title: 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.
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.
authors.affiliation: From the Departments of Oncology/Hematology and mikami@med.shimane-u.ac.jp.
authors.forename: Chie
authors.initials: C
authors.lastname: Onishi
authors.affiliation: From the Departments of Oncology/Hematology and mikami@med.shimane-u.ac.jp.
authors.forename: Chie
authors.initials: C
authors.lastname: Onish
authors.affiliation: Pediatrics and.
authors.forename: Satomi
authors.initials: S
authors.lastname: Mori-Kimachi
authors.affiliation: Pediatrics and.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Hirade
authors.affiliation: Pediatrics and.
authors.forename: Mariko
authors.initials: M
authors.lastname: Abe
authors.affiliation: Pediatrics and the Division of Blood Transfusion, Shimane University Hospital, 693-8501 Izumo, Japan, and.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Taketani
authors.affiliation: From the Departments of Oncology/Hematology and.
authors.forename: Junji
authors.initials: J
authors.lastname: Suzumiya
authors.affiliation: First Department of Internal Medicine, Shimane University School of Medicine, Izumo 693-8501, Japan.
authors.forename: Toshitsugu
authors.initials: T
authors.lastname: Sugimoto
authors.affiliation: Pediatrics and.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: the Department of Pediatrics and the Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Pediatrics and sfukuda@med.shimane-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000235:genetics*; D002633:Chemotaxis; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010641:Phenotype; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases
keywords: CXCL12; CXCR4; Cell Biology; Gene Regulation; Hematopoiesis; ITD-Flt3; Leukemia; Rho-associated Kinase; Signal Transduction