Mutations in splicing factors (SF) are highly enriched in a variety of cancer types, particularly myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL), in addition to solid tumors such as uveal melanoma. Our group has identified that cells bearing SF mutations cannot tolerate further perturbations to splicing catalysis and, consistent with this, we have identified that spliceosomal mutant cancer cells are preferentially sensitive to small molecules that disrupt pre-mRNA splicing. While the above effort has resulted in an ongoing phase I clinical trial of a spliceosome modulatory compound for patients with refractory myeloid leukemias, we do not currently know the safety or efficacy of pharmacologic modulation of core spliceosome function. To this end, our group has also recently identified that inhibiting spliceosomal assembly through inhibition of arginine methylation of Sm proteins provides an alternate means of therapeutic splicing inhibition. We have identified that inhibiting either symmetric arginine methylation (mediated by the protein arginine methyltransferase 5 (PRMT5)) or asymmetric dimethyl arginine methylation (mediated by type I PRMTs (PRMT1, 4, and 6)) reduces splicing fidelity resulting in strong preferential killing of SF-mutant leukemias over their wildtype counterparts. Here we aim to determine if in leukemia, SF-mutations portend greater vulnerability to a ?second hit? targeting splicing through inhibition of type I (PRMT1/4/6) and/or type II (PRMT5) PRMTs.
In Aim 1 we will define the therapeutic potential of inhibiting PRMT5, type I PRMTs, and core spliceosome function, alone or together in leukemia models with or without a SF mutation. In addition, we will understand the consequences of combined PRMT inhibition on RNA splicing and gene expression relative to inhibiting PRMT5 or Type I PRMTs alone. In parallel to the above studies, in Aim 2, we will define the molecular basis for the cooperation between PRMT inhibition and SF mutations, by first determining the methylation substrates of PRMT5 or Type I PRMTs, and secondly by determining if individual spliceosomal changes mediated by inhibiting PRMTs or core spliceosome function can be mimicked by anti-sense oligonucleotides, thereby providing an orthogonal novel therapeutic approach to eliminate SF-mutant cancer cells. The significance of these studies is that inhibitors of PRMTs are now entering phase I clinical trials in patients with a variety of cancer types and defining the mechanistic effects and therapeutic utility of PRMT inhibitors for specific genetic subsets of cancers may have incredible therapeutic importance. The health relatedness is that our studies may identify new therapeutic opportunities for a variety of cancer types that have no curative therapies for the majority of patients with these diseases currently.

Public Health Relevance

Recent work from our groups and others has shown that cancer cells bearing mutations in genes controlling a process known as RNA splicing are exquisitely sensitive to drugs that block the machinery that carries out RNA splicing. Because the safety and efficacy of this specific class of drugs is not yet known, here we propose to study an additional means to target RNA splicing by inhibiting a process known as protein arginine methylation. This study may have great therapeutic potential because a number of drugs targeting protein arginine methylation are entering early phase clinical trials now.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Mechanisms of Cancer Therapeutics - 2 Study Section (MCT2)
Program Officer
Venkatachalam, Sundaresan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Other Basic Sciences
Schools of Medicine
New York
United States
Zip Code