T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that results from a multistep cancer process in which the accumulation of several oncogenic events leads to the clonal expansion of malignant T-lymphoblasts characterized by developmental arrest. Nowadays, optimized protocols cure about 90% of children and 60% of the adult T-ALL cases. However, the outcome of therapy resistant and relapsed T-ALL patients remains poor. This has driven the need for a better understanding of the T-ALL genomic landscape to improve survival. Via detailed genomic characterization of a therapy resistant ETP-ALL patient, we have identified a novel chromosomal translocation resulting in a mono-allelic loss of IKZF1 expression. By using a spontaneous ETP-ALL Cd2-Lmo2Tg/+ mouse model, we have shown that homozygous loss of Ikzf1 on its own is sufficient to induce murine T-ALL, independently of Lmo2 overexpression. In addition, our preliminary results have shown that Ikzf1 deleted thymocytes can repopulate and self-renew the thymus in mice. However, the molecular mechanism on how Ikzf1 suppresses leukemogenesis or its role in pre-leukemic T-ALL is still not known yet and will be the main research question in this proposal.