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 3

Kinase assay–linked phosphoproteomics identifies candidate DYRK1A substrates in pre-B cells.

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Kinase assay–linked phosphoproteomics identifies candidate DYRK1A substr...
(A) Global differential phosphoproteomics analysis was performed on primary murine pre-B cells treated with 2 μM EHT 1610 or DMSO for 2 hours. Peptides that were 1.5-fold differentially phosphorylated were analyzed in the STRING database for upregulated KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways. (B) Venn diagram showing overlapping peptides from the kinase-dependent phosphoproteome and in vitro substrates from the experiments described in Supplemental Figure 4, A, E, and F. Numbers indicate unique peptides in each cohort, and circle sizes indicate the relative size of the protein group. (C) Scatter plot depicting dephosphorylated peptides from global phosphoproteomics versus phosphorylated peptides from kinase assay phosphoproteomics. Arrows indicate the top 5 highest-scoring hits. FC, fold change versus the negative control. (D) A total of 109 overlapping peptides from C and B were analyzed in the STRING database for GO Biological Process enrichment. Individual annotations are functionally color-coded in the key. n = 2 biological replicates for each proteomics assay (A–D).