Lee, Stanley CBonner, Elizabeth2025-10-022025-10-022025Bonner_washington_0250E_28019.pdfhttps://hdl.handle.net/1773/54068Thesis (Ph.D.)--University of Washington, 2025Somatic SF3B1 mutations are believed to arise early in the pathogenesis of clonal myeloid disorders such as myelodysplastic syndromes (MDS). Studies show that SF3B1 mutations bias hematopoietic stem and progenitor cells (HSPCs) toward the myeloid and erythroid lineages and impair terminal erythroid maturation. However, a direct mechanistic link between mutant SF3B1 and cell fate choice in primitive HSPCs has yet to be established. Recent studies suggest that mutant SF3B1 alters transcription via impaired transcriptional elongation and lead to altered transcriptional cell states of primitive progenitors. Given the central role of transcriptional regulators in modulating lineage-specific gene expression programs and cell fate determination in HSPCs, we hypothesize that mutant SF3B1 promotes aberrant splicing of core transcriptional cofactors, which, in turn, disrupt gene regulatory networks and drive biased hematopoietic differentiation. To investigate this, we analyzed SF3B1-mutant MDS patient data and identified CDK8 as a candidate driver. Using primary CD34+ HSPCS and preclinical modeling our study identifies CDK8 as an important regulator of HSPC homeostasis and cell fate determination in SF3B1-mutant MDS. CDK8 depletion not only biases HSPCs towards myelomonocytic and erythroid lineages but also mirrors phenotypes observed in SF3B1-mutant MDS. This finding directly connects an SF3B1-mutant splicing event to skewed hematopoietic differentiation, shedding new light on MDS etiology.application/pdfen-USCC BYHematopoiesisMyelodysplastic SyndromesSplicingSplicing factor mutationsTranscriptionCellular biologyMolecular biologyMolecular and cellular biologyThesis