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

Chie Onish, Satomi Mori-Kimachi, Tomohiro Hirade, Mariko Abe, Takeshi Taketani, Junji Suzumiya, Toshitsugu Sugimoto, Seiji Yamaguchi, Reuben Kapur, Seiji Fukuda

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)31053-31065
Number of pages13
JournalJournal of Biological Chemistry
Volume289
Issue number45
DOIs
StatePublished - Nov 7 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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