T lymphocytes are a specific subtype of immune cells developing in the thymic microenvironment. They develop into the mature state from multipotent early T cell precursors (ETPs) which receive NOTCH1 signaling followed by the activity of GATA3 to lock the commitment to T cell lineage and prevent the differentiation to other immune cell lineages. The malignant transformation of ETPs results in the development of an aggressive type of T cell Acute Lymphoblastic Leukemia (T-ALL), Early T cell Precursor-Acute Lymphoblastic Leukemia (ETP-ALL). A subset of ETP-ALL cases was reported to bear recurring mutations of the gene encoding GATA3, a master regulator of early T-cell development. This suggests that the aberrant activity of GATA3 may contribute to the emergence of ETP-ALL through the dysregulation of ETPs’ differentiation pathway. For this reason, this project aims to uncover the role of mutated GATA3 in promoting ETP-ALL. Using state-of-the-art methods, such as artificial thymic organoids, multiomics, DNA binding analysis and humanized mouse models, we will study the effect of the most common GATA3 mutation (R276Q) in ETP-ALL on the normal T cell development as well as its contribution to the development of leukemia upon the co-expression of other ETP-ALL-associated mutations. We anticipate that our work will unveil the underlying mechanisms through which GATA3 promotes ETP-ALL and provide novel leads for therapeutic intervention for this subtype of ALL with poor prognosis.