Understanding and Targeting Aberrant RNA Splicing in Leukemia - For the past 13 years my lab has sought to understand both the genetic basis of hematopoietic malignancies and the mechanisms through which mutations in splicing factors mediate oncogenesis. Our work on the genetic basis of myeloid and lymphoid leukemias has led to several advances, most notably (1) the discovery of the genetic alterations driving the development of systemic histiocytic neoplasms, findings which led to the U.S. FDA-approval of the first two treatments for patients affected by these disorders, (2) the identification of the cell-of-origin of hairy cell leukemia and demonstration of the efficacy of molecularly targeted therapy in this disease, and (3) the elucidation of the genetic causes of resistance to noncovalent inhibitors of Bruton’s Tyrosine Kinase (BTK) in patients with chronic lymphocytic leukemia (CLL) and subsequent early phase clinical trials which determined that BTK degraders are capable of overcoming these mutations . In parallel, my laboratory has focused on identifying the mechanisms by which altered RNA splicing drives the development of a wide range of myeloid and lymphoid malignancies characterized by somatic mutations in RNA splicing factors. Our work was responsible for the discovery that cancer-associated mutations in the RNA splicing machinery result in a neomorphic change of function. This discovery highlighted the concept of aberrant RNA splicing as a novel mechanism of oncogenesis and motivated the clinical development of therapies capable of targeting splicing factor mutant cells. This research is of major significance as mutations in RNA splicing factors are the single most common class of genetic alterations in patients with myelodysplastic syndrome (MDS) and are also very common in CLL, chronic myelomonocytic leukemia (CMML), myelofibrosis, and elderly patients with acute myeloid leukemia (AML). There are few effective FDA-approved therapies for patients with high-risk MDS, CMML, or elderly AML and, as such, developing means to target gain-of-function mutations present in >50% of such patients would be transformative. Currently my lab is exploring the exciting hypothesis that the neomorphic changes in RNA splicing produced by mutant RNA splicing factors leads to therapeutic liabilities which we can exploit to selectively target splicing factor-mutant cells. Specifically, in this R35 application we present a plan to solve three questions of both fundamental biological and therapeutic significance: (1) Do mutations in splicing factors lead to the production of therapeutically targetable neo- antigens derived from mis-spliced proteins? (2) Can we identify trans factors required for mis-splicing by mutant RNA splicing factors? (3) Can we identify protein isoforms unique to splicing factor mutant cells that are therapeutically targetable with small molecules? To address each of these questions we will utilize cutting-edge transcriptomic, immunogenomic, and chemoproteomic approaches to address each question. While ambitious, our extensive prior work and reagents to study mutant RNA splicing factors, in combination with a stellar group of collaborators places my laboratory in a unique position to address these questions.
