Identification of Functional Defects Leading to Bone Marrow Failure in GATA2 Deficiency

Hematopoiesis is regulated by several transcription factors that ensure both a proper blood cell production and the survival of immature hematopoietic stem and progenitor cells (HSPCs). Among them, GATA2 plays an essential role in HSPC development and differentiation, controlling gene transcription of multiple target genes. Disruption of this balance caused by germline monoallelic GATA2 mutations leads to variable phenotypes like immunodeficiency, cytopenia, lymphedema and others. Patients are at high risk to develop myelodysplastic syndrome or acute myeloid leukemia. We previously established a transgenic mouse model for GATA2 heterozygosity and showed that the transplantation of Gata2+/– HSPCs into lethally irradiated mice induced bone marrow failure and secondary leukemia. Gata2+/– HSPCs show poor engraftment within the first weeks after transplantation due to an increased apoptotic susceptibility. In vitro experiments showed that Gata2+/– HSPCs are more sensitive towards serum deprivation and the pan-kinase inhibitor staurosporine. We are currently characterizing apoptosis signaling in Gata2+/– HSPCs in more detail and focus on various stress signals including kinase inhibitors.

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Artikel online veröffentlicht:
12. Mai 2023