DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3
Rahul S. Bhansali, … , Sébastien Malinge, John D. Crispino
Rahul S. Bhansali, … , Sébastien Malinge, John D. Crispino
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e135937. https://doi.org/10.1172/JCI135937.
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Research Article Oncology

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.

Authors

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

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Figure 6

FOXO1 and DYRK1A are therapeutic targets in B-ALL.

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FOXO1 and DYRK1A are therapeutic targets in B-ALL. (A and B) MHH-CALL-4 ...
(A and B) MHH-CALL-4 and Nalm-6 cell lines were transplanted into NSG mice, and the animals were treated with EHT 1610 or AS1842856, respectively, for 2 weeks (yellow boxes). Kaplan-Meier analysis of mice treated with EHT 1610 (A) or AS1842856 (B) was performed. Graph titles describe the genetic backgrounds of the transplanted leukemia cells. P values and sample sizes (n) are shown in the key. (C) NSG mice were transplanted with a DS-ALL-03 luciferase-expressing PDX sample and treated with EHT 1610 or AS1842856. Representative images of leukemic burden within each treatment cohort are shown. Radiance scales are shown below each image. (D) Kaplan-Meier analysis of DS-ALL-03 cohorts after 3 weeks (yellow box) of treatment. Graph title describes the genetic background of the leukemia. P values and sample sizes (n) are shown in the key. (E) NSG mice were transplanted with the HeH-ALL-09 luciferase-expressing PDX sample and treated with EHT 1610 or AS1842856. Representative images of leukemic burden within each treatment cohort at the treatment endpoint are shown. Radiance scales are shown below each image. (F) Kaplan-Meier analysis of HeH-ALL-09 cohorts after 3 weeks (yellow box) of treatment. Graph title describes the genetic background of the leukemia. P values and sample sizes (n) are shown in the key. Significance was determined by log-rank (Mantel-Cox) test (A, B, D, and F). **P < 0.01, ***P < 0.001, and ****P < 0.0001. sr, steradian.