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Exploiting Vulnerabilities in RNA Splicing to Treat Hematologic Malignancies

Dr. Timothy Graubert

Timothy Graubert


Massachusetts General Hospital

Project Term: October 1, 2021 - September 30, 2026

RNA splicing is a central metabolic pathway that is frequently perturbed in hematopoietic malignancies (HMs) that harbor mutations in spliceosome components (most commonly affecting SRSF2, SF3B1, U2AF1, or ZRSR2). These mutations are particularly prevalent in myeloid malignancies (e.g., MDS, MDS/MPN, sAML), but recent pan-cancer studies have implicated aberrant splicing in >30 tumor types. The Project Leaders have probed the molecular consequences of aberrant splicing and identified critical pathways that are amenable to targeted inhibition, including the DNA damage response (Graubert/Walter), the nonsense-mediated RNA decay (NMD) pathway (You/Walter), the spliceosome itself (Abdel-Wahab/Walter/Graubert), and others. To date, effective therapies for HMs have not capitalized on these unique vulnerabilities. The goal of this SCOR is to generate testable clinical hypotheses based on careful mechanistic studies in pre-clinical models and to rapidly move these ideas into the clinic in the near term.

Lay Abstract

Many blood cancers (e.g. myelodysplastic syndromes, chronic myelomonocytic leukemia and acute myeloid leukemia) have mutations in spliceosome genes (e.g. SF3B1, SRSF2 and U2AF1) that control RNA splicing in cells. This SCOR will employ complementary approaches to identify and exploit vulnerabilities created by splicing factor mutations. Project 1 will build on our observation that cells with splicing factor mutations are sensitive to inhibition of an enzyme called ATR. Project 2 will capitalize on the observation that cells with splicing factor mutations produce nonsense mRNAs harboring premature translation termination codons due to mis-splicing, rendering them sensitive to inhibition of the RNA surveillance pathway called nonsense-mediated RNA decay (NMD). Project 3 has discovered that myeloid malignancies with splicing factor mutations are dependent on the RNA-binding protein RBM39 for their survival and will test the impact of RBM39 degraders in preclinical models and in the clinic. The SCOR is supported by cores which provide expertise in genomics and mouse models of myeloid malignancies. Collectively, this team will build the preclinical rationale to launch multiple clinical trials testing novel therapies for patients with splicing factor mutant blood cancers.

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