3D-GATA2

Germline heterozygous GATA2 mutations underlie a complex disorder characterized by bone marrow failure, immunodeficiency and high risk to develop myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Stem cell transplantation is the only cure but associated with multiple side effects; hence there is a clear unmet medical need. Since its discovery in 2011, important questions pertaining to the mechanism of GATA2 deficiency remain unanswered: (i) Why is the clinical presentation of GATA2 deficiency so variable? (ii) Is there a genotype-phenotype correlation? (iii) Which factors control disease penetrance? (iv) Can GATA2 mutations themselves promote MDS/AML or are further genetic or transcriptomic lesions essential for MDS/AML development? (v) Is there a GATA2-specific clonal architecture in patients’ bone marrow? (vi) What is the role of the microenvironment? (vii) What is the best therapy and at what time? (viii) Can MDS/AML be prevented? Answering these questions has been hampered by the absence of robust disease models and by decentralized efforts. Here we propose to unravel the mechanisms of malignant progression of GATA2 deficiency by combining centralized registry with multi-OMICs approaches, and in vitro and in vivo modelling. The specific objectives of the consortium are: 1) to develop a European GATA2 genotype-phenotype database with integration of OMICs data, 2) to decipher the genome/transcriptome and clonal architecture of GATA2-related MDS/AML, 3) to elucidate the functional consequences of recurrent aberrations in GATA2 itself and driver oncogenes in mouse xenograft models and study the role of bone marrow microenvironment, 4) to learn about patient perspectives and needs and 5) to integrate personalized therapy and surveillance approaches into patient care. The overarching vision is to build an international consortium of GATA2 experts that, through integrative approaches, will acquire a precise understanding on the origins, and biological significance of initiating driver events thus allowing for personalized therapeutic decisions.