| First Author | Soukup AA | Year | 2019 |
| Journal | J Clin Invest | Volume | 129 |
| Issue | 3 | Pages | 1180-1192 |
| PubMed ID | 30620726 | Mgi Jnum | J:295045 |
| Mgi Id | MGI:6459586 | Doi | 10.1172/JCI122694 |
| Citation | Soukup AA, et al. (2019) Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer. J Clin Invest 129(3):1180-1192 |
| abstractText | The development and function of stem and progenitor cells that produce blood cells are vital in physiology. GATA-binding protein 2 (GATA2) mutations cause GATA-2 deficiency syndrome involving immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. 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 embryonically 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 predisposition mutation inactivates enhancer regenerative activity, while sparing developmental activity. Mutational sensitization to stress that instigates hematopoietic failure constitutes a paradigm for GATA-2 deficiency syndrome and other contexts of GATA-2-dependent pathogenesis. |
