FLT3-ITD drives Ara-C resistance in leukemic cells via the induction of RUNX3

Anar Damdinsuren; Hiromichi Matsushita; Masatoshi Ito; Masayuki Tanaka; Guilan Jin; Hideo Tsukamoto; Satomi Asai; Kiyoshi Ando; Hayato Miyachi

doi:10.1016/j.leukres.2015.09.009

FLT3-ITD drives Ara-C resistance in leukemic cells via the induction of RUNX3

Anar Damdinsuren, Hiromichi Matsushita, Masatoshi Ito, Masayuki Tanaka, Guilan Jin, Hideo Tsukamoto, Satomi Asai, Kiyoshi Ando, Hayato Miyachi

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1405-1413
Number of pages	9
Journal	Leukemia Research
Volume	39
Issue number	12
DOIs	https://doi.org/10.1016/j.leukres.2015.09.009
Publication status	Published - 2014 Dec 31
Externally published	Yes

Keywords

Ara-C
Chemotherapy-resistance
FLT3-ITD
RUNX3

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.leukres.2015.09.009

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@article{6079b707027d4a7abdf34758fab59fca,

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.",

keywords = "Ara-C, Chemotherapy-resistance, FLT3-ITD, RUNX3",

author = "Anar Damdinsuren and Hiromichi Matsushita and Masatoshi Ito and Masayuki Tanaka and Guilan Jin and Hideo Tsukamoto and Satomi Asai and Kiyoshi Ando and Hayato Miyachi",

note = "Funding Information: This work was supported by a School of Medicine Research Grant from Tokai University (A. D.) , the Kurozumi Medical Foundation (Hi.M.) , the Charitable Trust Laboratory Medicine Research Foundation of Japan (Hi. M.) and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Ha. M.) (No. 24590709 ). Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd.",

year = "2014",

month = dec,

day = "31",

doi = "10.1016/j.leukres.2015.09.009",

language = "English",

volume = "39",

pages = "1405--1413",

journal = "Leukemia Research",

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number = "12",

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TY - JOUR

T1 - FLT3-ITD drives Ara-C resistance in leukemic cells via the induction of RUNX3

AU - Damdinsuren, Anar

AU - Matsushita, Hiromichi

AU - Ito, Masatoshi

AU - Tanaka, Masayuki

AU - Jin, Guilan

AU - Tsukamoto, Hideo

AU - Asai, Satomi

AU - Ando, Kiyoshi

AU - Miyachi, Hayato

N1 - Funding Information: This work was supported by a School of Medicine Research Grant from Tokai University (A. D.) , the Kurozumi Medical Foundation (Hi.M.) , the Charitable Trust Laboratory Medicine Research Foundation of Japan (Hi. M.) and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Ha. M.) (No. 24590709 ). Publisher Copyright: © 2015 Elsevier Ltd.

PY - 2014/12/31

Y1 - 2014/12/31

N2 - 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.

AB - 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.

KW - Ara-C

KW - Chemotherapy-resistance

KW - FLT3-ITD

KW - RUNX3

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UR - http://www.scopus.com/inward/citedby.url?scp=84951106339&partnerID=8YFLogxK

U2 - 10.1016/j.leukres.2015.09.009

DO - 10.1016/j.leukres.2015.09.009

M3 - Article

C2 - 26475207

AN - SCOPUS:84951106339

SN - 0145-2126

VL - 39

SP - 1405

EP - 1413

JO - Leukemia Research

JF - Leukemia Research

IS - 12

ER -

FLT3-ITD drives Ara-C resistance in leukemic cells via the induction of RUNX3

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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