Ribosome changes reprogram translation for chemosurvival in G0 leukemic cells
Menée in vitro, cette étude met en évidence un mécanisme par lequel la forte expression de la protéine FXR1 dans les cellules leucémiques quiescentes ou traitées chimiquement altère les ribosomes et déclenche par leur intermédiaire des signaux de stress qui redirigent les programmes traductionnels pour assurer la survie des cellules cancéreuses
Quiescent leukemic cells survive chemotherapy, with translation changes. Our data reveal that FXR1, a protein amplified in several aggressive cancers, is elevated in quiescent and chemo-treated leukemic cells and promotes chemosurvival. This suggests undiscovered roles for this RNA- and ribosome-associated protein in chemosurvival. We find that FXR1 depletion reduces translation, with altered rRNAs, snoRNAs, and ribosomal proteins (RPs). FXR1 regulates factors that promote transcription and processing of ribosomal genes and snoRNAs. Ribosome changes in FXR1-overexpressing cells, including RPLP0/uL10 levels, activate eIF2α kinases. Accordingly, phospho-eIF2α increases, enabling selective translation of survival and immune regulators in FXR1-overexpressing cells. Overriding these genes or phospho-eIF2α with inhibitors reduces chemosurvival. Thus, elevated FXR1 in quiescent or chemo-treated leukemic cells alters ribosomes that trigger stress signals to redirect translation for chemosurvival. Modification of ribosomal properties in therapy-treated AML drives production of survival proteins and thereby AML survival.
Science Advances 2022