2. Academic Validation
  3. DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

DYRK1A regulates B cell acute lymphoblastic leukemia through phosphorylation of FOXO1 and STAT3

  • J Clin Invest. 2021 Jan 4;131(1):e135937. doi: 10.1172/JCI135937.
Rahul S Bhansali 1,  Malini Rammohan 1,  Paul Lee 2,  Anouchka P Laurent 3,  Qiang Wen 1,  Praveen Suraneni 1,  Bon Ham Yip 4,  Yi-Chien Tsai 5,  Silvia Jenni 5,  Beat Bornhauser 5,  Aurélie Siret 3,  Corinne Fruit 6,  Alexandra Pacheco-Benichou 6,  Ethan Harris 7,  Thierry Besson 6,  Benjamin J Thompson 8,  Young Ah Goo 9,  Nobuko Hijiya 10,  Maria Vilenchik 11,  Shai Izraeli 12,  Jean-Pierre Bourquin 5,  Sébastien Malinge 3 13,  John D Crispino 1 4
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Hematology/Oncology, Northwestern University, Chicago, Illinois, USA.
  • 2 Abbvie, North Chicago, Illinois, USA.
  • 3 INSERM U1170, Gustave Roussy Institute, Villejuif, France.
  • 4 Division of Experimental Hematology, Department of Hematology, St. Jude Children's Hospital, Memphis, Tennessee, USA.
  • 5 Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
  • 6 Normandie University, UNIROUEN, Institut National des Sciences Appliquées (INSA) Rouen, CNRS, Chimie Organique et Bioorganique - Réactivité et Analyse (COBRA) UMR 6014, Rouen, France.
  • 7 College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA.
  • 8 Xencor Inc., San Diego, California, USA.
  • 9 Proteomics Center of Excellence, Northwestern University, Evanston, Illinois, USA.
  • 10 Division of Pediatric Hematology/Oncology, Columbia University, New York, New York, USA.
  • 11 Felicitex Therapeutics Inc., Boston, Massachusetts, USA.
  • 12 Pediatric Hematology Oncology, Schneider Children's Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel.
  • 13 Telethon Kids Institute, Telethon Kids Cancer Centre (TKCC), Nedlands, Western Australia, Australia.
PMID: 33393494 DOI: 10.1172/JCI135937
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.

Keywords

Leukemias; Oncology.

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