Impact of RPS15 mutations on the development and progression of chronic lymphocytic leukemia

Abstract

Large-scale sequencing of chronic lymphocytic leukemia (CLL) has uncovered vast genetic heterogeneity and novel putative CLL driver mutations, including in the ribosomal protein S15 (RPS15). RPS15, a component of the 40S subunit of the ribosome, is a part of the mRNA decoding site in actively translating ribosomes and has been directly implicated in the regulation of p53 stability via the MDMX/MDM2 axis. We generated a human CLL cell line harboring hotspot RPS15 mutations and a conditional knock-in mouse model of the most frequent RPS15-S138F mutation. We further modeled the common co-occurrence of RPS15 mutation and TP53 deletion identified in patient samples by developing ‘double-mutant’ cell lines and mice. Through this work, we demonstrated that RPS15 mutations alter B cell development, signaling and immune function. Comparative analysis at the transcriptional, translational and proteomic level revealed a strong upregulation of the MYC pathway in RPS15 mutant cells, possibly mediated by upregulation of Zap70. MYC activity increased further in the setting of TP53 deletion, suggesting that loss of TP53 enables RPS15 mutant-mediated MYC activation and disease development. Finally, we demonstrate that RPS15 and TP53 mutation alone can drive CLL-like disease, and that RPS15 and TP53 double mutants develop disease that is morphologically and functionally distinct from either mutation alone.