Ribosomal Protein L22 Loss Predisposes Stem Cells to Transformation By Altering Metabolism

While mutations in ribosomal proteins (RP) have long been associated with increased cancer risk, the molecular basis for this association remains unclear. The prevailing view is that mutations in RP increase cancer risk either by impairing the biogenesis or function of the ribosome. Here, we report that loss of the RP, Rpl22, is frequently observed in human myelodysplastic syndrome (MDS) and is associated with reduced survival in acute myelogenous leukemia (AML). The link between Rpl22 loss and aggressiveness of myeloid disease is causal, since it is replicated in mice lacking Rpl22. Importantly, the development of an MDS-like syndrome in Rpl22-deficient mice and the accelerated development of myeloid leukemia are not caused by reduced protein synthesis in hematopoietic stem cells (HSC). Instead, whole transcriptome analysis of HSC reveals that Rpl22 loss alters the expression of genes controlling cell metabolism and results in an increase in fatty acid oxidation. Moreover, the increased fatty acid oxidation is required for the increased self-renewal and reduced differentiation displayed by Rpl22-deficient HSC, as well as the survival of Rpl22-deficient myeloid leukemia cells. Together, these findings indicate that RP are capable of suppressing transformation potential in ways that do not involve effects on global protein synthesis. Indeed, Rpl22 suppresses transformation by suppressing lipid oxidation, suggesting that MDS and AML patients with reduced Rpl22 expression might benefit from pharmacologic interventions targeting lipid oxidation.