DYRK1A Regulates B Cell Acute Lymphoblastic Leukemia Through Phosphorylation of FOXO1 and STAT3

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2021 Jan 4

PMID 33393494

Citations 40

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

Aurelie 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

Sebastien Malinge

John D Crispino

Affiliations

Soon will be listed here.

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.

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