Molecular pathology of splicing and transcription factor mutations in myelodysplastic syndromes
- Author(s): Huang, Yi-Jou
- Advisor(s): Zhang, Dong-Er
- et al.
Myelodysplastic Syndromes (MDS) are hematopoietic disorders characterized by myeloid dysplasia, inefficient hematopoiesis, and the propensity to transform into acute myeloid leukemia (AML). Recent advances in sequencing technologies uncovered various types of mutations associated with the disease. In particular, mutations of the splicing factor SRSF2 were significantly associated with mutations of RUNX1, a transcription factor with an established role in hematological disorders. These findings suggest a critical role of these factors in hematopoiesis and disease pathogenesis through their cooperative effects in regulating gene expression and alternative splicing. First, we characterized the roles of SRSF2 mutations in blood cell development and the splicing alternations caused by these mutations. Second, we uncovered that, besides their canonical roles in splicing, SRSF2 mutations also trigger excessive R-loop formation, leading to replication stress and DNA damage response. Third, we discovered the convergent effect of SRSF2 mutations and RUNX1 mutations in facilitating the development of MDS phenotypes, altering global splicing and gene expression programs, which elucidated the pathways critical for disease development. These findings laid a critical foundation to understand the contribution of individual mutations to MDS and the synergy effects among them and provided insights to develop novel therapeutic strategies in the future.