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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 1 (01 04 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 33393494 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Forkhead Box Protein O1
• Foxo1 protein, mouse
• Neoplasm Proteins
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases

Topics

• Animals
• Female
• Forkhead Box Protein O1 (genetics, metabolism)
• Male
• Mice
• Mice, Transgenic
• Neoplasm Proteins (genetics, metabolism)
• Phosphorylation (genetics)
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Protein-Tyrosine Kinases (genetics, metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• Dyrk Kinases