How a Ribosomal Mutation Paves the Way for Leukemia

We are thrilled to share our new study establishing mutant RPS15 as a bona fide driver of B-cell malignancy, now published in Nature Communications!

RPS15 is recurrently mutated in aggressive, relapsed CLL, yet how these mutations actually cause leukemia had remained unclear. Using an in vivo mouse model of the hotspot RPS15-S138F mutation, we show that mutant RPS15 disrupts ribosome biogenesis and rewires translation, triggering oxidative stress and DNA damage that initially activate a p53-dependent brake on cell proliferation. Over time, however, a subset of aged mice develop B-cell leukemia — tumors marked by elevated Myc activity and strong pro-survival signatures. The key insight is that mutant RPS15 creates a state of chronic genomic instability that sets the stage for secondary hits, such as TP53 deletion, that ultimately overcome the cell cycle block and unleash full malignancy.