Critical Roles for Immunoglobulin Translocations and Cyclin D Dysregulation in Multiple Myeloma

Immunol Rev. 2003 Aug;194:96-104. doi: 10.1034/j.1600-065x.2003.00052.x.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cyclin D
  • Cyclins / genetics
  • Cyclins / metabolism*
  • Humans
  • Immunoglobulins / genetics
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / immunology
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Oncogenes / genetics
  • Translocation, Genetic / genetics*

Substances

  • Cyclin D
  • Cyclins
  • Immunoglobulins