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 5

FOXO1 is required for the B-ALL DNA damage response and can be targeted with AS1842856.

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FOXO1 is required for the B-ALL DNA damage response and can be targeted ...
(A) FOXO1 mRNA expression (RPKM) distribution across cell lines from the Broad Institute’s CCLE, ordered by median FOXO1 expression levels (line), the IQR (box), and up to 1.5 times the IQR (bars). HL, Hodgkin lymphoma. (B) FOXO1 mRNA expression versus the RCN across B-ALL (n = 16), T-ALL (n = 16), AML (n = 35), and solid tumors (non–small cell [n = 122] and small cell [n = 50] lung, colorectal [n = 57], breast [n = 57], and prostate [n = 8]) from the CCLE. Dots represent individual cell lines. (C) Western blot showing total FOXO1 protein in B-ALL cell lines (MHH-CALL-4, MUTZ-5, MHH-CALL-2, REH, RCH-ACV, 697, and 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 1C, which was separately probed for DYRK1A. Pound sign indicates the nonspecific band. (D) Western blot showing total FOXO1 protein in Nalm-6 and 697 cells after treatment with EHT 1610 for 8 hours. C, cytoplasmic; N, nuclear. (E) IC50 values for B-ALL cell lines, patient samples, and primary murine pre-B cells treated with AS1842856 for 48 hours, based on data in Supplemental Figure 6B. (F) IC50 values for patient samples (DS-ALL, HeH-ALL, and nonaneuploid B-ALL control) treated with AS1842856 or idarubicin. Dots represent 3 biological replicates of different patient samples. (G) Quantification of the percentage of γ-H2AX+ cells from the data in Supplemental Figure 6B. Data indicate the mean ± SD. (H) FOXO1 target gene mRNA expression from qRT-PCR in Nalm-6 (top) and 697 (bottom) cells after treatment with EHT 1610, AS1842856, or both. Data indicate the mean ± SD (from triplicate wells of a representative sample). (I) Heatmap of CI values when combining EHT 1610 with AS1842856 at the multiples of IC50 values indicated in Supplemental Table 3. n = 3 biological replicates (C–I). Significance was determined by ANOVA with post hoc Bonferroni’s correction (G and H). **P < 0.01, ***P < 0.001, and ****P < 0.0001.