Targeting SF3B1 splicing factor mutant myeloid malignancies through dependency on GPATCH8
Jeetayu Biswas
MD, PhDMemorial Sloan Kettering Cancer Center
Project Term: July 1, 2024 - June 30, 2027
Mutations in RNA splicing factors, particularly those involving the core splicing factor SF3B1 are amongst the most common mutations found in myeloid neoplasms. We recently identified a cofactor protein known as GPATCH8 which is required for the aberrant function of mutant SF3B1. We now seek to understand and target the ways in which GPATCH8 and SF3B1 interact. In so doing we hope to develop new treatments for leukemias containing mutant splicing factors.
DNA sequencing of patients with myelodysplastic syndromes (MDS) and related forms of myeloid leukemias have found a high abundance of mutations in proteins that perform RNA splicing. These splicing factors are essential for the proper formation of protein sequences throughout the cell and appear to be excellent therapeutic targets for the treatment of MDS. Despite these insights, the molecular mechanisms by which mutations in splicing factors drive MDS development is not well understood and effective therapeutic means to target splicing factor mutant blood cancers have not yet been developed. Our lab recently developed tools to visualize aberrant splicing within leukemia cells and mouse models of disease. We have now combined these tools with CRISPR-Cas9 screening to understand the proteins that are necessary for this aberrant splicing to occur. The top hit from this screen is a previously uncharacterized protein, GPATCH8. We have since discovered that in models of splicing factor mutant MDS, knockout of GPATCH8 reverses the effect of splicing factor mutations. Importantly, it also appears that GPATCH8 is not essential in otherwise normal cells.
In the proposal we will perform rigorous evaluation of the requirement of GPATCH8 in mouse and human models of MDS and leukemia. Additionally, we will use biochemical methods to understand how GPATCH8 is essential for the function of mutant splicing factors. Finally, we will use small molecules that are predicted to bind to GPATCH8 and our previously developed tools to visualize aberrant splicing to eradicate cells that have mutant splicing factors. We anticipate that targeting GPATCH8 will decrease the burden of leukemic cells while increasing the number of normal cells in the bone marrow. This work will have implications for acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and clonal hematopoiesis. We aim to lay the foundation for targeting splicing factors in leukemia and other blood cancers. If successful, we will pursue further development of methods to target splicing factors through their reliance of GPATCH8 and attempt to translate our work into a phase one clinical trial.