Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism

Harris, B.; Singh, D. K.; Verma, M.; Fahl, S. P.; Rhodes, M.; Sprinkle, S. R.; Wang, M.; Zhang, Y.; Perrigoue, J.; Kessel, R.; Peri, S.; West, J.; Giricz, O.; Boultwood, J.; Pellagatti, A.; Ramesh, K.; Montangna, C.; Pradhan, K.; Tyner, J.; Kennedy, B. K.; Holinstat, M.; Steidl, U.; Sykes, S.; Verma, A.; Wiest, D. L.

doi:10.1101/2023.05.31.543132

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bioRxiv · 10.1101/2023.05.31.543132

Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism

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Abstract

We report here that expression of the ribosomal protein, RPL22, is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); and, reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from altered metabolism including increased fatty acid oxidation (FAO) and a striking induction of the stemness factor Lin28b in the resulting leukemia. Lin28b promotes a substantial increase in lipid content, upon which the survival of Rpl22-deficient leukemias depends. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSC through regulation of FAO and promotes leukemogenesis through Lin28b promotion of lipid synthesis. HighlightsO_LIRPL22 insufficiency is observed in MDS/AML and is associated with reduced survival C_LIO_LIRpl22-deficiency produces an MDS-like syndrome and facilitates leukemogenesis C_LIO_LIRpl22-deficiency does not impair global protein synthesis by HSC C_LIO_LIRpl22 controls leukemia survival through control of lipid synthesis C_LI eTOC: Rpl22 controls the function and transformation potential of hematopoietic stem cells through regulation of lipid metabolism.

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Harris, B., Singh, D. K., Verma, M., Fahl, S. P., Rhodes, M., Sprinkle, S. R., Wang, M., Zhang, Y., Perrigoue, J., Kessel, R., Peri, S., West, J., Giricz, O., Boultwood, J., Pellagatti, A., Ramesh, K., Montangna, C., Pradhan, K., Tyner, J., Kennedy, B. K., Holinstat, M., Steidl, U., Sykes, S., Verma, A., Wiest, D. L.. 2023-06-01. Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism. https://doi.org/10.1101/2023.05.31.543132

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