We continue to identify and characterize Ig translocations in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). First, we have identified MAFA (8q24.3) as a new recurrent translocation partner. This translocation, which occurs in about 1% of MM tumors, is associated with the same gene expression profile (most notably, very high expression of CYCLIN D2) as c-MAF and MAFB translocations that we identified previously. Second, we have cloned the first Ig lambda translocation in MM, and have identified the dysregualated target as NFKB-inducing kinase (NIK/MAP3K14). We are actively investigating the role of NFKB in the pathogenesis of MM. Third, we have done array CGH analyses on our panel of 46 human MM cell lines (HMCL), and have identified recurrent bi-allelic deltions and amplifications of genes that are likely important in oncogenesis. This also has enabled us to map more precisely translocation breakpoints that target c-MYC, CYCLIN D1, and other genes. Fourth, we have just completed molecular cytogenetic analyses of 46 HMCL and 50 primary MM tumors. This has enabled us to gain insights regarding the mechanisms causing and roles of primary vs secondary translocations in MM. Finally, our studies on translocations and gene expression profiling enabled to propose the hypothesis that dysregulation of a CYCLIN D gene is a an early and unifying event in MGUS and MM tumors. These studies also enabled us to propose a TC (translocation/ CYCLIN D) classification, which identified 8 groups of tumors with differing biolgical and clinical properties.We continue to investigate other oncogenic events in MM. First, we have determined that K- and N-RAS mutations are infrequent (less than 5%) in MGUS but occur in about 30% of MM tumors, so that RAS mutations may sometimes be a marker if not a causal event in the MGUS/MM transition. In addition, we found that the prevalence of K-RAS mutations is similar in all TC groups, whereas the prevalence of N-RAS mutations differs markedly among the different TC groups, a finding that we do not yet understand. Second, we have determine that p16INK4a is usually expressed at very low levels in MM tumors independent of whether or not the gene is methylated, although some MM tumors and cell lines express quite high levels of this gene. Third, we have determined that the expression p18INK4c, which seems to be a key regulator of the G1>S transition in normal plasma cells, provides an important marker of proliferation. In approximately 30% of HMCL and nearly 10% of proliferative MM tumors, the bi-allelic deletion of p18 appears to be a critical event that leads to increased proliferation. Paradoxically, however, about 60% of both HMCL and MM tumors that are hightly proliferative have increased levels of p18, suggesting that these tumor cells are insensitive to the increased levels of p18 that occur as a consequence of increased proliferation. A small fraction of the HMCL and proliferative tumors that express high levels of p18 have inactivated RB1, which would explain the insensitivy to high p18 levels. We are continuing to attempt to identify other mechanisms responsible for increased proliferation when there are high p18 levels. Finally, we have been determing the mechanisms by which p53 is inactivated in more than 90% of our panel of 46 HMCL.
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