MIP-1alpha (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma.
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-1alpha) was the single most differentially altered gene. MIP-1 alpha promoter function, gene expression, and protein secretion were each down-regulated following inhibition of FGFR3 signaling. Down-regulation of MIP-1 alpha was not, however, observed following FGFR3 inhibition in MM cells with RAS mutations implicating RAS-MAPK in MIP-1 alpha regulation. As confirmation, inhibition of ERK1 also down-regulated MIP-1 alpha in FGFR3 inhibitor-resistant cells harboring RAS mutations. MIP-1 alpha 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.
Masih-Khan
Esther
E
Department of Medical Oncology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
Trudel
Suzanne
S
Heise
Carla
C
Li
Zhihua
Z
Paterson
Joshua
J
Nadeem
Vincent
V
Wei
Ellen
E
Roodman
David
D
Claudio
Jaime O
JO
Bergsagel
P Leif
PL
Stewart
A Keith
AK
D001847:Bone Diseases / Q000209:etiology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000150:complications / Q000209:etiology* / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering / Q000494:pharmacology; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004791:Enzyme Inhibitors; D019402:Macrophage Inflammatory Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D051498:Receptor, Fibroblast Growth Factor, Type 3; D018631:ras Proteins