Translated genes in G0, the post-transcriptional mechanisms involved, and outcomes on cancer persistence remain to be investigated. These data suggest that alternate post-transcriptional mechanisms in G0 cancer cells may regulate a distinct translatome to mediate their resistance. Our previous data demonstrated that translation mechanisms are distinct in G0 leukemic cells, with decreased canonical translation mechanisms and increase in alternative mechanisms that involve non-canonical translation initiation factors and 3вЂІUTR-mediated specific mRNA translation. Altered polyadenylation site selection on mRNAs produces longer 3вЂІ-untranslated regions (3вЂІUTRs) in G0 compared to proliferating cells-which increases 3вЂІUTR elements that can mediate post-transcriptional gene expression regulation. Analyses from multiple groups revealed some genes upregulated at the transcriptional level. G0 cells show specific gene expression that may underlie their resistance and other properties. Such cells are anti-proliferative, anti-differentiation, and anti-apoptotic and show distinct properties including resistance to harsh conditions. Quiescent (G0) cells are an assortment of reversibly arrested cells, including dormant stem cells, which are found as a clinically relevant subpopulation in cancers. Furthermore, co-inhibiting p38 MAPK and TNFО± prior to or along with chemotherapy substantially reduces chemoresistance in primary leukemic cells ex vivo and in vivo. Conversely, inhibition of TTP phosphorylation by p38 MAPK inhibitors and non-phosphorylatable TTP mutant decreases ARE-bearing TNFО± and DUSP1 mRNAs and sensitizes leukemic cells to chemotherapy. This permits expression of ARE mRNAs that promote chemoresistance. Mechanistically, we find the stress-responsive p38 MAPK-MK2 signaling pathway stabilizes ARE mRNAs by phosphorylation and inactivation of mRNA decay factor, Tristetraprolin (TTP) in G0.

Importantly, AU-rich elements (AREs) are significantly enriched in the upregulated G0 translatome and transcriptome. In G0 cells, canonical translation initiation is inhibited yet we find that inflammatory genes are highly translated, indicating alternative post-transcriptional regulation. We find that our resistant G0 cells recapitulate gene expression profiles of in vivo chemoresistant leukemic and G0 models. To study post-transcriptional regulation in G0 leukemic cells, we systematically analyzed their transcriptome, translatome, and proteome. We induce chemoresistant and G0 leukemic cells by serum starvation or chemotherapy treatment.

Program kasir assembler