title: FLT3-ITD drives Ara-C resistance in leukemic cells via the induction of RUNX3.
abstract: Internal tandem duplication (ITD) mutations of the FLT3 gene (FLT3-ITD) are well known to correlate with a poor prognosis in acute myeloid leukemia (AML). We previously reported that FLT3-ITD confers resistance to cytosine arabinoside (Ara-C), a key cytotoxic agent in AML treatments. In order to elucidate the detailed molecular mechanisms underlying the Ara-C resistance induced by FLT3-ITD, we performed a microarray gene expression analysis of the human leukemic cell line K562 transduced with FLT3-ITD (K562/FLT3-ITD) and identified RUNX3 as a downstream target of FLT3-ITD. The transcriptional induction of the RUNX3 expression by FLT3-ITD was noted on a Luciferase assay. The knockdown of the RUNX3 expression in the K562/FLT3-ITD cells increased the sensitivity to Ara-C, and the exogenous expression of RUNX3 per se resulted in the enhancement of Ara-C resistance in the K562 cells. A relationship between the FLT3-ITD-induced RUNX3 expression and Ara-C resistance was also observed in AML cells with an endogenous FLT3-ITD expression. Collectively, these findings demonstrate that RUNX3 is a prerequisite for Ara-C resistance via FLT3-ITD signaling.
authors.affiliation: Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Anar
authors.initials: A
authors.lastname: Damdinsuren
authors.affiliation: Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan. Electronic address: hmatsu@is.icc.u-tokai.ac.jp.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Matsushita
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Ito
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Guilan
authors.initials: G
authors.lastname: Jin
authors.affiliation: Support Center for Medical Research and Education, Tokai University, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Asai
authors.affiliation: Division of Hematology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Miyachi
mesh_terms: D045744:Cell Line, Tumor; D050677:Core Binding Factor Alpha 3 Subunit / Q000502:physiology*; D003561:Cytarabine / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020080:Tandem Repeat Sequences; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000502:physiology*
chemical_list: C581634:BCR-ABL1 fusion protein, human; D050677:Core Binding Factor Alpha 3 Subunit; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C493729:Runx3 protein, human; D003561:Cytarabine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D016044:Fusion Proteins, bcr-abl
keywords: Ara-C; Chemotherapy-resistance; FLT3-ITD; RUNX3