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KOS 2007: Molecular Principles Underlying Myeloma
P. Leif Bergsagel, MD
Mayo Clinic
Scottsdale, AZ, USA
06.26.07



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AUTHORS: P.L. Bergsagel, M. Chesi, J. Keats, W.-J. Chng, M. Sebag, R. Tiedemann, T. Henry, E. Braggio, W.M. Kuehl, A.K. Stewart, R. Fonseca
Mayo Clinic, Research Department, Scottsdale, AZ, USA

SUMMARY:
by Lynne Lederman, PhD

Gene expression profiling (GEP) of multiple myeloma cells from patients at the University of Arkansas provides an explanation for the heterogeneity of this disease. The primary determinants are nderlying genetic abnormalities, which include recurrent immunoglobulin gene translocations in 60% of patients and hyperdiploidy in 40% of patients. These primary events can be divided into five homogeneous groups based FISH analysis. The three translocation groups involve disregulation of growth factor genes, oncogenes, or cell cycle control genes, the hyperdipoid group involves trisomies of eight chromosomes, and the fifth group, the remaining 20%, is not otherwise classified, although it is associated with altered cyclin (cell cycle regulator) expression. Each of these is associated with characteristic secondary events that result in unique GEP and clinical courses. Other genetic abnormalities may not be evident by FISH, and are more readily detected by array comparative genomic hybridization (aCGH), e.g., biallelic deletion of p53 on chromosome 17p. Other genetic events that may not affect the GEP but are important for the pathogenesis and prognosis of myeloma include activation of the oncogene ras, amplifications of chromosome 1q, deletion of chromosome 13q, and mutations in the non-canonical (non-classical) NF-κB pathway, of which TRAF3 mutations are the most common. This pathway affects the processing of the oncogene myc, which is dysregulated in 15% of newly diagnosed myelomas, in 40% of advanced myelomas, and in 90% of myeloma cell lines, and seems therefore to be related to disease progession. In an analysis of patients treated in the APEX trial of bortezomib compared with high dose dexamethasone, inactivation of TRAF3 was associated with increased response to bortezomib and decreased response to dexamethasone. This not only provides further evidence for clinical activity of bortezomib via the non-canonical NF-κB pathway, and suggests that the activity of dexamethasone may be via the canonical (classical) pathway, but it also may provide a way in the future to select patients more likely to respond to bortezomib therapy. At this time, GEP is not practical as a clinical tool.


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