Role and Regulation of Pro-survival BCL-2 Proteins in Multiple Myeloma

Abstract

Apoptosis plays a key role in protection against genomic instability and maintaining tissue homeostasis, and also shapes humoral immune responses. During generation of an antibody response, multiple rounds of B-cell expansion and selection take place in germinal centers (GC) before high antigen affinity memory B-cells and long-lived plasma cells (PC) are produced. These processes are tightly regulated by the intrinsic apoptosis pathway, and malignant transformation throughout and following the GC reaction is often characterized by apoptosis resistance. Expression of pro-survival BCL-2 family protein MCL-1 is essential for survival of malignant PC in multiple myeloma (MM). In addition, BCL-2 and BCL-XL contribute to apoptosis resistance. MCL-1, BCL-2, and BCL-XL expression is induced and maintained by signals from the bone marrow microenvironment, but overexpression can also result from genetic lesions. Since MM PC depend on these proteins for survival, inhibiting pro-survival BCL-2 proteins using novel and highly specific BH3-mimetic inhibitors is a promising strategy for treatment. This review addresses the role and regulation of pro-survival BCL-2 family proteins during healthy PC differentiation and in MM, as well as their potential as therapeutic targets.

Keywords: B-cell malignancy; BCL-2 family; BH3-mimetic; MCL-1; apoptosis; germinal center; multiple myeloma; plasma cell differentiation.

Figure 1

Expression of pro-survival BCL-2 family proteins during PC differentiation and after malignant transformation of (post-) GC B-cells. Upon encounter of a naïve B-cell with its cognate antigen, and in the presence of adequate T cell help, a germinal center (GC) is formed where the B-cell undergoes multiple cycles of expansion and hypermutation in the dark zone (DZ), and affinity-based selection in the light zone (LZ). Low-affinity B-cells undergo apoptosis, while high-affinity B-cells can undergo further selection, or exit the GC as a memory B-cell or plasma cell (PC). In the GC, BCL-2 expression is strongly repressed and expression of MCL-1, BCL-XL, and BFL-1 is increased. MCL-1, but not BCL-XL, was shown to be essential for survival of GC B-cells. Naïve and memory B-cells have high expression of BCL-2 and are sensitive to its inhibition, and PC depend on MCL-1 expression for survival. Erroneous targeting of activation-induced cytidine deaminase (AID) during somatic hypermutation and class switch recombination can lead to mutations that promote malignant transformation, resulting in a variety of GC-derived malignancies (dashed lines). Multiple GC-derived malignancies, such as follicular lymphoma (FL), diffuse-large B-cell lymphoma (DLBCL), some B-cell chronic lymphocytic leukemias (B-CLL), and multiple myeloma (MM) depend on overexpression of BCL-2 family proteins for survival. BL, Burkitt's lymphoma; BM, bone marrow; CLL, chronic lymphocytic leukemia; DLBCL, diffuse-large cell B-cell lymphoma; DZ, dark zone; FL, follicular lymphoma; HL, Hodgkin lymphoma; LZ, light zone; MCL, mantle cell lymphoma; MM, multiple myeloma; PC, plasma cell; WM, Waldenström macroglobulinemia.

Figure 2

Signals and cellular processes that mediate apoptosis resistance in MM. MM cells receive signals from the bone marrow microenvironment that stimulate their survival. These signals include IL-6 and IFN-α, leading to JAK/STAT signaling and expression of MCL-1, BCL-XL, and VEGF. VEGF, in turn, promotes IL-6 production by neighboring cells. Other signals from the bone marrow microenvironment include BAFF and APRIL, which signal via TRAFs and induce expression of MCL-1 and BCL-2. IGF-1 signaling downregulates BIM, transcriptionally as well as post-translationally. MM cells also have high expression of the PC transcriptional regulator BLIMP-1, which promotes MCL-1 and represses BIM expression. Amplification of the 1q chromosome arm often occurs in MM. The genes for both MCL-1 and the IL-6 receptor (IL-6R) are present on this locus, possibly leading to overexpression in 1q-amplified MM. In addition to transcriptional regulation, MCL-1 is heavily regulated post-transcriptionally, which may contribute to the high MCL-1 protein levels found in MM. Dashed lines represent methods for interference in apoptosis resistance by MM drugs dexamethasone and bortezomib, and by BH3-mimetics. APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BCMA, B-cell maturation antigen; BH-3, BCL-2 homolog 3; BLIMP-1, B lymphocyte-induced maturation protein 1; IFN-α, interferon alpha; IGF-1, insulin-like growth factor 1; IL-6, interleukin 6; IL-6R, interleukin 6 receptor; JAK, janus kinase; STAT3, signal transducer and activator of transcription 3; TACI, transmembrane activator and calcium-modulating ligand interactor; TRAF, TNF receptor-associated factor; VEGF, vascular endothelial growth factor.