GATA2 hypomorphism induces chronic myelomonocytic leukemia in mice

Abstract

The transcription factor GATA2 regulates normal hematopoiesis, particularly in stem cell maintenance and myeloid differentiation. Various heteroallelic GATA2 gene mutations are associated with a variety of hematological neoplasms, including myelodysplastic syndromes and leukemias. Here, we report that impaired GATA2 expression induces myelodysplastic and myeloproliferative neoplasm development in elderly animals, and this neoplasm resembles chronic myelomonocytic leukemia in humans. GATA2 hypomorphic mutant (G2 ^fGN/fGN) mice that were generated by the germline insertion of a neo‐cassette into the Gata2 gene locus avoided the early embryonic lethality observed in Gata2‐null mice. However, adult G2 ^fGN/fGN mice suffered from exacerbated leukocytosis concomitant with progressive anemia and thrombocytopenia and eventually developed massive granulo‐monocytosis accompanied by tri‐lineage dysplasia. The reconstitution activity of G2 ^fGN/fGN mouse stem cells was impaired. Furthermore, G2 ^fGN/fGN progenitors showed myeloid lineage‐biased proliferation and differentiation. Myeloid progenitor accumulation started at a younger age in G2 ^fGN/fGN mice and appeared to worsen with aging. G2 ^fGN/fGN mice exhibited increased expression of transcripts encoding cytokine receptors, such as M‐CSFR and IL6R, in granulocyte‐monocyte progenitors. This increased expression may be correlated with the hypersensitive granulo‐monocytic proliferation reaction when the mice were exposed to lipopolysaccharide. Taken together, these observations demonstrate that GATA2 hypomorphism leads to a hyperreactive defense response to infections, and this reaction is attributed to a unique intrinsic cell defect in the regulation of myeloid expansion that increases the risk for hematological neoplasm transformation.

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