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- W2919643642 abstract "Abstract Quiescent (G0) cells are transient cell-cycle-arrested subpopulations in cancers that include dormant cancer stem cells. While leukemic stem cells/minimal-residual-disease were studied transcriptionally, their translation profile and post-transcriptional mechanisms that control their proteome—and thereby, survival—are unknown. We find G0 leukemic cells are chemoresistant, with altered canonical translation and similar proteome and translatome—rather than transcriptome—to cells isolated post-chemotherapy, implicating post-transcriptional regulation in chemoresistance. Mechanistically, we find DNA-damage-responsive-ATM and stress-activated-p38-MAPK/MK2 alter post-transcriptional mechanisms, regulating mRNA-decay-factor, TTP, to increase AU-rich-element-bearing mRNAs. This permits translation of AU-rich-element-bearing pro-inflammatory-cytokine TNFα, and immune modulators (CD47) that promote survival. Co-inhibiting p38-MAPK/MK2 and TNFα—prior to/alongwith chemotherapy—decreases chemoresistance in vivo and in patient samples. Disrupting TTP regulation reduces TNFα and chemoresistance, revealing TTP as a regulator of inflammation-mediated chemoresistance. These studies uncover a pro-inflammatory subpopulation in cancer that enables chemoresistance via DNA-damage- and stress-regulated post-transcriptional mechanisms, and develop a new combination therapy against chemo-survival. Statement of Significance These studies reveal the significance of post-transcriptional regulation of inflammatory/immune response in chemoresistance, mediated by AU-rich-elements, mRNA-decay-regulator TTP, and non-canonical translation. These results reveal DNA-damage/stress-induced TTP as a key regulator of inflammation-mediated chemoresistance and developed a new combination therapy to reduce resistance in cell lines, patient samples and in vivo." @default.
- W2919643642 created "2019-03-11" @default.
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- W2919643642 date "2019-03-01" @default.
- W2919643642 modified "2023-09-27" @default.
- W2919643642 title "CARDIAC TAMPONADE: AN UNCOMMON PRESENTATION OF COMMON INFLUENZA INFECTION" @default.
- W2919643642 doi "https://doi.org/10.1016/s0735-1097(19)33568-5" @default.
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