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

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

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rho-Associated Kinases
Chemotaxis
Down-Regulation
Genes
Mutation
Proteins
Cell Movement
Acute Myeloid Leukemia
Bone Marrow
Bone
Gene Expression
Phosphorylation
Myeloid Cells
Chemokines

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

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

In: Journal of Biological Chemistry, Vol. 289, No. 45, 07.11.2014, p. 31053-31065.

Research output: Contribution to journalArticle

Onish, Chie ; Mori-Kimachi, Satomi ; Hirade, Tomohiro ; Abe, Mariko ; Taketani, Takeshi ; Suzumiya, Junji ; Sugimoto, Toshitsugu ; Yamaguchi, Seiji ; Kapur, Reuben ; Fukuda, Seiji. / 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. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 45. pp. 31053-31065.
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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.",
author = "Chie Onish and Satomi Mori-Kimachi and Tomohiro Hirade and Mariko Abe and Takeshi Taketani and Junji Suzumiya and Toshitsugu Sugimoto and Seiji Yamaguchi and Reuben Kapur and Seiji Fukuda",
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AU - Mori-Kimachi, Satomi

AU - Hirade, Tomohiro

AU - Abe, Mariko

AU - Taketani, Takeshi

AU - Suzumiya, Junji

AU - Sugimoto, Toshitsugu

AU - Yamaguchi, Seiji

AU - Kapur, Reuben

AU - Fukuda, Seiji

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