Critical roles for immunoglobulin translocations and cyclin D dysregulation in multiple myeloma.
Multiple myeloma (MM) is a tumor of long-lived bone marrow plasma cells (PCs). Nearly 40% of MM tumors have immunoglobulin H (IgH) translocations involving four recurrent chromosomal loci (oncogenes): 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (MMSET and FGFR3), and 16q23 (c-maf). Other MM tumors have Ig translocations involving different loci, none of which is involved in more than 1% of tumors. At least 25% of MM tumors have no Ig translocation. Unlike normal PCs, MM tumors usually express one of the three cyclin D genes at a high level. Translocations involving 4p16 and 16q23 do not directly target a cyclin D gene, but they are associated with a high level of cyclin D2 expression. Although cyclin D1 is not expressed in normal hematopoietic cells, one-third of MM tumors ectopically express cyclin D1 in the absence of t(11;14). Despite a low proliferation index in MM, dysregulation of a cyclin D gene seems to be a unifying oncogenic event. Analysis of 34 MM cell lines indicates that tumors having an IgH translocation are significantly over-represented, whereas tumors that ectopically express cyclin D1 are not represented. We speculate that ectopic cyclin D1 expression without t(11;14) is dependent on tumor-specific interaction with bone marrow stromal cells.
Bergsagel
P Leif
PL
Weill Medical College of Cornell University, New York, NY 10021, USA. plbergsa@med.cornell.edu
Kuehl
W Michael
WM
D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D009101:Multiple Myeloma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009857:Oncogenes / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*
D056741:Cyclin D; D016213:Cyclins; D007136:Immunoglobulins