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.
