GATA2 deficiency and MDS/AML: Experimental strategies for disease modelling and future therapeutic prospects

The importance of predisposition to leukaemia in clinical practice is being increasingly recognized. This is emphasized by the establishment of a novel WHO disease category in 2016 called myeloid neoplasms with germline predisposition. A major syndrome within this group is GATA2 deficiency, a heterogeneous immunodeficiency syndrome with a very high lifetime risk to develop myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). GATA2 deficiency has been identified as the most common hereditary cause of MDS in adolescents with monosomy 7. Allogenic haematopoietic stem cell transplantation is the only curative option; however, chances of survival decrease with progression of immunodeficiency and MDS evolution. Penetrance and expressivity within families carrying GATA2 mutations is often variable, suggesting that co-operating extrinsic events are required to trigger the disease. Predictive tools are lacking, and intrafamilial heterogeneity is poorly understood; hence there is a clear unmet medical need. On behalf of the ERAPerMed GATA2 HuMo consortium, in this review we describe the genetic, clinical, and biological aspects of familial GATA2-related MDS, highlighting the importance of developing robust disease preclinical models to improve early detection and clinical decision-making of GATA2 carriers.

Automated summary

The importance of predisposition to leukemia, especially GATA2 deficiency, with a high risk of developing myelodysplastic syndrome and acute myeloid leukemia, is increasingly recognized. Allogenic hematopoietic stem cell transplantation is the only curative option, but chances of survival decrease with progression of immunodeficiency and disease evolution. Variability in penetrance and expressivity within families carrying GATA2 mutations suggests the involvement of cooperating extrinsic events in triggering the disease. Lack of predictive tools and understanding of intrafamilial heterogeneity highlights the need for further research in this area.