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

Wangisa Dunuwille; William C Wilson; Hassan Bjeije; Nancy Issa; Wentao Han; Tyler M Parsons; Andrew L Young; Infencia Xavier Raj; Aishwarya Krishnan; Tarang Gaur; Eunice S Wang; Andrew P Weng; Matthew C Stubbs; Hamza Celik; Amanda F Cashen; John R Edwards; Grant A Challen

doi:10.1016/j.bneo.2024.100040

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

Blood Neoplasia. 2024 Sep 5;1(4):100040. doi: 10.1016/j.bneo.2024.100040. eCollection 2024 Dec.

Authors

Wangisa Dunuwille¹, William C Wilson¹, Hassan Bjeije¹, Nancy Issa¹, Wentao Han¹, Tyler M Parsons¹, Andrew L Young², Infencia Xavier Raj¹, Aishwarya Krishnan¹, Tarang Gaur¹, Eunice S Wang³, Andrew P Weng⁴, Matthew C Stubbs⁵, Hamza Celik⁵, Amanda F Cashen¹, John R Edwards⁶, Grant A Challen¹

Affiliations

¹ Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
² Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
³ Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
⁴ Department of Pathology and Laboratory Medicine, Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, Canada.
⁵ Myeloid Biology Group, Incyte Research Institute, Wilmington, DE.
⁶ Department of Medicine, Center for Pharmacogenomics, Washington University School of Medicine, St. Louis, MO.

Abstract

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. DNMT3A 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 DNMT3A mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant DNMT3A, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene BIRC5 was upregulated in patients with DNMT3A-mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of BIRC5 in vivo lead to rapid depletion of DNMT3A-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.