Our major focus has been to identify and characterize translocations to the IgH locus (chromosome 14q32) in multiple myeloma (MM) tumors. We assembled a panel of 50 EBV negative MM cell lines, and find that: 1) Ig translocations are present in all 36 MM cell lines (HMCL) analyzed, including IgH (33/36 = 92%), Iglambda (5/23 = 23%), and Igkappa (0/21); 2) the location of cloned IgH breakpoints is consistent with errors of B cell specific mechanisms (switch mostly but perhaps somatic hypermutation in a small fraction) in most cases; 3) cloned breakpoints are scattered over a large region, as far as 1 Mb from the dysregulated, overexpressed oncogene; 4) at least 15 of 30 (50%) lines have two (10) or three (5) independent IgH translocations; 5) there are a minimum of 18 (6 recurrent) translocation partners identified by ourselves and others in primary MM tumors; 6) apart from c-myc at 8q24 (see below) five chromosomal loci (cyclin D1 at 11q13; cyclin D3 at 6p21; FGFR3 tyrosine kinase receptor and MM.SET at 4p16.3; and the c-maf or mafB basic zip transcription factors at 16q23 and 20q11,respectively) are recurrent; ; 7) in a panel of 50 advanced tumors, translocations are somewhat less frequent (IgH in 58%, 2 independent IgH in 15% 3 independent IgH in none, Iglambda in 16%, Igkappa in 2%, and no Ig translocation in 35%). Analyses of premalignant MGUS and smoldering MM tumor by others show that IgH translocations are present in 47% of pre-malignant tumors. Our working hypothesis is that primary translocations to Ig loci provide one of the initial immortalizing events in the molecular pathogenesis of myeloma in about 50% of tumors, and usually occur during plasma cell development in germinal centers. In addition, secondary translocations involving one of the Ig loci - but lacking the hallmarks of a process mediated by a B cell specific recombination mechanism - occur as a tumor progression events in tumors that do or do not have primary translocations.. It appears that primary and secondary translocations involve different chromosomal partners (oncogenes), although there might be some overlap.? ? A second focus is to clarify the significance of our finding that there is selective expression of L-myc or one c-myc allele in 9 informative HMCL despite the apparent absence of a translocation, rearrangement, or amplification involving the c-myc locus. From a combination of FISH and SKY analyses, we have evidence for karyotypic abnormalities of L-myc (one HMCL) or c-myc locus in 28/32 (88%) HMCL that we have examined. Thus it seems clear that the selective expression of one c-myc allele is a consequence of a tumor specific, complex structural abnormality (complex translocation, insertion, duplication, inversion, with frequent involvement of 3 different chromosomes but not always an Ig locus) that alters the chromosomal context of one of the two L-myc or c-myc alleles. In all informative cases, it is clear that the myc structural abnormality was present in the primary tumor as well as in the HMCL. The incidence of c-myc abnormalities appears to be much lower (45%) in advanced, primary tumor samples. Some primary tumors show heterogeneity of the karyotypic abnormalities of c-myc, and one tumor had a karyotypic abnormality of N-myc. We have hypothesized that the complex karyotypic abnormalites that appear to dysregulate c-myc rarely - if ever- occur as an early event in tumorigenesis. Instead it appears that the dysregulation of c-myc occurs as a very late progression event, most often a complex translocation that is not mediated by B cell specific DNA modification processes. ? ? A third focus is to define other kinds of genetic and phenotypic abnormalities in MM.
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