Model for activation of apoptosis in multiple myeloma by interferons (IFNs). After transcriptional induction by IFNs, Apo2 ligand (Apo2L) engages its death receptor 5 (DR5) or DR4 and through an adaptor Fas-associated death domain (FADD) recruits caspase 8 to the cell membrane, which can be blocked by a dominant-negative DR5Δ. After caspase 8 activation by proteolysis, Bid is cleaved and translocates to mitochondria, causing release of low levels of cytochrome c (cyto c) into the cytosol, a process that leads to caspase 9 and 3 activation. This process results in attack of the antiapoptotic protein Bcl-2 on the mitochondrial membranes, producing a truncated Bcl-2Δ protein, which causes release of more cyto c, caspase activation, and apoptosis. Bcl-xL or Mcl-1 transcriptional down-regulation mediated by signal transducers and activators of transcription 3 (Stat 3) is an additional mechanism by which IFNs may decrease levels of antiapoptotic proteins and shift the balance toward a proapoptotic state. (Modified from [6], with permission.) TRAIL indicates tumor necrosis factor–related apoptosis-inducing factor ligand; DD, death domain.

Apoptotic pathways. The death receptor (DR) pathway is activated by ligation of the death ligands (eg, Apo2L/TRAIL [tumor necrosis factor–related apoptosis-inducing factor ligand] and FasL) to their cognate receptors on the cell surface. This process results in sequential binding of Fas-associated death domain (FADD) and pro–caspase 8. Active caspase 8 cleaves and activates caspase 3. In addition, caspase 8 cleaves Bid, and truncated Bid translocates to the mitochondria to promote the release of cytochrome c (Cyto c). The mitochondrial pathway is activated by a number of stimuli, including chemotherapeutic drugs and ionizing radiation (IR). All these stimuli result in activation and oligomerization of Bax and Bak. These changes contribute to pore formation in the outer mitochondrial membrane and the release of cyto c and other apoptogenic factors. Cyto c promotes activation of caspase 9 and of the effector caspases. DNA-damaging agents such as IR induce activation of the p53 that promotes transcription of proapoptotic Bcl-2 family members such as the multidomain Bax and the Bcl-2 homology 3 (BH3)-only proteins Puma, Noxa, and Bik. Activation of the BH3-only molecules either directly or indirectly results in activation of Bax and Bak. AIF indicates apoptosis-inducing factor.

Growth and survival pathways. Receptors for a proliferation-inducing ligand (APRIL) and B-cell–activating factor (BAFF) include B-cell maturation antigen (BCMA), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and BAFF receptor (BAFFR). FLT1 is a high-affinity vascular endothelial growth factor (VEGF) receptor. CXCR4 is a receptor for stromal cell–derived factor (SDF1α). These receptors, along with interleukin 6 receptor (IL6-R), insulin-like growth factor 1 receptor (IGF1-R), and CD40, mediate downstream activation of the various pathways. These pathways include nuclear factor κB (NF-κB), Janus kinase/signal transducers and activators of transcription (JAK/STAT), phosphatidylinositol 3-kinase (PI3K)/Akt, and Ras/Raf/mitogen-activated protein kinase (MAPK). These pathways ultimately lead to cytokine production (IL-6, IGF-1, VEGF), resistance to apoptosis (Bcl-2, inhibitors of apoptosis [IAPs]), cell proliferation, and migration of multiple myeloma (MM) cells. The bone marrow stromal cell (BMSC)/MM cell interaction is mediated by the surface receptors lymphocyte function–associated antigen 1 (LFA1), mucin, (MUC1) integrin α₄β₁ (VLA4), intracellular adhesion molecule 1 (ICAM1), vascular adhesion molecule 1 (VCAM1), and fibronectin (FN). Activation of ICAM by cell-cell interaction leads to secretion of various cytokines from the BMSCs. FGFR3 indicates fibroblast growth factor receptor 3; MEK, mitogen-activated protein/ERK kinase; SHP2, Src homology region 2 domain-containing phosphatase 2; gp130, glycoprotein 130; PKC, protein kinase C; BAD, Bcl-2 antagonist of cell death; FKHR, forkhead homolog of rhabdomyosarcoma; Casp9, caspase 9; mTOR, mammalian target of rapamycin; CycD, cyclin D; ERK, extracellular signal–regulated kinase; nuc, nucleus.