Effect of somatic STAG2 mutations on clonal hematopoiesis in GATA2 associated familial myelodysplastic syndromes

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GATA2 haploinsufficiency presents the most common predisposing germline defect in myeloid dysplastic syndrome (MDS) in children and is associated with a high risk of progression to acute myeloid leukemia (AML). GATA2 deficient patients often acquire additional somatic mutations in key regulators of hematopoietic stem cells which can accelerate disease progression. Mutational analysis of GATA2 deficient patients in a pilot cohort revealed a previously unknown significant enrichment of mutations in the cohesin-subunit STAG2. Biological mechanisms and effects of STAG2 mutations on disease progression in GATA2 deficient patients are currently unknown. Therefore, we will use deep targeted sequencing of bone marrow samples of patients with GATA2 deficiency syndrome in a larger cohort to identify acquired somatic mutations and to characterize clonal dynamics in serial samples. By correlating these data with clinicopathologic variables we will investigate how acquired STAG2 mutations affect the clinical phenotype. To further define the role of STAG2 mutations in hematopoietic stem cell function we will study the impact of Stag2 deficiency on hematopoietic stem cell self-renewal capacity and lineage-specific differentiation in Gata2 haploinsufficient mice. Moreover, we will determine combinatorial effects of STAG2 loss and GATA2 haploinsufficiency on global transcription, chromatin accessibility and GATA2 target gene occupancy in an isogenic myeloid leukemia cell line model to elucidate the underlying mechanisms that promote the occurrence of STAG2 mutations in GATA2 deficient patients. The investigation of pathomechanistic principles of cooperative mutations in key hematopoietic regulatory genes such as GATA2 and STAG2 and their influence on disease progression is not only essential to provide the best medical care for patients with familial MDS syndromes but also to gain a better understanding of how clonal expansion evolves in myeloid malignancies in general.