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M. Kuehl,1 L. Brents,1 C. Cultraro,1 Y. Demchenko, A Dib,1 A. Gabrea,1 A. Zingone,1 L. Staudt,1 B. Barlogie,2 J. Shaughnessy,2 P.L. Bergsagel3SUMMARY:
1National Cancer Institute, Bethesda; 2University of Arkansas Medical Sciences, Little Rock; 3Mayo Clinic (Arizona), Scottsdale, USA
by Lynne Lederman, PhD
In this presentation, seven recurrent IgH translocations seen in non-hyperdiploid myelomas were classified into three groups involving the cyclin D genes, MAF translocations with cyclin D2, or MMSET/FGFR3. Dysregulation of cyclin D genes appears to be an early, unifying event in the pathogenesis of both MGUS and myeloma. Four events associated with disease progression were discussed, and include 1) secondary Ig translocations, including myc translocations, a late secondary event; 2) N-ras mutations, which occur early in the transition from MGUS to myeloma; 3) an increase in proliferation associated with Rb pathway inactivation, which paradoxically is associated with increased levels of p18 RNA and insensitivity to p18; and 4) dyregulation of the NF-κB pathway, which may result in independence of myeloma cells from external signaling previously provided by the microenvironment. The contribution of hyperdiploidy to pathogenesis is still not known, nor is the role of the microenvironment in the transition from MGUS to myeloma. Because mutations can affect both classical and non-classical NF-κB pathways, and because there is probably cross-talk between these pathways, a therapeutic strategy might be to select agents capable of blocking NF-κB signaling via both pathways.