Unknown,Transcriptomics,Genomics,Proteomics

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RIPK3 restricts myeloid leukemogenesis by promoting cell death and differentiation of leukemia initiating cells

ABSTRACT: Examination of gene expression patterns in lineage negative FLT3-ITDâ and pMIG-transduced BM cells via microarray study. We performed a global mRNA profiling analysis of murine Linâ FLT3-ITD+ cells compared to empty-vector controls, purified 48h after transduction. We examined association patterns of FLT3-ITD and pMIG cells and identified a specific gene expression signature associated with FLT3-ITD signalling. Total RNA obtained from isolated lineage negative BM cells subjected to 48h of FLT3-ITD signalling compared to empty vector control.

ORGANISM(S): Mus musculus

SUBMITTER: Philipp Jost

PROVIDER: E-GEOD-79040 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells.

Höckendorf Ulrike U Yabal Monica M Herold Tobias T Munkhbaatar Enkhtsetseg E Rott Stephanie S Jilg Stefanie S Kauschinger Johanna J Magnani Giovanni G Reisinger Florian F Heuser Michael M Kreipe Hans H Sotlar Karl K Engleitner Thomas T Rad Roland R Weichert Wilko W Peschel Christian C Ruland Jürgen J Heikenwalder Mathias M Spiekermann Karsten K Slotta-Huspenina Julia J Groß Olaf O Jost Philipp J PJ

Cancer cell 20160701 1

Since acute myeloid leukemia (AML) is characterized by the blockade of hematopoietic differentiation and cell death, we interrogated RIPK3 signaling in AML development. Genetic loss of Ripk3 converted murine FLT3-ITD-driven myeloproliferation into an overt AML by enhancing the accumulation of leukemia-initiating cells (LIC). Failed inflammasome activation and cell death mediated by tumor necrosis factor receptor caused this accumulation of LIC exemplified by accelerated leukemia onset in Il1r1(- ...[more]

PMID: 27411587

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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

Dataset Information

RIPK3 restricts myeloid leukemogenesis by promoting cell death and differentiation of leukemia initiating cells

Publications

RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells.

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