BIRC5 upregulation enhances DNMT3A-mutant T-ALL cell survival and pathogenesis.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. Although the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL population. Development of new treatments requires understanding the mechanisms driven by specific mutations. mutations are identified in ∼10% to 18% of adult patients with T-ALL and are associated with poor clinical outcomes. Here, using primary human specimens, we show that cells from patients with T-ALL with mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant , and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene was upregulated in patients with -mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of in vivo lead to rapid depletion of -mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.