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. <i>DNMT3A</i> 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 <i>DNMT3A</i> mutations are resistant to apoptosis and certain chemotherapies. Elevated JAK/STAT signaling drove prosurvival programs in patients with mutant <i>DNMT3A</i>, and JAK/STAT inhibition restored sensitivity to chemotherapy. The prosurvival gene <i>BIRC5</i> was upregulated in patients with <i>DNMT3A</i>-mutant T-ALL, and these cells were specifically sensitive to the Baculoviral IAP Repeat Containing 5 (BIRC5) inhibitor YM155. Genetic inhibition of <i>BIRC5</i> in vivo lead to rapid depletion of <i>DNMT3A</i>-mutant T-ALL cells in patient-derived xenografts, positioning BIRC5 as a precision medicine target for these patients.
Authors
- Infencia Xavier Raj (ORCID: https://orcid.org/0000-0002-4889-4643)
- Wangisa Dunuwille
- Hassan Bjeije (ORCID: https://orcid.org/0000-0002-5869-8574)
- Aishwarya Krishnan
- Tyler M. Parsons (ORCID: https://orcid.org/0000-0003-0277-1557)
- Tarang Gaur
- Eunice S. Wang (ORCID: https://orcid.org/0000-0002-8644-0968)
- Grant Anthony Challen (ORCID: https://orcid.org/0000-0003-4669-8814)
- Andrew P. Weng (ORCID: https://orcid.org/0000-0001-7394-5425)
- Matthew C. Stubbs (ORCID: https://orcid.org/0000-0003-3771-7083)
- Nancy Issa
- Andrew L. Young (ORCID: https://orcid.org/0000-0001-7698-3267)
- William C. Wilson (ORCID: https://orcid.org/0000-0002-1526-5939)
- Hamza Celik
- Wentao Han (ORCID: https://orcid.org/0000-0002-6470-9655)
- John R. Edwards
- Amanda F. Cashen
Institutions
- BC Cancer Agency (CA)
- Roswell Park Comprehensive Cancer Center (US)
- Washington University in St. Louis (US)
- Terry Fox Research Institute (CA)
- Incyte (United States) (US)
Publication Details
- Journal
- Blood Neoplasia
- Published
- 2024-09-05
- DOI
- https://doi.org/10.1016/j.bneo.2024.100040
- Citations
- 1
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 0.54
Funders
- American Cancer Society
- Leukemia and Lymphoma Society
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- Musculoskeletal Research Center, Washington University in St. Louis
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases