Hematopoiesis is a tightly regulated process by which hematopoietic stem cells (HSCs) give rise to progenitor cells (HPCs), ultimately generating all blood cell lineages. This regulation is controlled by transcription factors and cofactors that orchestrate the proliferation, differentiation, and survival of immature cells. Among these, GATA2 is a crucial transcription factor essential for the maintenance and development of hematopoietic stem and progenitor cells (HSPCs). Haploinsufficiency of GATA2 disrupts this balance, resulting in a spectrum of hematological and immune phenotypes that range from reduced HSPC compartments and cytopenias to lymphedema, immunodeficiency, and a markedly increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).​ To date, approximately 400 germline GATA2 mutations have been identified, including point mutations, splice variants, and complete gene deletions. However, malignant progression in GATA2 deficiency is primarily driven by acquired somatic genetic alterations, such as chromosomal abnormalities (e.g., monosomy 7 and trisomy 8) and recurrent somatic mutations. These secondary genetic events are generally considered central to disease evolution and malignant transformation (maladaptive), but emerging evidence suggests that not all such mutations are equivalent: some may provide selective advantages to hematopoietic cells without necessarily promoting leukemic transformation (adaptive).

In our research group, our primary goal is to clarify the roles and contributions of these somatic events in GATA2 deficiency, aiming to uncover mechanisms underlying disease evolution. By doing so, we seek to identify potential compensatory genetic and epigenetic changes that may modify disease trajectories and ultimately suggest avenues for novel therapeutic interventions.