TY - JOUR
T1 - DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3
AU - Bhansali, Rahul S.
AU - Rammohan, Malini
AU - Lee, Paul
AU - Laurent, Anouchka P.
AU - Wen, Qiang
AU - Suraneni, Praveen
AU - Yip, Bon Ham
AU - Tsai, Yi Chien
AU - Jenni, Silvia
AU - Bornhauser, Beat
AU - Siret, Aurélie
AU - Fruit, Corinne
AU - Pacheco-Benichou, Alexandra
AU - Harris, Ethan
AU - Besson, Thierry
AU - Thompson, Benjamin J.
AU - Goo, Young Ah
AU - Hijiya, Nobuko
AU - Vilenchik, Maria
AU - Izraeli, Shai
AU - Bourquin, Jean Pierre
AU - Malinge, Sébastien
AU - Crispino, John D.
N1 - Funding Information:
This work was supported by the NIH (CA101774, to JDC, and CA211534, to QW). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional support was provided by the Samuel Waxman Cancer Research Foundation, the Rally Foundation, the Leukemia Research Foundation (to SM, 2012), the European Hematology Association (EHA) (to SM, 2013), the Fondation Lejeune (grant no. 1806), the Children’s Leukaemia and Cancer Research Foundation (CLCRF), and the United States – Israel Binational Science Foundation (BSF). RSB received support from the Alpha Omega Alpha Carolyn L. Kuckein Award, the American Society of Hematology (ASH) HONORS (Hematology Opportunities for the Next Generation of Research Scientists) Award, and a Howard Hughes Medical Institute (HHMI) Medical Research Fellowship. APL was supported by the Cancéropôle Ile-de-France. PL received support from the Junior Board of the Children’s Research Fund. SI was supported by the Israel Cancer Research Foundation, the Israel Science Foundation, and the Ministry of Health of Israel. JPB was supported by the Swiss National Research Foundation and the Clinical Research Priority Program of the University of Zurich. SM is supported by a Fellowship from the Cancer Council Western Australia (CCWA). CF and TB thank Normandie University and LABEX SynOrg (ANR-11-LABX-0029) for financial support. Proteomics services were provided by the Northwestern University Proteomics Core Facility (supported by National Cancer Institute [NCI], NIH, Cancer Center Support Grants [CCSGs] P30 CA060553 and P41 GM108569) as well as the University of Michigan Proteomics Facility. Imaging was performed at the Northwestern University Center for Advanced Microscopy, which is supported by the NCI, CCSG grant P30 CA060553. Multiphoton microscopy was performed on a Nikon A1R multiphoton microscope, acquired through the support of NIH grant 1S10OD010398-01. The authors thank Eric Delabesse and Diana Fan for their advice and Johanna Melo-Cardenas for technical assistance. The graphical abstract was created with BioRender.com.
Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/1/4
Y1 - 2021/1/4
N2 - 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.
AB - 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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U2 - 10.1172/JCI135937
DO - 10.1172/JCI135937
M3 - Article
C2 - 33393494
AN - SCOPUS:85098893206
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
M1 - e135937
ER -
