Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profile of mock and FLT3-ITD-expressing K562 cells.

ABSTRACT: We used whole genome microarray expression profiling as a discovery platform to identify genes regulated by FLT3-ITD activity. Viral particles with pMY-puro, pMY-puro-FLT3-ITD-1 or pMY-puro-FLT3-ITD-2, were generated using PLAT-gp packaging cells and infected to K562 cells. The vector-transduced cells were selected with 2µg/ml puromycin treatment.

ORGANISM(S): Homo sapiens

SUBMITTER: Anar Damdinsuren

PROVIDER: E-GEOD-64330 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Transcriptional profiling of murine bone marrow c-kit+, Sca-1+ lineage neative (KSL) cells from p21CDKN1a-/- and p21+/+ overexpressing Flt3/ITD. The goal was to determine the effect on global gene expression by loss of p21 in Flt3/ITD transformed KSL cells Internal tandem duplication (ITD) mutations in the Flt3 gene (Flt3-ITD) are associated with poor prognosis in patients with acute myeloid leukemia (AML). Few inhibitors of Flt3-ITD are effective against Flt3-ITD+ AML due to the development of drug-resistance. In this study, we demonstrate 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 drug resistance. Flt3-ITD up-regulated p21 expression in mouse bone marrow c-kit+-Sca-1+-Lin- (KSL) cells and in Ba/F3 cells. Loss of p21 expression enhanced growth factor-independent proliferation and sensitivity to cytarabine as a consequence of enriching the S+G2/M phase population concomitant with a significant increase in the expression of Pbx1, but not Evi-1, in Flt3-ITD+ cells. This enhancement of cell proliferation by loss of p21 was partially abrogated when Pbx1 expression was silenced in Flt3-ITD+ primary bone marrow colony-forming cells (CFCs) and Ba/F3 cells. Antagonizing Flt3-ITD using AC220, a selective inhibitor of Flt3-ITD, decreased the expression of p21, coincident with the up-regulation of Pbx1 mRNA 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 refractory to AC220, whereas silencing p21 accelerated their development. These data demonstrate that Flt3-ITD is capable of inhibiting the proliferation of Flt3-ITD+ cells through the p21/Pbx1 axis and that antagonizing Flt3-ITD contributes to the subsequent development of cells refractory to Flt3-ITD inhibitor by disrupting p21 expression. biological replicates: 3 KSL cell replicates overexpressing ITD-Flt3 from p21+/+ and p21-/- cells, 1 KSL cell replicate from p21+/+ and p21-/- cells

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Gene expression profile of mock and FLT3-ITD-expressing K562 cells.

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