TY - JOUR
T1 - DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3
AU - Bhansali, Rahul S
AU - Rammohan, Malini
AU - Lee, Paul
AU - Laurent, Anouchka P
AU - Wen, Qiang
AU - Suraneni, Praveen
AU - Yip, Bon Ham
AU - Tsai, Yi-Chien
AU - Jenni, Silvia
AU - Bornhauser, Beat
AU - Siret, Aurélie
AU - Fruit, Corinne
AU - Pacheco-Benichou, Alexandra
AU - Harris, Ethan
AU - Besson, Thierry
AU - Thompson, Benjamin J
AU - Goo, Young Ah
AU - Hijiya, Nobuko
AU - Vilenchik, Maria
AU - Izraeli, Shai
AU - Bourquin, Jean-Pierre
AU - Malinge, Sébastien
AU - Crispino, John D
PY - 2021/1/4
Y1 - 2021/1/4
N2 - 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.
AB - 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.
KW - Animals
KW - Female
KW - Forkhead Box Protein O1/genetics
KW - Male
KW - Mice
KW - Mice, Transgenic
KW - Neoplasm Proteins/genetics
KW - Phosphorylation/genetics
KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics
KW - Protein Serine-Threonine Kinases/genetics
KW - Protein-Tyrosine Kinases/genetics
KW - STAT3 Transcription Factor/genetics
KW - Dyrk Kinases
UR - https://www.scopus.com/pages/publications/85098893206
U2 - 10.1172/JCI135937
DO - 10.1172/JCI135937
M3 - Article
C2 - 33393494
SN - 0021-9738
VL - 131
JO - The Journal of Clinical Investigation
JF - The Journal of Clinical Investigation
IS - 1
M1 - e135937
ER -
