title: RNA binding protein MSI2 positively regulates FLT3 expression in myeloid leukemia.
abstract: FLT3 is frequently mutated and overexpressed in acute myelogenous leukemia (AML) and other hematologic malignancies. Although signaling events downstream of FLT3 receptor tyrosine kinase have been studied in depth, molecular mechanisms of how FLT3 expression is regulated at the post-transcriptional level in particular remain elusive. In this study, we investigated the roles of an RNA binding protein MSI2 as a regulator of FLT3 expression. MSI2 and FLT3 are significantly co-regulated in human AML and chronic myelogenous leukemia in blast crisis (BC-CML). Genetic loss of MSI2 leads to down-regulation of the FLT3 receptor in both AML and BC-CML cells and concomitant impairment of clonogenic growth potential. Furthermore, we demonstrate that MSI2 protein is physically bound to FLT3 mRNA transcripts, suggesting post-transcriptional control of FLT3 expression. Collectively, these results reveal a novel mode of FLT3 regulation essential for leukemia growth, which may aid in designing a targeted therapy to treat human myeloid leukemia.
authors.affiliation: Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, and UGA Cancer Center, The University of Georgia, Athens, GA 30602, United States.
authors.forename: Ayuna
authors.initials: A
authors.lastname: Hattori
authors.affiliation: Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, and UGA Cancer Center, The University of Georgia, Athens, GA 30602, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: McSkimming
authors.affiliation: Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, and UGA Cancer Center, The University of Georgia, Athens, GA 30602, United States.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Kannan
authors.affiliation: Department of Biochemistry and Molecular Biology, Franklin College of Arts and Sciences, and UGA Cancer Center, The University of Georgia, Athens, GA 30602, United States. Electronic address: ito@bmb.uga.edu.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ito
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016601:RNA-Binding Proteins / Q000502:physiology*; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C438151:MSI2 protein, human; D016601:RNA-Binding Proteins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3
keywords: Acute myelogenous leukemia; Chronic myelogenous leukemia; FLT3; Post-transcriptional regulation; RNA binding proteins