Internal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cells

dc.contributor.authorAbe, Mariko
dc.contributor.authorPelus, Louis M.
dc.contributor.authorSingh, Pratibha
dc.contributor.authorHirade, Tomohiro
dc.contributor.authorOnishi, Chie
dc.contributor.authorPurevsuren, Jamiyan
dc.contributor.authorTaketani, Takeshi
dc.contributor.authorYamaguchi, Seiji
dc.contributor.authorFukuda, Seiji
dc.contributor.departmentDepartment of Microbiology and Immunology, IU School of Medicineen_US
dc.date.accessioned2017-05-30T15:33:54Z
dc.date.available2017-05-30T15:33:54Z
dc.date.issued2016
dc.description.abstractInternal 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.en_US
dc.eprint.versionFinal published versionen_US
dc.identifier.citationAbe, M., Pelus, L. M., Singh, P., Hirade, T., Onishi, C., Purevsuren, J., … Fukuda, S. (2016). Internal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cells. PLoS ONE, 11(7), e0158290. http://doi.org/10.1371/journal.pone.0158290en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttps://hdl.handle.net/1805/12776
dc.language.isoen_USen_US
dc.publisherPublic Library of Science (PLoS)en_US
dc.relation.isversionof10.1371/journal.pone.0158290en_US
dc.relation.journalPloS Oneen_US
dc.rightsAttribution 3.0 United States
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/
dc.sourcePMCen_US
dc.subjectGene Expressionen_US
dc.subjectBone Marrow Cellsen_US
dc.subjectCell Proliferationen_US
dc.subjectCell Cycle and Cell Divisionen_US
dc.subjectGrowth Factorsen_US
dc.subjectAcute Myeloid Leukemiaen_US
dc.subjectGene Regulationen_US
dc.subjectSignal Inhibitionen_US
dc.titleInternal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cellsen_US
dc.typeArticleen_US
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