Cyclin D dysregulation: An early and unifying pathogenic event in multiple myeloma

P. Leif Bergsagel, W. Michael Kuehl, Fenghuang Zhan, Jeffrey Sawyer, Bart Barlogie, John Shaughnessy

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476 Scopus citations

Abstract

Two oncogenic pathways have been hypothesized for multiple myeloma (MM) and premalignant monoclonal gammopathy of undetermined significance (MGUS) tumors: a nonhyperdiploid pathway associated with a high prevalence of IgH translocations and a hyperdiploid pathway associated with multiple trisomies of 8 chromosomes. Cyclin D1, D2, or D3 expression appears to be increased and/or dysregulated in virtually all MM tumors despite their low proliferative capacity. Translocations can directly dysregulate CCND1 (11q13) or CCND3 (6p21), or MAF (16q23) or MAFB (20q11) transcription factors that target CCND2. Biallelic dysregulation of CCND1 occurs in nearly 40% of tumors, most of which are hyperdiploid. Other tumors express increased CCND2, either with or without a t(4;14) translocation. Using gene expression profiling to identify 5 recurrent translocations, specific trisomies, and expression of cyclin D genes, MM tumors can be divided into 8 TC (translocation/cyclin D) groups (11q13, 6p21, 4p16, maf, D1, D1+D2, D2, and none) that appear to be defined by early, and perhaps initiating, oncogenic events. However, despite subsequent progression events, these groups have differing gene expression profiles and also significant differences in the prevalence of bone disease, frequency at relapse, and progression to extramedullary tumor.

Original languageEnglish (US)
Pages (from-to)296-303
Number of pages8
JournalBlood
Volume106
Issue number1
DOIs
StatePublished - Jul 1 2005

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Bergsagel, P. L., Kuehl, W. M., Zhan, F., Sawyer, J., Barlogie, B., & Shaughnessy, J. (2005). Cyclin D dysregulation: An early and unifying pathogenic event in multiple myeloma. Blood, 106(1), 296-303. https://doi.org/10.1182/blood-2005-01-0034