Impact of RPS15 mutation on development and progression of chronic lymphocytic leukemia
Mentor: Catherine Ju-Ying Wu, M.D. (Dana Farber Cancer Institute)
It is increasingly understood that ribosomes play a dynamic and highly regulated role in the cell. Their numerous functions in modulating the cell cycle, migration, metabolism and cell growth, as well as the heterogeneity and plasticity reported in ribosomal composition and function, make them a growing area of interest to the cancer research community. Recent studies have introduced the possibility of there being an“oncogenic ribosome” driving cancer development and progression, namely because of the many ribosomal proteins that have been frequently found to be mutated across different cancer types. In chronic lymphocytic leukemia (CLL), for example, a specific mutation of the RPS15 gene, located in the 40S ribosomal subunit, has been found to be identified in ~5% of all CLL patients, and in ~20% of patients who have relapsed after fludarabine, cyclophosphamide and rituximab (FCR) therapy. The Wu lab has developed a novel, conditional knock-in mouse model to study the effects of mutated RPS15 on B cell biology (such as its impact on ribosomal function and translation of mRNA) and on CLL development and progression. We will assess the effects of this mutation in -vivo by longitudinally studying mice with B cell-restricted expression of mutated RPS15 alone or in combination with other common CLL-associated genetic aberrations, so as to determine whether this mutation alone can drive the development of CLL, or whether it affects the latency and penetrance of CLL when combined with other mutations. To monitor the state of disease of these mice we will use flow cytometric detection of the CLL surface markers, B220+ and CD5+, as well as measure the clonality of any CLL that arises (by measuring IgK+ expression). Characterizing the impact of RPS15 mutation on tumor development, progression and drug resistance will have broad implications applicable across cancers, and will further provide insight on the role of RPs and their mutations in cancer, relapse, and chemotherapeutic resistance. Additionally, this work may identify novel therapeutic targets that may be leveraged in the clinic.
Mouse models of RPS15 mutation with and without other known CLL-inducing aberrations. Source: