Ribosomal protein mutations are increasingly associated with cancer risk and thought to perturb ribosome function. At the same time, they reportedly activate p53, a critical anti-cancer barrier. To determine how these mutations overcome this protective block to enable tumorigenesis, we generate an in vivo model of the hotspot ribosomal protein RPS15-S138F mutation identified as a putative driver of chronic lymphocytic leukemia. Under pre-leukemic conditions, this mutation induces ribosome biogenesis defects and altered translation resulting in oxidative stress, DNA damage and induction of a p53-dependent response that promote initial cellular hypo-proliferation. However, a subset of aged mice with mutated Rps15 eventually develop B-cell leukemia (37% penetrance), which exhibits increased Myc activity with strong pro-survival and proliferation signatures. Mutant RPS15 thus induces both hypo- and hyper-proliferative signals, initially weighted towards cell cycle arrest; and that through translational rewiring, oxidative stress, DNA damage response defects and genomic instability set the stage for the acquisition of additional driving mutations, such as TP53 deletion, that can overcome this cell cycle block to trigger tumorigenesis. Ribosomal Protein S15 (RPS15) is recurrently mutated in B-cell leukemia but its leukemogenic role remains unclear. Here, the authors establish mutant RPS15 as a cancer driver and reveal mechanisms by which these mutations induce translational defects, DNA damage and genomic instability that together promote leukemogenesis.
Gutierrez et al. (Mon,) studied this question.