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

Pediatrics

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

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

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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{d9c297ee6b254aaf8420f835859c22f2,

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 = "Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",

year = "2021",

month = jan,

day = "4",

doi = "10.1172/JCI135937",

language = "אנגלית",

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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.

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

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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 -

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

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