DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

Rahul S. Bhansali; Malini Rammohan; Paul Lee; Anouchka P. Laurent; Qiang Wen; Praveen Suraneni; Bon Ham Yip; Yi Chien Tsai; Silvia Jenni; Beat Bornhauser; Aurélie Siret; Corinne Fruit; Alexandra Pacheco-Benichou; Ethan Harris; Thierry Besson; Benjamin J. Thompson; Young Ah Goo; Nobuko Hijiya; Maria Vilenchik; Shai Izraeli; Jean Pierre Bourquin; Sébastien Malinge; John D. Crispino

doi:10.1172/JCI135937

DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

Rahul S. Bhansali, Malini Rammohan, Paul Lee, Anouchka P. Laurent, Qiang Wen, Praveen Suraneni, Bon Ham Yip, Yi Chien Tsai, Silvia Jenni, Beat Bornhauser, Aurélie Siret, Corinne Fruit, Alexandra Pacheco-Benichou, Ethan Harris, Thierry Besson, Benjamin J. Thompson, Young Ah Goo, Nobuko Hijiya, Maria Vilenchik, Shai IzraeliJean Pierre Bourquin, Sébastien Malinge, John D. Crispino^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

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.

Original language	English (US)
Article number	e135937
Journal	Journal of Clinical Investigation
Volume	131
Issue number	1
DOIs	https://doi.org/10.1172/JCI135937
State	Published - Jan 4 2021

Funding

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.

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General Medicine

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10.1172/JCI135937

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Bhansali, R. S., Rammohan, M., Lee, P., Laurent, A. P., Wen, Q., Suraneni, P., Yip, B. H., Tsai, Y. C., Jenni, S., Bornhauser, B., Siret, A., Fruit, C., Pacheco-Benichou, A., Harris, E., Besson, T., Thompson, B. J., Goo, Y. A., Hijiya, N., Vilenchik, M., ... Crispino, J. D. (2021). DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3. Journal of Clinical Investigation, 131(1), Article e135937. https://doi.org/10.1172/JCI135937

@article{03a0dc5e8718456fa26ae61afc46b67d,

title = "DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3",

abstract = "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.",

author = "Bhansali, {Rahul S.} and Malini Rammohan and Paul Lee and Laurent, {Anouchka P.} and Qiang Wen and Praveen Suraneni and Yip, {Bon Ham} and Tsai, {Yi Chien} and Silvia Jenni and Beat Bornhauser and Aur{\'e}lie Siret and Corinne Fruit and Alexandra Pacheco-Benichou and Ethan Harris and Thierry Besson and Thompson, {Benjamin J.} and Goo, {Young Ah} and Nobuko Hijiya and Maria Vilenchik and Shai Izraeli and Bourquin, {Jean Pierre} and S{\'e}bastien Malinge and Crispino, {John D.}",

note = "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{\textquoteright}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 Canc{\'e}rop{\^o}le Ile-de-France. PL received support from the Junior Board of the Children{\textquoteright}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: {\textcopyright} 2021, American Society for Clinical Investigation.",

year = "2021",

month = jan,

day = "4",

doi = "10.1172/JCI135937",

language = "English (US)",

volume = "131",

journal = "Journal of Clinical Investigation",

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Bhansali, RS, Rammohan, M, Lee, P, Laurent, AP, Wen, Q, Suraneni, P, Yip, BH, Tsai, YC, Jenni, S, Bornhauser, B, Siret, A, Fruit, C, Pacheco-Benichou, A, Harris, E, Besson, T, Thompson, BJ, Goo, YA, Hijiya, N, Vilenchik, M, Izraeli, S, Bourquin, JP, Malinge, S & Crispino, JD 2021, 'DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3', Journal of Clinical Investigation, vol. 131, no. 1, e135937. https://doi.org/10.1172/JCI135937

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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DO - 10.1172/JCI135937

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SN - 0021-9738

VL - 131

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 1

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ER -

DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

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