BIRC5 Upregulation Enhances DNMT3A-Mutant T-ALL Cell Survival and Pathogenesis

• DNMT3A mutations confer enhanced survival to T-ALL cells through increased JAK/STAT signaling.

• BIRC5 represents a specific genetic dependency and therapeutic vulnerability of T-ALL cells with DNMT3A mutations.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm. While the prognosis of pediatric T-ALL has improved with intensified chemotherapy regimens, this benefit has largely not translated to the adult T-ALL patient population. Development of new treatments requires understanding the mechanisms driven by specific mutations. DNMT3A mutations are identified in ∼10-18% of adult T-ALL patients and are associated with poor clinical outcomes. Using primary human specimens, here we show T-ALL patient cells with DNMT3A mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove pro-survival programs in DNMT3A-mutant patients, and JAK/STAT inhibition restored sensitivity to chemotherapy. The pro-survival gene BIRC5 was upregulated in DNMT3A-mutant T-ALL patients, and these cells were specifically sensitive to the BIRC5 inhibitor YM155. Genetic inhibition of BIRC5 in vivo lead to rapid depletion of DNMT3A-mutant T-ALL cells in patient-derived xenografts (PDXs), positioning BIRC5 as a precision medicine target for these patients.