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 1

DYRK1A is required for B-ALL.

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DYRK1A is required for B-ALL. (A) DYRK1A mRNA expression (reads per kb p...
(A) DYRK1A mRNA expression (reads per kb per million mapped reads [RPKM]) distribution across cell lines from the Broad Institute’s CCLE, ordered by the median DYRK1A expression level (dotted line), the IQR (box), and up to 1.5 times the IQR (bars). NA, not assigned lineage. (B) DYRK1A mRNA expression versus the relative copy number (RCN) compared across B-ALL (n = 16), T-ALL (n = 16), AML (n = 35), and solid tumors (NSCLC [n = 122] and small-cell lung cancer [n = 50], colorectal [n = 57], breast [n = 57], and prostate [n = 8]) from the CCLE. Dots represent individual cell lines. Arrows indicate specific leukemic cell lines with chromosome 21 aneuploidy. (C) Western blot showing total DYRK1A protein in B-ALL cell lines (MHH-CALL-4, MUTZ-5, MHH-CALL-2, REH, RCH-ACV, 697, Nalm-6), patient samples (DS-ALL-02, DS-ALL-03, and HeH-ALL-09), and human BMMCs. Data are from the same gel as in Figure 5C, which was separately probed for FOXO1. Data are representative of 3 independent experiments. (D) Western blot showing total DYRK1A protein in primary murine CD19+ cells expressing BCR-ABL (p190). Data are representative of 3 independent experiments. (E–G) Lethally irradiated mice were transplanted with BCR-ABL (p190) B-ALL cells from the bone marrow of Dyrk1afl/fl or Dyrk1afl/+ mice, with or without Mx1-Cre, and then treated with pI:pC for 2 weeks (n = 2 per cohort). Data were analyzed 1 week after completion of pI:pC treatment. (E) Dyrk1a mRNA expression following quantitative reverse transcription PCR (qRT-PCR) of sorted CD19+GFP+ cells from murine bone marrow. Data indicate the mean ± SD (from triplicate wells of a representative sample). (F) Percentage of CD19+GFP+ cells in live bone marrow of individual mice. (G) Spleen weights of individual mice. (H and I) Kaplan-Meier analysis of mice transplanted with BCR-ABL (p190) B-ALL cells from the bone marrow of Dyrk1afl/fl (H) or Dyrk1afl/+ (I) mice with (red line) or without (blue line) Mx1-Cre after pI:pC injection for 2 weeks (yellow box). P values and sample sizes (n) are shown in the key. Data are representative of 2 independent transplantation experiments. Significance was determined by ANOVA with post hoc Bonferroni’s correction (E) or log-rank (Mantel-Cox) test (H and I). **P < 0.01 and ****P < 0.0001.