Abstract
<jats:p>T-cell acute lymphoblastic leukemia is a heterogeneous hematologic malignancy in which LMO2 gamma/delta-like T cell acute lymphoblastic leukemia (T-ALL) represents a rare but clinically aggressive subtype associated with poor treatment response and inferior survival. Integrated transcriptomic analyses identified high SOX11 expression as a defining feature of high-risk LMO2 gamma/delta-like T-ALL, where elevated SOX11 levels correlated with refractory disease and poor clinical outcome. To investigate the functional role of SOX11 in gamma/delta T-cell biology and leukemogenesis, we generated a conditional mouse model enabling lineage-specific SOX11 overexpression in T-cell progenitors. SOX11 expression promoted expansion of the innate gamma/delta T-cell compartment in thymus, spleen, and bone marrow, accompanied by transcriptional activation of gamma/delta T-cell differentiation, activation, and cytotoxicity programs. However, SOX11 overexpression alone was insufficient to induce leukemia or confer thymocyte self renewal capacity. In contrast, combined SOX11 and LMO2 overexpression markedly accelerated T-ALL development and strongly increased the incidence of gamma/delta-like leukemias, thereby recapitulating the human high risk LMO2 gamma/delta-like T-ALL subtype. Mechanistically, SOX11 expanded the preleukemic DN3 thymocyte compartment in LMO2 driven mouse model while promoting differentiation toward the gamma/delta T-cell lineage. Transcriptomic profiling identified activation of MYCN-associated transcriptional programs in SOX11/LMO2 preleukemic thymocytes. Consistently, MYCN was highly expressed in human LMO2 gamma/delta-like T-ALL, and recurrent stabilizing MYCN P44L mutations were enriched in this subtype. Functional validation using genetic and transplantation-based mouse models demonstrated that SOX11 cooperates with MYCN to accelerate T-ALL onset. Together, these findings establish a cooperative SOX11-MYCN oncogenic axis driving gamma/delta-like T-ALL and provide a novel preclinical model for investigating therapeutic vulnerabilities in this high risk leukemia subtype.</jats:p>