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Therapeutic Targeting of SF3B1-Mutant Stem Cells
Martina Sarchi1,2, Courtnee A. Clough1,3, Edie I. Crosse4,5, Jason Kim1, Laura D. Baquero Galvis1,3, Anna Gallì7, J. Philip Creamer1, Sintra Stewart1, Sara Pozzi2, Elisabetta Molteni7, Chiara Elena7, Robert K. Bradley4,5,6, Luca Malcovati2,7, and Sergei Doulatov1,6,8
1Division of Hematology, Department of Medicine, University of Washington, Seattle WA, 98195
2Department of Molecular Medicine, University of Pavia, Pavia, Italy
3Molecular and Cellular Biology Program, University of Washington, Seattle, WA
4Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109
5Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109
6Department of Genome Sciences, University of Washington, Seattle, WA 98195
7Department of Hematology, IRCCS S. Matteo Hospital Foundation, Pavia, Italy
8Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle WA, 98195
Myeloid neoplasms are comprised of distinct genetic and stem cell states, but it remains poorly understood how their interplay shapes disease evolution and response to therapy. Splicing factor SF3B1 mutations are common initiating events in myelodysplastic syndromes, while secondary mutations can drive leukemic transformation. To study clonal evolution in a defined genetic context, we developed a gene editing strategy to engineer precise SF3B1 K700E and high-risk co-mutations in primary human hematopoietic stem cells (HSCs). High-risk SF3B1 co-mutations converged on the expansion of HSCs, which displayed differential response to approved and investigational therapeutics, including spliceosome-modulating compounds. We identified CHK1 inhibitor prexasertib which selectively targeted SF3B1-mutant HSCs across all genotypes, and eradicated engraftment in vivo. Notably, the mitotic checkpoint function of CHK1 was essential in response to prexasertib. Mis-splicing of mitotic regulators by mutant SF3B1 delayed G2/M progression leading to CHK1 activation, thereby sensitizing mutant cells to prexasertib. Our findings demonstrate that that genetic and HSC states impact responses to targeted therapies, and identify CHK1 inhibition as a promising therapeutic strategy to eradicate SF3B1-mutated stem cells.
Speakers
Sergei Doulatov