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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. This Article Full Text (PDF) Supplemental Tables All Versions of this Article: blood-2006-04-017087v1 108/10/3465    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Masih-Khan, E. Articles by Stewart, A K. Search for Related Content PubMed PubMed Citation Articles by Masih-Khan, E. Articles by Stewart, A K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 17, 2006 Accepted May 22, 2006 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, Jaimie Claudio, Leif Bergsagel, and A Keith Stewart* Department of Medical Oncology, Princess Margaret Hospital, Princess Margaret Hospital Chiron Corporation University of Pittsburgh Mayo Clinic Arizona * Corresponding author; email: stewart.keith{at}mayo.edu. Over expression 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 employed three FGFR selective kinase inhibitors - CHIR- 258, PD173074, 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 five modifiers 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Terpos, O. Sezer, P. Croucher, and M.-A. Dimopoulos Myeloma bone disease and proteasome inhibition therapies Blood, August 15, 2007; 110(4): 1098 - 1104. [Abstract] [Full Text] [PDF]

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