Project: Human disease modeling of GATA2-related Myelodysplastic Syndromes and Acute Myeloid Leukemia

Acronym	GATA2-HuMo (Reference Number: ERAPERMED2018-123)
Duration	01/03/2019 - 28/02/2022
Project Topic	Germline heterozygous GATA2 mutations underlie a complex disorder characterized by immunodeficiency, bone marrow failure and high risk to develop myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML). GATA2 deficiency has been established as the most common hereditary cause of MDS in children and adolescents. So far, allogeneic stem cell transplantation is the only curative therapy; hence there is a clear unmet medical need. A better understanding of the molecular basis of this entity may pave the way for personalized surveillance and treatment approaches. Since its discovery in 2011, important questions pertaining to mechanism GATA2 deficiency remain unanswered: (i) Is GATA2 mutation itself enough to promote MDS/AML development? (ii) Is there a genotype-phenotype association? (iii) What factors control disease penetrance? (iv) Which genetic or epigenetic lesions are essential for malignant transformation and how do they crosstalk? (v) Is there a GATA2-specific clonal architecture in MDS marrow? (vi) What is the role of microenvironment? Answering these questions has been hampered by the absence of robust disease models. Here we propose to unravel the mechanisms underlying the malignant progression of GATA2 deficiency by combining genomic approaches (genome, transcriptome, methylome) with in vitro and in vivo models. The SPECIFIC objectives of the consortium are: 1) to develop a European GATA2 registry and specimen biobank allowing for genotype-phenotype characterization, 2) to decipher the genome/epigenome and clonal architecture of GATA2-related MDS/AML 3) to elucidate the functional consequences of recurrent/novel GATA2 and driver mutations in human (induced pluripotent stem cells) and mouse-based disease models, and, 4) to develop algorithms for clinical management based on personalized molecular and functional data. The overarching goal is to acquire a precise understanding of myeloid transformation allowing for a personalized approach to patient care.
Network	ERA PerMed
Call	1st Joint Transnational Call for Proposals (2018)

Project partner

Number	Name	Role	Country
1	Fundacio Centre de Medicina Regenerativa de Barcelona	Coordinator	Spain
2	Fundació Institut Mar d’Investigacions Mèdiques	Partner	Spain
3	Albert-Ludwigs-Universität Freiburg	Partner	Germany
4	Semmelweis University	Partner	Hungary