1. Our characterization of secondary rearrangements that dysregulate MYC during tumor progression provided new insights regarding the role of MYC in the pathogenesis of MM: a) FISH and array comparative genomic hybridization CGH) analyses on 53 MMCL enabled us to detect and characterize MYC rearrangements in 42 (79%), including one MMCL each with a MYCN or MYCL rearrangement;b) analysis of MMRC array CGH data from 239 MM tumors showed that MYC rearrangements are much more frequent in primary MM tumors (45% of newly diagnosed MM tumors, 51% of previously treated MM tumors, and 55% of smoldering MM tumors) than the 15% prevalence reported by others from interphase FISH analyses;c) the mean level of MYC expression is significantly increased in MM tumors that have rearrangements in the MYC locus;d) the mean level of MYC expression in MM tumors that do not have a detectable MYC rearrangement still is significantly higher than in MGUS tumors;e) we identified MYC exonic and intronic polymorphisms that enabled us to show for both MMCL and MM tumors that MYC expression is mostly monoallelic when a rearrangement is detected but mostly biallelic when a rearrangement is not detected;f) MYC rearrangements are heterogeneous in about 15% of tumors, confirming that they sometimes are late secondary progression events;g) using mate pair sequences in MMCL and whole genome sequences provided by the MMRC for MM tumors we have identified recurrent non-immunoglobulin sites and associated enhancer - but mostly super enhancer - sequences that are implicated in rearrangements that dysregulate MYC;and g) we showed that germinal center activation of a MYC oncogene causes MM in an MGUS prone mouse strain but not in a mouse strain that rarely develops MGUS. Together, these results suggest that progression of MGUS to MM sometimes is caused by MYC rearrangements even though this progression often occurs by increased MYC expression without a MYC rearrangement. These results were published in 2014. 2. We have determined that secondary IGH rearrangements in MM often are not detected by diagnostic Vysis FISH probes. However, our in-house FISH probes and commercial Cytocell FISH probes, both of which include 3'IGH enhancer sequences, detect most secondary IGH rearrangements. These results were published in 2014. 3. We have determined that large (10 to 500 kb) duplicated sequences are sometimes found at breakpoints of translocations, insertions, and inversions in MM. In addition, we determined that most insertions show a copy number gain. A manuscript describing these results is in preparation. 4. We have determined that 3 of 50 MMCL have complex translocations (two involving IGH loci, and one involving a novel non-immunoglobulin locus) that are associated with ectopic expression of a novel transcription factor.
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