A Study on the Role of DYRK1A in Acute Lymphoblastic Leukemia

Rammohan, Malini Krishna

doi:https://doi.org/10.21985/n2-9pj7-0g31

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A Study on the Role of DYRK1A in Acute Lymphoblastic Leukemia

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Down syndrome occurs in approximately 1 in 700 births annually in the United States. It is caused by trisomy of chromosome 21, and is characterized by dysmorphic features and congenital abnormalities. Although children with DS have a decreased risk of developing solid tumors, they have an increased risk of acquiring hematologic malignancies. Recent studies have shown that children with DS have a 20-fold increased risk of developing pre-B cell acute lymphoblastic leukemia (DS-ALL). There are several lines of evidence that show trisomy 21 genes play a critical role in lymphoid development. Recent studies have implicated DYRK1A to be a key genetic contributor to the increased risk of the DS-ALL. DYRK1A, which encodes dual-specificity tyrosine phosphorylation-regulated kinase 1A, is located in Down Syndrome critical region (DSCR) in trisomy 21. While its role has been extensively studied in neurological and cognitive defects, it was only recently that DYRK1A had been characterized as a potent megakaryoblastic tumor promoting gene. Interestingly, analysis of Oncomine database revealed DYRK1A levels to be elevated in both T-ALL and B-ALL, however, the role of DYRK1A in lymphoid leukemia remained largely unknown. Our lab had previously shown DYRK1A to be critical for lymphoid cell development. Conditional knockout of DYRK1A in mice resulted in ablation of total number of B and T lymphocytes, while having no significant effect on myeloid lineage. This selective effect on lymphoid population made DYRK1A a valuable therapeutic target. We discovered 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 which are indispensable in B cell development, are critical substrates of DYRK1A. Loss of DYRK1A-mediated FOXO1 and STAT3 signaling disrupts DNA damage and ROS regulation, respectively, leading to preferential cell death in leukemic B cells. Thus, we have identified a novel DYRK1A-FOXO1-STAT3 axis that facilitates the development and maintenance of B-ALL. Conventional chemotherapies prescribed to DS-ALL patients result in low-quality outcomes compared to non-DS cohort due to higher treatment related mortality and a higher relapse rate. Through our studies, we discovered DYRK1A and FOXO1 to be efficacious targets in B-ALL, and may hold therapeutic value in models of disease with chromosome 21 aneuploidy. Additionally, in B-ALL with increased JAK signaling, selective inhibition of its downstream target, STAT3, could offer a new therapeutic approach.

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