Understanding and preventing bone marrow failure in the GATA2 syndrome

• Applicant: Dr. Juncal Fernandez Orth, Ph.D.
• Subject Area: Hematology, Oncology ; Pediatric and Adolescent Medicine
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499909114

Myelodysplastic syndrome (MDS) in young individuals occurs often in association with genetic predisposition. GATA2, a transcription factor shaping the hematopoietic system, is found mutated in the germline of a large fraction of pediatric and adolescent patients with apparently “primary” MDS. As shown in large international cohorts, the penetrance of myeloid neoplasia is exceedingly high in affected individuals (80% risk at the age of 40 years). Despite this high risk of developing MDS and leukemia, the mechanisms underlying malignant transformation are only insufficiently studied. With the help of a genetically modified mouse lacking exon 5 of the Gata2 gene which does not express any GATA2 protein in their hematopoietic system, we have developed a mouse model that allows us to study leukemogenesis. Thus, stem and progenitor cell transplantation was performed into lethally irradiated WT hosts. We could observe that all animals that succumbed due to leukemia (30%) developed bone marrow (BM) failure first (40%). In contrast, 60% of the recipients remained healthy. Furthermore, development of leukemia but not BM failure required somatic mutations and/or chromosomal aberrations, indicating clonal evolution. These somatic aberrations found were overlapping with those occurring in humans with GATA2 syndrome. The main objective of this project is to understand and prevent BM failure in the Gata2+/- hematopoietic system. By doing so, we expect to prevent also leukemia. The aims are to i) identify functional defects of Gata2+/- stem and progenitor cells in response to proliferation and cell death signals; ii) analyze the response of Gata2+/- LSK cells to inflammation and physiological DNA damage, iii)improve early engraftment of Gata2+/- LSK cells and determine how this affects long-term hematopoiesisThis will be done using a plethora of techniques both in vivo and in vitro such as polyI:C induced BM failure, RNAseq and functional assays. The work sets the stage for secondary MDS and leukemia. The findings will also lead to the identification of biomarkers that can be used to predict the individual risk of patients with GATA2 syndrome for the development of leukemia, a prerequisite for leukemia prevention.

• DFG Programme: Research Grants
• Co-Investigators: Professorin Dr. Melanie Börries; Privatdozentin Dr. Miriam Erlacher; Baris Ismail Yirgit