Internal tandem duplication mutations in FLT3 gene augment chemotaxis to Cxcl12 protein by blocking the down-regulation of the Rho-associated kinase via the Cxcl12/Cxcr4 signaling axis.

Autor:	Onishi C; From the Departments of Oncology/Hematology and mikami@med.shimane-u.ac.jp., Mori-Kimachi S; Pediatrics and., Hirade T; Pediatrics and., Abe M; Pediatrics and., Taketani T; Pediatrics and the Division of Blood Transfusion, Shimane University Hospital, 693-8501 Izumo, Japan, and., Suzumiya J; From the Departments of Oncology/Hematology and., Sugimoto T; First Department of Internal Medicine, Shimane University School of Medicine, Izumo 693-8501, Japan., Yamaguchi S; Pediatrics and., Kapur R; the Department of Pediatrics and the Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202., Fukuda S; Pediatrics and sfukuda@med.shimane-u.ac.jp.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2014 Nov 07; Vol. 289 (45), pp. 31053-65. Date of Electronic Publication: 2014 Sep 18.
DOI:	10.1074/jbc.M114.568287
Abstrakt:	Internal tandem duplication mutations in the Flt3 gene (ITD-FLT3) enhance cell migration toward the chemokine Cxcl12, which is highly expressed in the therapy-protective bone marrow niche, providing a potential mechanism underlying the poor prognosis of ITD-FLT3(+) acute myeloid leukemia. We aimed to investigate the mechanisms linking ITD-FLT3 to increased cell migration toward Cxcl12. Classification of the expression of Cxcl12-regulated genes in ITD-FLT3(+) cells demonstrated that the enhanced migration of ITD-FLT3(+) cells toward Cxcl12 was associated with the differential expression of genes downstream of Cxcl12/Cxcr4, which are functionally distinct from those expressed in ITD-FLT3(-) cells but are independent of the Cxcr4 expression levels. Among these differentially regulated genes, the expression of Rock1 in the ITD-FLT3(+) cells that migrated toward Cxcl12 was significantly higher than in ITD-FLT3(-) cells that migrated toward Cxcl12. In ITD-FLT3(-) cells, Rock1 expression and Mypt1 phosphorylation were transiently up-regulated but were subsequently down-regulated by Cxcl12. In contrast, the presence of ITD-FLT3 blocked the Cxcl12-induced down-regulation of Rock1 and early Mypt1 dephosphorylation. Likewise, the FLT3 ligand counteracted the Cxcl12-induced down-regulation of Rock1 in ITD-FLT3(-) cells, which coincided with enhanced cell migration toward Cxcl12. Rock1 antagonists or Rock1 shRNA abolished the enhanced migration of ITD-FLT3(+) cells toward Cxcl12. Our findings demonstrate that ITD-FLT3 increases cell migration toward Cxcl12 by antagonizing the down-regulation of Rock1 expression. These findings suggest that the aberrant modulation of Rock1 expression and activity induced by ITD-FLT3 may enhance acute myeloid leukemia cell chemotaxis to the therapy-protective bone marrow niche, where Cxcl12 is abundantly expressed. (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze:	MEDLINE
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