Internal tandem duplication in FLT3 attenuates proliferation and regulates resistance to the FLT3 inhibitor AC220 by modulating p21Cdkn1a and Pbx1 in hematopoietic cells

Mariko Abe, Louis Pelus, Pratibha Singh, Tomohiro Hirade, Chie Onishi, Jamiyan Purevsuren, Takeshi Taketani, Seiji Yamaguchi, Seiji Fukuda

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Internal tandem duplication (ITD) mutations in the Fms-related tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor prognosis in patients with acute myeloid leukemia (AML). Due to the development of drug resistance, few FLT3-ITD inhibitors are effective against FLT3-ITD+ AML. In this study, we show that FLT3-ITD activates a novel pathway involving p21Cdkn1a (p21) and pre-B cell leukemia transcription factor 1 (Pbx1) that attenuates FLT3-ITD cell proliferation and is involved in the development of drug resistance. FLT3-ITD up-regulated p21 expression in both mouse bone marrow c-kit+-Sca-1+-Lin- (KSL) cells and Ba/F3 cells. The loss of p21 expression enhanced growth factor-independent proliferation and sensitivity to cytarabine as a consequence of concomitantly enriching the S+G2/M phase population and significantly increasing the expression of Pbx1, but not Evi-1, in FLT3-ITD+ cells. This enhanced cell proliferation following the loss of p21 was partially abrogated when Pbx1 expression was silenced in FLT3-ITD+ primary bone marrow colony-forming cells and Ba/F3 cells. When FLT3-ITD was antagonized with AC220, a selective inhibitor of FLT3-ITD, p21 expression was decreased coincident with Pbx1 mRNA up-regulation and a rapid decline in the number of viable FLT3-ITD+ Ba/F3 cells; however, the cells eventually became refractory to AC220. Overexpressing p21 in FLT3-ITD+ Ba/F3 cells delayed the emergence of cells that were refractory to AC220, whereas p21 silencing accelerated their development. These data indicate that FLT3-ITD is capable of inhibiting FLT3-ITD+ cell proliferation through the p21/Pbx1 axis and that treatments that antagonize FLT3-ITD contribute to the subsequent development of cells that are refractory to a FLT3-ITD inhibitor by disrupting p21 expression.

Original languageEnglish (US)
Article numbere0158290
JournalPLoS One
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2016

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Cell proliferation
Refractory materials
Bone
Cytarabine
cells
Pharmaceutical Preparations
Protein-Tyrosine Kinases
Intercellular Signaling Peptides and Proteins
Transcription Factors
Genes
cell proliferation
myeloid leukemia
Cells
Cell Proliferation
drug resistance
Messenger RNA
Drug Resistance
Acute Myeloid Leukemia
bone marrow
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Internal tandem duplication in FLT3 attenuates proliferation and regulates resistance to the FLT3 inhibitor AC220 by modulating p21Cdkn1a and Pbx1 in hematopoietic cells. / Abe, Mariko; Pelus, Louis; Singh, Pratibha; Hirade, Tomohiro; Onishi, Chie; Purevsuren, Jamiyan; Taketani, Takeshi; Yamaguchi, Seiji; Fukuda, Seiji.

In: PLoS One, Vol. 11, No. 7, e0158290, 01.07.2016.

Research output: Contribution to journalArticle

Abe, Mariko ; Pelus, Louis ; Singh, Pratibha ; Hirade, Tomohiro ; Onishi, Chie ; Purevsuren, Jamiyan ; Taketani, Takeshi ; Yamaguchi, Seiji ; Fukuda, Seiji. / Internal tandem duplication in FLT3 attenuates proliferation and regulates resistance to the FLT3 inhibitor AC220 by modulating p21Cdkn1a and Pbx1 in hematopoietic cells. In: PLoS One. 2016 ; Vol. 11, No. 7.
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AU - Abe, Mariko

AU - Pelus, Louis

AU - Singh, Pratibha

AU - Hirade, Tomohiro

AU - Onishi, Chie

AU - Purevsuren, Jamiyan

AU - Taketani, Takeshi

AU - Yamaguchi, Seiji

AU - Fukuda, Seiji

PY - 2016/7/1

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