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Secondary insult reveals etiology of GATA2 enhancer mutation-associated blood disorder

The transcription factor GATA-2 is critical regulator of hematopoietic stem and progenitor cell (HSPC) development and function, and mutations in the enhancer region of GATA2 are linked to blood disorders. In this episode, Emery Bresnick and colleagues develop and characterize a mouse model that harbors a human disease-associated GATA2 enhancer mutation. In this model, hematopoietic development and function were normal unless the animals were exposed to a secondary stress that necessitated blood cell regeneration. The results of this study provide important insight into GATA-2-dependent pathogenesis.

Published March 1, 2019, by Corinne Williams

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Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer
Alexandra A. Soukup, … , Sunduz Keles, Emery H. Bresnick
Alexandra A. Soukup, … , Sunduz Keles, Emery H. Bresnick
Published January 8, 2019
Citation Information: J Clin Invest. 2019;129(3):1180-1192. https://doi.org/10.1172/JCI122694.
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Research Article Hematology

Single-nucleotide human disease mutation inactivates a blood-regenerative GATA2 enhancer

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Abstract

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.

Authors

Alexandra A. Soukup, Ye Zheng, Charu Mehta, Jun Wu, Peng Liu, Miao Cao, Inga Hofmann, Yun Zhou, Jing Zhang, Kirby D. Johnson, Kyunghee Choi, Sunduz Keles, Emery H. Bresnick

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