MIP-1α (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, Peter Leif Bergsagel, Alexander Keith Stewart

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

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-1α) was the single most differentially altered gene. MIP-1α promoter function, gene expression, and protein secretion were each down-regulated following inhibition of FGFR3 signaling. Down-regulation of MIP-1α was not, however, observed following FGFR3 inhibition in MM cells with RAS mutations implicating RAS-MAPK in MIP-1α regulation. As confirmation, inhibition of ERK1 also down-regulated MIP-1α in FGFR3 inhibitor-resistant cells harboring RAS mutations. MIP-1α 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.

Original languageEnglish (US)
Pages (from-to)3465-3471
Number of pages7
JournalBlood
Volume108
Issue number10
DOIs
StatePublished - Nov 15 2006

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Receptor, Fibroblast Growth Factor, Type 3
Chemokine CCL3
Multiple Myeloma
Bone Diseases
Gene expression
Bone
Genes
Gene Expression
Mutation
Cell growth
Small Interfering RNA
Cell Survival
Carcinogenesis
Phosphotransferases
Down-Regulation
Observation

ASJC Scopus subject areas

  • Hematology

Cite this

MIP-1α (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma. / Masih-Khan, Esther; Trudel, Suzanne; Heise, Carla; Li, Zhihua; Paterson, Joshua; Nadeem, Vincent; Wei, Ellen; Roodman, David; Claudio, Jaime O.; Bergsagel, Peter Leif; Stewart, Alexander Keith.

In: Blood, Vol. 108, No. 10, 15.11.2006, p. 3465-3471.

Research output: Contribution to journalArticle

Masih-Khan, E, Trudel, S, Heise, C, Li, Z, Paterson, J, Nadeem, V, Wei, E, Roodman, D, Claudio, JO, Bergsagel, PL & Stewart, AK 2006, 'MIP-1α (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma', Blood, vol. 108, no. 10, pp. 3465-3471. https://doi.org/10.1182/blood-2006-04-017087
Masih-Khan E, Trudel S, Heise C, Li Z, Paterson J, Nadeem V et al. MIP-1α (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma. Blood. 2006 Nov 15;108(10):3465-3471. https://doi.org/10.1182/blood-2006-04-017087
Masih-Khan, Esther ; Trudel, Suzanne ; Heise, Carla ; Li, Zhihua ; Paterson, Joshua ; Nadeem, Vincent ; Wei, Ellen ; Roodman, David ; Claudio, Jaime O. ; Bergsagel, Peter Leif ; Stewart, Alexander Keith. / MIP-1α (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma. In: Blood. 2006 ; Vol. 108, No. 10. pp. 3465-3471.
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abstract = "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-1α) was the single most differentially altered gene. MIP-1α promoter function, gene expression, and protein secretion were each down-regulated following inhibition of FGFR3 signaling. Down-regulation of MIP-1α was not, however, observed following FGFR3 inhibition in MM cells with RAS mutations implicating RAS-MAPK in MIP-1α regulation. As confirmation, inhibition of ERK1 also down-regulated MIP-1α in FGFR3 inhibitor-resistant cells harboring RAS mutations. MIP-1α 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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AU - Li, Zhihua

AU - Paterson, Joshua

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AU - Wei, Ellen

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