MDM4 overexpression alleviates developmental and hematopoietic defects in Fancg deficient mice.

Fanconi anemia (FA) is the most frequent inherited cause of bone marrow failure (BMF). Most FA patients experience hematopoietic stem cell attrition and cytopenia during childhood, which along with intrinsic chromosomal instability, favor clonal evolution and the frequent emergence of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in their teens or young adulthood. In the present study, we have developed a joint molecular and cellular approach to get further insights into the mechanisms that set this "pre-leukemic" state up. For this purpose, we developed a mouse model of MDM4 overexpression by introducing a wide genomic region surrounding the gene that includes its proximal regulatory sequences. Finally, we evaluated the consequences of alteration of the FA pathway in HSPCs in KO or in KOTg mice at steady state and under Poly-IC (pIC) stress.