Bhansali, Rahul SRammohan, MaliniLee, PaulLaurent, Anouchka PWen, QiangSuraneni, PraveenYip, Bon HamTsai, Yi-ChienJenni, SilviaBornhauser, BeatSiret, AurélieFruit, CorinnePacheco-Benichou, AlexandraHarris, EthanBesson, ThierryThompson, Benjamin JGoo, Young AhHijiya, NobukoVilenchik, MariaIzraeli, ShaiBourquin, Jean-PierreMalinge, SébastienCrispino, John D
Summary
DYRK1A is an enzyme that is coded on human chromosome 21 (HSA21) that has previously been highlighted as contributing to many of the effects of Down syndrome (DS). These effects include cognitive issues and Alzheimer's disease, particularly early onset. Another common effect seen in children with DS is a predisposition to developing leukemia, especially B cell acute lymphoblastic leukemia (B-ALL). However, the HSA21 genes that contribute to this have not been defined until this study. In this project, researchers report that the enzyme DYRK1A is overexpressed and required for B-ALL, contributing to the predisposition to B-ALL in children with DS.
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.
Conditions
Alzheimer Disease, Cancer, Death, Leukemia, Neoplasms, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cell Lymphoblastic Leukemia-Lymphoma