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Blood, 1 July 2005, Vol. 106, No. 1, pp. 328-337.
Prepublished online as a Blood First Edition Paper on March 22, 2005; DOI 10.1182/blood-2004-09-3686.
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NEOPLASIA
Constitutively activated FGFR3 mutants signal through PLC -dependent and -independent pathways for hematopoietic transformation
Jing Chen,
Ifor R. Williams,
Benjamin H. Lee,
Nicole Duclos,
Brian J. P. Huntly,
Daniel J. Donoghue, and
D. Gary Gilliland
From the Howard Hughes Medical Institute, Harvard Medical School, and Department of Pathology, Brigham and Women's Hospital, Boston, MA; the Department of Pathology, Emory University, Atlanta, GA; and the Department of Chemistry and Biochemistry, University of California–San Diego, La Jolla, CA.
Ectopic expression of fibroblast growth factor receptor 3 (FGFR3) associated with t(4;14) has been implicated in the pathogenesis of human multiple myeloma. Some t(4;14) patients have activating mutations of FGFR3, of which a minority are K650E (thanatophoric dysplasia type II [TDII]). To investigate the role of autophosphorylated tyrosine residues in FGFR3 signal transduction and transformation, we characterized a series of FGFR3 TDII mutants with single or multiple Y F substitutions. Phenylalanine substitution of Y760, essential for phospholipase C (PLC) binding and activation, significantly attenuated FGFR3 TDII–mediated PLC activation, as well as transformation in Ba/F3 cells and a murine bone marrow transplant leukemia model. In contrast, single substitution of Y577, Y724, or Y770 had minimal to moderate effects on TDII-dependent transformation. Substitution of all 4 non–activation loop tyrosine residues significantly attenuated, but did not abolish, TDII transforming activity. Similar observations were obtained in the context of a constitutively activated fusion TEL-FGFR3 associated with t(4;12)(p16;p13) peripheral T-cell lymphomas. Moreover, 2 independent EµSR-FGFR3 TDII transgenic mouse lines developed a pro-B-cell lymphoma, and PLC was highly activated in primary lymphoma cells as assessed by tyrosine phosphorylation. These data indicate that engagement of multiple signaling pathways, including PLC-dependent and PLC-independent pathways, is required for full hematopoietic transformation by constitutively activated FGFR3 mutants.
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