for a group of heterogeneous diseases that include diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), and follicular lymphoma (FL) as the main types. These different types of B-NHL correspond to different stages of B cell development and have unique pathological and genetic features (Klanova and Klener, 2020) (Figure 1A). HDAC6 inhibitors have also been shown be useful in the treatment of B-NHL.…”

“…Through a series of cellular events including V(D)J recombination, pro-B cells develop into pre-B cells, immature B cells, and migrate to the secondary lymphoid organs after successfully expressing B cell surface receptors. Upon the stimulation by antigens, naive B cells undergo class-switch recombination, somatic hypermutation, and differentiate into plasma cells, which perform immune functions by producing antibodies (Monroe and Dorshkind, 2007;Abolhassani et al, 2014;Klanova and Klener, 2020). Some B cells develop into memory B cells and participate in secondary immunity (Corcoran and Tarlinton, 2016).…”