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 2

Inhibition of DYRK1A with EHT 1610 impairs B-ALL cell growth.

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Inhibition of DYRK1A with EHT 1610 impairs B-ALL cell growth. (A) Repres...
(A) Representative flow cytometric plot of a CellTrace Violet dye dilution assay in GFP+ cultured pre-B cells transduced with MIGR1 or MIGR1-Dyrk1aK188R. (B) Quantification of the CellTrace Violet dye dilution assay data shown in A (48 and 72 hours after transduction). Data indicate the mean ± SD. (C) Quantification of the CellTrace Violet dye dilution assay data shown in Supplemental Figure 2A (120 hours after transduction). Data indicate the mean ± SD. (D) Western blot showing p–cyclin D3 (Thr283) and total cyclin D3 protein in MHH-CALL-4 cells after 5 hours of treatment with EHT 1610. (E) Representative flow cytometric plots of DNA versus RNA content in Nalm-6 and MUTZ-5 cells after a 48-hour treatment with EHT 1610. Numbers indicate the percentage of cells in each gate. (F) Cell-cycle phase distribution based on the gating in E and Supplemental Figure 2B. Data indicate the mean ± SD. (G) IC50 values of B-ALL cell lines and patient samples treated with EHT 1610 for 72 or 96 hours based on the data in Supplemental Figure 3. (H) IC50 values for patient samples treated with the DYRK1A inhibitors EHT 1610, harmine, or INDY. Dots represent the mean of 3 biological replicates of each patient sample. SR, standard risk; MR, medium risk; HR/VHR, high risk/very high risk. (I) Heatmap of CI values when combining EHT 1610 with dexamethasone (Dex), cytarabine (AraC), or methotrexate (MTX) at the multiples of IC50 values indicated in Supplemental Table 3. n = 3 biological replicates (A–I). Significance was determined by unpaired t test (B) or ANOVA with post hoc Bonferroni’s correction (C and F). For F, values were compared with DMSO within each cell line. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.