Investigating the role of chromatin dynamics in lineage restriction from bipotent to unipotent erythroid progenitors

About This Grant

PROJECT SUMMARY Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis, with anemia as its most common and clinically consequential manifestation. Recent integrative genomic analyses have revealed that STAG2-mutant MDS represents the most erythropoietin (EPO)–refractory genetic subtype across IPSS-M risk categories, underscoring a critical unmet need to understand the molecular basis of erythroid failure in this disease. Our prior work demonstrated that loss of Stag2 disrupts erythroid differentiation and leads to elevated circulating EPO in vivo, indicating a state of profound EPO resistance. In newly accepted work, we show that Stag2-dependent chromatin accessibility enforces erythroid-specific GATA1 cistrome engagement, and that Stag2 loss leads to accessibility-driven retargeting of GATA1 toward megakaryocytic loci, thereby impairing erythroid output. The objective of this one year R56 bridge project is to advance a focused subset of aims by determining whether STAG2 dependent defects in erythroid differentiation and transcription factor engagement are functionally reversible. Specifically, this project will interrogate the impact of STAG2 loss and restoration on erythroid output, EPO responsiveness, and chromatin dependent GATA1 activity in vivo, and will establish a tractable experimental system to test the reversibility of these erythroid defects. These studies will provide critical mechanistic and feasibility data and will inform subsequent efforts to restore erythroid competence in STAG2 mutant MDS. Together, these studies will directly address the mechanistic basis of EPO resistance in STAG2-mutant MDS and provide critical feasibility and validation data to support a revised R01 focused on therapeutic restoration of erythroid function.