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Blood, 15 November 2006, Vol. 108, No. 10, pp. 3465-3471.
Prepublished online as a Blood First Edition Paper on July 18, 2006; DOI 10.1182/blood-2006-04-017087.
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NEOPLASIA
MIP-1 (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma
Esther Masih-Khan,
Suzanne Trudel,
Carla Heise,
Zhihua Li,
Joshua Paterson,
Vincent Nadeem,
Ellen Wei,
David Roodman,
Jaime O. Claudio,
P. Leif Bergsagel, and
A. Keith Stewart
From the Department of Medical Oncology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada; Chiron Corporation, Emoryville, CA; the University of Pittsburgh, PA; and the Mayo Clinic, Scottsdale, AZ.
Overexpression of fibroblast growth factor receptor 3 (FGFR3) is a hallmark of t(4;14) multiple myeloma (MM). To dissect the mechanism of FGFR3 oncogenesis in MM, we used 3 FGFR selective kinase inhibitors—CHIR258, PD173074, and SU5402—and FGFR3-specific siRNA to modulate FGFR3 activity. Conversely, the ligand FGF was used to stimulate FGFR3 function in human MM cells. The transcriptional response to FGFR3 modification was recorded, and gene expression changes common to all 5 modifiers were documented. Ten genes were commonly regulated. Macrophage inflammatory protein-1 alpha (MIP-1 ) was the single most differentially altered gene. MIP-1 promoter function, gene expression, and protein secretion were each down-regulated following inhibition of FGFR3 signaling. Down-regulation of MIP-1 was not, however, observed following FGFR3 inhibition in MM cells with RAS mutations implicating RAS-MAPK in MIP-1 regulation. As confirmation, inhibition of ERK1 also down-regulated MIP-1 in FGFR3 inhibitor-resistant cells harboring RAS mutations. MIP-1 is implicated in the survival and proliferation of MM cells and the pathogenesis of MM bone disease. Our observation is the first to directly link an initiating IgH translocation not only to MM-cell growth and survival but also to the disease-associated bone disease.
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[Abstract]
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