Human leukemia mutations corrupt but do not abrogate GATA-2 function
| Autor: | Charu Mehta, Alexandra A. Soukup, Koichi R. Katsumura, Emery H. Bresnick, Erik A. Ranheim, Kirby D. Johnson, Isabela Fraga de Andrade, Kyle J. Hewitt |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Myeloid Haploinsufficiency Regulatory Sequences Nucleic Acid Biology Mice 03 medical and health sciences Cell Line Tumor medicine Animals Humans Cell Proliferation Zinc finger Multidisciplinary Stem Cells GATA2 Myeloid leukemia Cell Differentiation Zinc Fingers medicine.disease Hematopoiesis Cell biology GATA2 Transcription Factor Complementation Leukemia Myeloid Acute Haematopoiesis Leukemia 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation PNAS Plus Myelodysplastic Syndromes Mutation |
| Zdroj: | Proceedings of the National Academy of Sciences. 115 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1813015115 |
| Popis: | By inducing the generation and function of hematopoietic stem and progenitor cells, the master regulator of hematopoiesis GATA-2 controls the production of all blood cell types. Heterozygous GATA2 mutations cause immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. GATA2 disease mutations commonly disrupt amino acid residues that mediate DNA binding or cis-elements within a vital GATA2 intronic enhancer, suggesting a haploinsufficiency mechanism of pathogenesis. Mutations also occur in GATA2 coding regions distinct from the DNA-binding carboxyl-terminal zinc finger (C-finger), including the amino-terminal zinc finger (N-finger), and N-finger function is not established. Whether distinct mutations differentially impact GATA-2 mechanisms is unknown. Here, we demonstrate that N-finger mutations decreased GATA-2 chromatin occupancy and attenuated target gene regulation. We developed a genetic complementation assay to quantify GATA-2 function in myeloid progenitor cells from Gata2 −77 enhancer-mutant mice. GATA-2 complementation increased erythroid and myeloid differentiation. While GATA-2 disease mutants were not competent to induce erythroid differentiation of Lin(−)Kit(+) myeloid progenitors, unexpectedly, they promoted myeloid differentiation and proliferation. As the myelopoiesis-promoting activity of GATA-2 mutants exceeded that of GATA-2, GATA2 disease mutations are not strictly inhibitory. Thus, we propose that the haploinsufficiency paradigm does not fully explain GATA-2–linked pathogenesis, and an amalgamation of qualitative and quantitative defects instigated by GATA2 mutations underlies the complex phenotypes of GATA-2–dependent pathologies. |
| Databáze: | OpenAIRE |
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