In terms of prognosis, deletion of 17p13, involving the tumor suppressor gene p53, is the most important cytogenetic factor; it is associated with worse treatment outcomes (Table 1) [23,24]. up to 75% of patients with MM [24,29,31]. The most common of these translocations leads to dysregulation of oncogenes at translocation partner regions (Table 1) [23,24]. Frequent translocations involving the IgH gene locus and 14q32 are t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23) [23C27, 30], some of which have been associated with poor survival [28,32]. In terms of prognosis, deletion of 17p13, involving the tumor suppressor gene p53, is the most important cytogenetic factor; it is associated with 25,26-Dihydroxyvitamin D3 worse treatment outcomes (Table 1) [23,24]. However, 13q deletion, which has been traditionally considered an adverse prognostic factor, is associated with poor prognosis only if other cytogenetic abnormalities, such as t(4;14) and deletion of 17p13, are present Mouse monoclonal antibody to ATIC. This gene encodes a bifunctional protein that catalyzes the last two steps of the de novo purinebiosynthetic pathway. The N-terminal domain has phosphoribosylaminoimidazolecarboxamideformyltransferase activity, and the C-terminal domain has IMP cyclohydrolase activity. Amutation in this gene results in AICA-ribosiduria [28]. Although several genetic mutations seen 25,26-Dihydroxyvitamin D3 in MM patients have been linked to disease progression, clinical findings, and response to therapy, it is important to note that the behavior of MM cells at the biological and clinical level is also crucially influenced by interactions between tumor cells and the bone marrow microenvironment [33]. Table 1 Chromosomal aberrations in multiple myeloma (MM) [23C30]. than thalidomide [72], and are more potent T-cell co-stimulators [73]. To date, clinical data on this class of compounds have come predominantly from studies on lenalidomide (phases I-IV), with pomalidomide currently in phase IICIII development [73C78]. Lenalidomide is administered orally, has a favorable safety profile and has been shown to be highly effective in treating MM [79]. It is currently approved for use with dexamethasone in patients with MM who have received at least one prior therapy. Although their exact mode of action in MM remains unknown, studies suggest that immunomodulatory agents have a combination of anti-myeloma actions including direct tumoricidal effects, disruption of stromal cell support from the bone marrow microenvironment, and a number of immunomodulatory effects including anti-proliferative, apoptotic, anti-inflammatory, and anti-angiogenic effects. Recently, expression of cereblon (CRBN), a thalidomide-binding protein and teratogenic target [80] has been shown to 25,26-Dihydroxyvitamin D3 be an essential requirement for immunomodulatory activity [81], and to be an important molecular target of lenalidomide and pomalidomide [82]. A positive association has been identified between high levels of CRBN expression and a good 25,26-Dihydroxyvitamin D3 clinical response to treatment with lenalidomide and dexamethasone [83]. The multiple effects of immunomodulatory agents have been cited as the likely reason for the breadth of activity of this class of drugs [84]. 6. Direct tumoricidal effects and modulation of the tumor microenvironment Immunomodulatory agents have been shown to have several direct and indirect effects on MM cells, via both direct tumoricidal effects and modulation of the bone marrow microenvironment, including the prevention of angiogenesis and osteoclastogenesis. Lenalidomide down-regulates expression of the MM cell survival factor interferon regulatory factor-4 [85C87]. Conversely, it induces the expression of cyclin-dependent kinase inhibitors, including p21, p27, and p15, and the early response transcription factors Egr1, Egr2, and Egr3, which are implicated in the regulation of tumor suppressor and cell-cycle regulatory genes [85,88,89]. Lenalidomide has also been shown to activate caspases, directly triggering tumor cell death [89,90], with the activation of caspases 3, 8, and 9 by lenalidomide being synergistically enhanced by dexamethasone [89,90]. Lenalidomide and pomalidomide also act by disrupting the stromal support within the bone marrow that is needed for the production of a range of cytokines including VEGF, IL-6, and TNF- [72,91,92]. By inhibiting TNF- expression, and thereby, reducing the expression of adhesion molecules on both MM cells and BMSCs [93], immunomodulatory agents have been shown to reduce levels of IL-6 induced by MMCBMSC interactions [44,91]. 25,26-Dihydroxyvitamin D3 The down-regulation of adhesion molecules also has implications for signaling pathways. Indeed, lenalidomide has been shown to down-regulate NF-B [92], resulting in reduced expression of anti-apoptotic proteins [93]. Angiogenesis in MM has been associated with active disease and the adhesion-molecule-mediated interactions between MM cells and the microvasculature have been implicated in the ability of a tumor to disseminate [94,95]. The anti-angiogenic effects of immunomodulatory agents are likely to be due to anti-migratory mechanisms mediated via modulation of chemotactic factors such as TNF, VEGF, and basic fibroblast growth factor rather than direct inhibition of endothelial cell.