Molecular pathogenesis and a consequent classification of multiple myeloma

Peter Leif Bergsagel, W. Michael Kuehl

Research output: Contribution to journalArticle

398 Citations (Scopus)

Abstract

There appear to be two pathways involved in the pathogenesis of premalignant non-immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Nearly half of tumors are nonhyperdiploid, and mostly have one of five recurrent IgH translocations: 16% 11q13 (CCN D1), 3% 6p21 (CCN D3), 5% 16q23 (MAF), 2% 20q12 (MAFB), and 15% 4p16 (FGFR3 and MMSET). The remaining hyperdiploid tumors have multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15, 19, and 21, and infrequently one of these five translocations. Although cyclin D1 is not expressed by healthy lymphoid cells, it is bi-allelically dysregulated in a majority of hyperdiploid tumors. Virtually all MM and MGUS tumors have dysregulated and/or increased expression of cyclin D1, D2, or D3, providing an apparent early, unifying event in pathogenesis. The patterns of translocations and cyclin D expression (TC) define a novel classification that includes eight groups: 11q; 6p; MAF; 4p; D1 (34%); D1 + D2 (6%); D2 (17%); and none (2%). The hyperdiploid D1 group is virtually absent in extramedullary MM and MM cell lines, suggesting a particularly strong dependence on interaction with the bone marrow microenvironment. Despite shared progression events (RAS mutations, MYC dysregulation, p53 mutations, and additional disruption of the retinoblastoma pathway), the phenotypes of MGUS and MM tumors in the eight TC groups is determined mainly by early oncogenic events. Similar to acute lymphocytic leukemia, MM seems to include several diseases (groups) that have differences in early or initiating events, global gene expression patterns, bone marrow dependence, clinical features, prognosis, and response to therapy.

Original languageEnglish (US)
Pages (from-to)6333-6338
Number of pages6
JournalJournal of Clinical Oncology
Volume23
Issue number26
DOIs
StatePublished - 2005

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Multiple Myeloma
Monoclonal Gammopathy of Undetermined Significance
Polyploidy
Cyclin D1
Neoplasms
Bone Marrow
Cyclin D3
Cyclin D2
Cyclin D
Chromosomes, Human, Pair 5
Mutation
Chromosomes, Human, Pair 3
Retinoblastoma
Trisomy
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Lymphocytes
Phenotype
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Molecular pathogenesis and a consequent classification of multiple myeloma. / Bergsagel, Peter Leif; Kuehl, W. Michael.

In: Journal of Clinical Oncology, Vol. 23, No. 26, 2005, p. 6333-6338.

Research output: Contribution to journalArticle

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