Ribosome changes elicit non-canonical translation for chemosurvival in G0 leukemic cells

Abstract

AbstractQuiescent leukemic cells survive chemotherapy, with translation changes. Our data reveal that FXR1, a protein amplified in several aggressive cancers, increases in quiescent and chemo- treated leukemic cells, and promotes chemosurvival. This suggests undiscovered roles for this RNA- and ribosome-associated protein in chemosurvival. FXR1 depletion decreases translation and ribosome subunits, with altered rRNAs, snoRNAs, and ribosomal proteins (RPs). We find that FXR1 binds factors that promote ribosome gene transcription and bind snoRNAs. Ribosome changes increased in FXR1-overexpressing cells, including increased snoRNAs and RPLP0/uL10, activate eIF2α kinases. Accordingly, phospho-eIF2α increases, enabling non- canonical translation of survival and immune regulators in FXR1-overexpressing cells. Overriding these with inhibitors reduces chemosurvival. Thus, increased FXR1 in quiescent or chemo-treated leukemic cells, alters ribosomes that trigger stress signals to re-direct translation for chemosurvival.One Sentence SummaryFXR1 alters ribosomes in G0, which induce stress signals to elicit noncanonical translation for AML drug and immune survival.