Genomic Rearrangements in Multiple Myeloma

Kuehl, Walter

Abstract

This project is a continuation of a portion of the project entitled The Molecular Pathogenesis of Multiple Myeloma, Z01 SC 006581. Progress during the past year has resulted in several publications. First, comprehensive FISH analyses on metaphase chromosomes in 47 multiple myeloma cell lines and 48 advanced multiple myeloma tumors showed the following: 1) primary IgH translocations, mostly balanced, involving 5 recurrent partners were present in 68% of cell lines, 70% of non-hyperdiploid tumors, but only 12% of hyperdiploid tumors; 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; 3) two of the 5 recurrent translocations rarely occur within the same tumor cell; and 4) the 5 recurrent translocations sometimes can be secondary events. Second, we summarized FISH and array comparative genomic hybridization analyses on 47 multiple myeloma cells lines that enabled us to detect and characterize MYC rearrangements in 43 ( more than 90%) of the cell lines. Together with our previous results, this gave us further support for our hypothesis that MYC rearrangements represent a late progression event that provides a general paradigm for secondary translocations in multiple myeloma. Third, in a collaborative study we identified and characterized aberrant IgH switch recombination and switch translocations in activated B cell-like diffuse large cell lymphoma. In unpublished work we have cloned some breakpoints that are found in complex translocations that involve MYC, including some translocations in which no Ig sequences are involved, and others in which MYC, one of the MAF oncogenes, and an Ig enhancer are re-positioned near one another.