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.This work was supported by ERA PerMed GATA2-HuMo Funding Mechanism (Spain: Acció instrumental de SLT011/18/00006 of the Department of Health of the Government of Catalonia, to AG and AB; Hungary: ED-18-1-2019-001 grant from the National Research, Development and Innovation Office to CB; and Germany: German Federal Ministry of Education and Research (BMBF) 2018-123/01KU1904 to MWW), ÚNKP-21-2-I-SE-21 and Hungarian National Academy of Scientist Education grant to KL, TKP2021-NVA-15, TKP2021-EGA-24 and EU's Horizon 2020 research and innovation programme under grant agreement no. 739593 and Elixir Hungary to CB, MSCA No 101029927-scGATA2track (H2020-MSCA-IF-2020) to OM-B, the Spanish Ministry of Economy, Industry, and Competitiveness (MINECO PID2020-15591RB-100), La Marató de TV3 (202001-32), FPS Grant 2018 by Fondazione Pisana per la Scienza ONLUS and CERCA Programme/Generalitat de Catalunya for institutional support to AG, Vera and Joseph Dresner Foundation, Evans MDS Foundation, American Lebanese Syrian Associated Charities, and BMBF MyPred 01GM1911A to MWW. Open access funding enabled and organized by ProjektDEAL