[R35] Understanding and Targeting Aberrant RNA Splicing in Leukemia
Ente: National Cancer Institute
Scadenza: 2032-07-31
Importo max: 1.015.176 EUR
Paese: US
Descrizione
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.
Istituzione: SLOAN-KETTERING INST CAN RESEARCH
PI: Omar Abdel-Wahab
Progetto: 5R35CA304457-02
Settori: National Cancer Institute
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