of our accomplishments for this project include the following. A) comprehensive FISH analyses on metaphase chromosomes in 47 multiple myeloma cell lines (MMCL) and 48 advanced MM tumors showed that: 1) primary IGH translocations involving 5 recurrent partners were present in 68% of cell lines and 70% of non-hyperdiploid tumors, but only 12% of hyperdiploid tumors;and 2) secondary translocations (IGH translocations not involving the five recurrent loci, IGL and IGK translocations, and MYC translocations) usually are unbalanced, with complex structures, and occur with a similar prevalence in hyperdiploid and non-hyperdiploid tumors. B) we continue to characterize secondary rearrangements that dysregulate MYC during tumor progression: 1)FISH and array comparative genomic hybridization analyses on 51 MMCL that enabled us to detect and characterize MYC rearrangements in 44 (88%);2) analysis of MMRC array CGH data on 239 MM tumors showed that MYC rearrangements are much more frequent in primary MM tumors, i.e., about 45% of newly diagnosed tumors and 51% of previously treated tumors, than the 15% prevalence reported by other from FISH analyses;3) analysis of the MMRC data set also showed that MYC expression is significantly increased in tumors that have rearrangements in the MYC locus;4) we identified MYC 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. 5) 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 sequences that are implicated in rearrangements that dysregulate MYC. C) we have determined that secondary IGH rearrangements in myeloma often are not detected by diagnostic FISH probes. D) we have determined that large (10 to 500 kb) duplicated sequences are sometimes found at breakpoints of translocations, insertions, and inversions in MM. E) 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. The results for B,C,D provide the data for three manuscripts that will be submitted in the near future.

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Onozawa, Masahiro; Zhang, Zhenhua; Kim, Yoo Jung et al. (2014) Repair of DNA double-strand breaks by templated nucleotide sequence insertions derived from distant regions of the genome. Proc Natl Acad Sci U S A 111:7729-34
Affer, M; Chesi, M; Chen, W D et al. (2014) Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia 28:1725-35
Bergsagel, P L; Kuehl, W M (2013) Degree of focal immunoglobulin heavy chain locus deletion as a measure of B-cell tumor purity. Leukemia 27:2067-8
Kuehl, W Michael; Bergsagel, P Leif (2012) Molecular pathogenesis of multiple myeloma and its premalignant precursor. J Clin Invest 122:3456-63
Kuehl, W Michael; Bergsagel, P Leif (2012) MYC addiction: a potential therapeutic target in MM. Blood 120:2351-2
Zingone, Adriana; Kuehl, W Michael (2011) Pathogenesis of monoclonal gammopathy of undetermined significance and progression to multiple myeloma. Semin Hematol 48:4-12
Zingone, A; Cultraro, C M; Shin, D-M et al. (2010) Ectopic expression of wild-type FGFR3 cooperates with MYC to accelerate development of B-cell lineage neoplasms. Leukemia 24:1171-8
Dib, Amel; Glebov, Oleg K; Shou, Yaping et al. (2009) A der(8)t(8;11) chromosome in the Karpas-620 myeloma cell line expresses only cyclin D1: yet both cyclin D1 and MYC are repositioned in close proximity to the 3'IGH enhancer. DNA Repair (Amst) 8:330-5
Vatsveen, Thea Kristin; Tian, Erming; Kresse, Stine H et al. (2009) OH-2, a hyperdiploid myeloma cell line without an IGH translocation, has a complex translocation juxtaposing MYC near MAFB and the IGK locus. Leuk Res 33:1670-7
Dib, Amel; Gabrea, Ana; Glebov, Oleg K et al. (2008) Characterization of MYC translocations in multiple myeloma cell lines. J Natl Cancer Inst Monogr :25-31

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