DYRK1A inhibition results in MYC and ERK activation rendering KMT2A-R acute lymphoblastic leukemia cells sensitive to BCL2 inhibition
Unbiased kinome-wide CRISPR screening identified DYRK1A as a potential therapeutic target in KMT2A-rearranged (KMT2A-R) B-acute lymphoblastic leukemia (ALL). Mechanistically, we demonstrate that DYRK1A is regulated by the KMT2A fusion protein and affects cell proliferation by regulating MYC expression and ERK phosphorylation. We further observed that pharmacologic DYRK1A inhibition markedly reduced human KMT2A-R ALL cell proliferation in vitro and potently decreased leukemia proliferation in vivo in drug-treated patient-derived xenograft mouse models. DYRK1A inhibition induced expression of the proapoptotic factor BIM and reduced the expression of BCL-XL, consequently sensitizing KMT2A-R ALL cells to BCL2 inhibition. Dual inhibition of DYRK1A and BCL2 synergistically decreased KMT2A-R ALL cell survival in vitro and reduced leukemic burden in mice. Taken together, our data establishes DYRK1A as a novel therapeutic target in KMT2A-R ALL and credential dual inhibition of DYRK1A and BCL2 as an effective translational therapeutic strategy for this high-risk ALL subtype.
Authors
- Thomas A. Milne (ORCID: https://orcid.org/0000-0002-0413-4271)
- Shikha Gaur
- Huimin Geng (ORCID: https://orcid.org/0000-0001-5339-5446)
- Xianxin Hua (ORCID: https://orcid.org/0000-0003-4862-4691)
- Wayne E. Childers (ORCID: https://orcid.org/0000-0003-0527-3684)
- Martin Carroll (ORCID: https://orcid.org/0000-0002-5622-3735)
- V.S.S. Abhinav Ayyadevara (ORCID: https://orcid.org/0000-0003-2085-2588)
- Junwei Shi (ORCID: https://orcid.org/0000-0002-8427-6316)
- Thierry Besson (ORCID: https://orcid.org/0000-0003-3025-6659)
- Rahul S. Bhansali (ORCID: https://orcid.org/0000-0002-3616-7393)
- Christian Hurtz (ORCID: https://orcid.org/0000-0001-8346-190X)
- Sarah K. Tasian (ORCID: https://orcid.org/0000-0003-1327-1662)
- Sung June Lee (ORCID: https://orcid.org/0000-0002-0627-5393)
- John D. Crispino (ORCID: https://orcid.org/0000-0002-8182-8306)
- Kathrin M. Bernt (ORCID: https://orcid.org/0000-0002-0691-356X)
- John Chukinas
- Gerald Wertheim (ORCID: https://orcid.org/0000-0002-1585-846X)
- Anil Kumar (ORCID: https://orcid.org/0000-0003-2287-5388)
- Srividya Swaminathan (ORCID: https://orcid.org/0000-0002-3459-7488)
- Joseph P. Loftus
Institutions
- Centre National de la Recherche Scientifique (FR)
- City Of Hope National Medical Center (US)
- St. Jude Children's Research Hospital (US)
- Children's Hospital of Philadelphia (US)
- Cancer Research Institute (US)
- University of California, San Francisco (US)
- Loma Linda University (US)
- University of Oxford (GB)
- City of Hope (US)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Princess Máxima Center (NL)
- UPMC Hillman Cancer Center (US)
- Beckman Research Institute
- Université de Rouen Normandie (FR)
- University of Pennsylvania (US)
- Temple University (US)
- Institut National des Sciences Appliquées Rouen Normandie (FR)
Publication Details
- Journal
- Leukemia
- Published
- 2025-03-27
- DOI
- https://doi.org/10.1038/s41375-025-02575-w
- Citations
- 3
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- U.S. Department of Defense
- Damon Runyon Cancer Research Foundation
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Rally Foundation
- Pennsylvania Department of Health
- Leukemia and Lymphoma Society
- Children's Hospital of Philadelphia
- University of Pennsylvania
- Indian National Science Academy
- Temple University
- Centre National de la Recherche Scientifique
- Région Normandie
- National Institutes of Health
- University of California, Irvine
- Medical Research Council
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases