Onish, ChieMori-Kimachi, SatomiHirade, TomohiroAbe, MarikoTaketani, TakeshiSuzumiya, JunjiSugimoto, ToshitsuguYamaguchi, SeijiKapur, ReubenFukuda, Seiji2016-10-192016-10-192014-11-07Onish, C., Mori-Kimachi, S., Hirade, T., Abe, M., Taketani, T., Suzumiya, J., … Fukuda, S. (2014). 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. The Journal of Biological Chemistry, 289(45), 31053–31065. http://doi.org/10.1074/jbc.M114.5682871083-351Xhttps://hdl.handle.net/1805/11199Internal 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.en-USPublisher PolicyChemokine CXCL12geneticsMutationReceptors, CXCR4metabolismfms-Like Tyrosine Kinase 3rho-Associated KinasesArticle