GSE123080
Mus musculus Gata2 +9.5 Ets C>T transition untreated and 10 days post 5-FU LSK cells
The development and function of stem and progenitor cells that produce blood cells are vital in physiology. GATA2 mutations cause immunodeficiency, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). GATA-2 physiological activities necessitate that it be strictly regulated and cell type-specific enhancers fulfill this role. The +9.5 intronic enhancer harbors multiple conserved cis-elements, and germline mutations of these cis-elements are pathogenic in humans. Since mechanisms underlying how GATA2 enhancer disease mutations impact hematopoiesis and pathology are unclear, we generated mouse models of the enhancer mutations. While a multi-motif mutant was embryonic lethal, a single-nucleotide Ets motif mutant was viable and steady-state hematopoiesis was normal. However, the Ets motif mutation abrogated stem/progenitor cell regeneration following stress. These results reveal a new mechanism in human genetics in which a disease mutation inactivates enhancer regenerative activity, while sparing developmental activity. Mutational sensitization to stress that instigates hematopoietic failure constitutes a paradigm for GATA-2-dependent pathogenesis. Overall design: WT and Gata2 +9.5(Ets)-/- mice were injected with PBS or 250 mg/kg 5-fluorouracil. 10 days post injected, bone marrow was harvested and LSK cells sorted for sequencing. 16 samples were analyzed, using 3-5 replicates per condition.