GATA2 hypomorphism induces chronic myelomonocytic leukemia in mice

• Published in: Cancer science Vol. 110; no. 4; pp. 1183 - 1193
• Main Authors: Harada, Nobuhiko, Hasegawa, Atsushi, Hirano, Ikuo, Yamamoto, Masayuki, Shimizu, Ritsuko
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.04.2019
• Subjects: Age Factors; aging; Animals; Biomarkers; Disease Models, Animal; GATA2 hypomorphism; GATA2 Transcription Factor - genetics; GATA2 Transcription Factor - metabolism; Gene Expression; Genetic Predisposition to Disease; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Leukemia, Myelomonocytic, Chronic - genetics; Leukemia, Myelomonocytic, Chronic - metabolism; Leukemia, Myelomonocytic, Chronic - pathology; Leukocyte Count; Leukocytosis - genetics; Leukocytosis - metabolism; Leukocytosis - pathology; Mice; Mice, Knockout; Monocytes; myelodysplastic syndrome; myeloproliferative disorder; Original; Polymorphism, Genetic; RNA, Messenger; stem cell dysfunction; myeloproliferative disorder; stem cell dysfunction; aging; GATA2 hypomorphism; myelodysplastic syndrome
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13959

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 (G2fGN/fGN) mice that were generated by the germline insertion of a neocassette into the Gata2 gene locus avoided the early embryonic lethality observed in Gata2‐null mice. However, adult G2fGN/fGN mice suffered from exacerbated leukocytosis concomitant with progressive anemia and thrombocytopenia and eventually developed massive granulomonocytosis accompanied by trilineage dysplasia. The reconstitution activity of G2fGN/fGN mouse stem cells was impaired. Furthermore, G2fGN/fGN progenitors showed myeloid lineage‐biased proliferation and differentiation. Myeloid progenitor accumulation started at a younger age in G2fGN/fGN mice and appeared to worsen with age. G2fGN/fGN mice showed increased expression of transcripts encoding cytokine receptors, such as macrophage colony‐stimulating factor receptor and interleukin‐6 receptor, in granulocyte‐monocyte progenitors. This increased expression could be correlated with the hypersensitive granulomonocytic proliferation reaction when the mice were exposed to lipopolysaccharide. Taken together, these observations indicate 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 of hematological neoplasm transformation. GATA2 hypomorphism causes a hyperreactive defense response to infections in mice, thus increasing the risk of hematological neoplasm. In elderly animals, GATA2 hypomorphism induces myelodysplastic/myeloproliferative neoplasm development, which resemble chronic myelomonocytic leukemia in humans.