Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 1, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI135937
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Funding
- European Hematology Association (EHA)
- Fondation Lejeune [1806]
- Children's Leukaemia and Cancer Research Foundation (CLCRF)
- United States - Israel Binational Science Foundation (BSF)
- Alpha Omega Alpha Carolyn L. Kuckein Award
- American Society of Hematology (ASH) HONORS (Hematology Opportunities for the Next Generation of Research Scientists) Award
- Howard Hughes Medical Institute (HHMI) Medical Research Fellowship
- Canceropole Ile-de-France
- Junior Board of the Children's Research Fund
- Israel Cancer Research Foundation
- Israel Science Foundation
- Ministry of Health of Israel
- Swiss National Research Foundation
- Clinical Research Priority Program of the University of Zurich
- Cancer Council Western Australia (CCWA)
- Normandie University
- LABEX SynOrg [ANR-11-LABX-0029]
- National Cancer Institute [NCI], NIH, Cancer Center Support Grants [CCSGs] [P30 CA060553, P41 GM108569]
- NCI, CCSG [P30 CA060553]
- NIH [CA101774, CA211534, 1S10OD010398-01]
- Samuel Waxman Cancer Research Foundation
- Rally Foundation
- Leukemia Research Foundation
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The study reveals that DYRK1A is overexpressed in and essential for B-ALL, with FOXO1 and STAT3 being critical substrates. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupts DNA damage and ROS regulation, leading to preferential cell death in leukemic B cells.
DYRK1A is a serine/threonine kinase encoded on human chromosome 21 (HSA21) that has been implicated in several pathologies of Down syndrome (DS), including cognitive deficits and Alzheimer's disease. Although children with DS are predisposed to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL), the HSA21 genes that contribute to malignancies remain largely undefined. Here, we report that DYRK1A is overexpressed and required for B-ALL. Genetic and pharmacologic inhibition of DYRK1A decreased leukemic cell expansion and suppressed B-ALL development in vitro and in vivo. Furthermore, we found that FOXO1 and STAT3, transcription factors that are indispensable for B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupted DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we reveal a DYRK1A/FOXO1/STAT3 axis that facilitates the development and maintenance of B-ALL.
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