Human leukemia mutations corrupt but do not abrogate GATA-2 function
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels des mutations du gène GATA-2 favorisent le développement d'une leucémie myéloïde
GATA-2 functions in stem and progenitor cells to control blood cell development, and its mutations cause blood diseases (immunodeficiency, myelodysplasia, and myeloid leukemia). How GATA-2 mutations cause these diseases is unclear. We innovated a genetic complementation assay to analyze functional ramifications of GATA-2 disease mutations. The activities of GATA-2 and mutants were quantified in blood progenitor cells from mice engineered to express a low level of GATA-2 due to deletion of an essential Gata2 enhancer. Unexpectedly, the mutants were not only competent to induce myeloid cells, but their activities exceeded that of GATA-2. These results transform the current paradigm that disease mutations are solely inhibitory, and ectopically low GATA-2 levels/activity constitute the disease mechanism. 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.