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

Bhansali, Rahul S.; Rammohan, Malini; Lee, Paul; Laurent, Anouchka P.; Wen, Qiang; Suraneni, Praveen; Yip, Bon Ham; Tsai, Yi Chien; Jenni, Silvia; Bornhäuser, Beat; Siret, Aurélie; Fruit, Corinne; Pacheco-Benichou, Alexandra; Harris, Ethan; Besson, Thierry; Thompson, Benjamin J.; Goo, Young Ah; Hijiya, Nobuko; Vilenchik, Maria; Izraeli, Shai; Bourquin, Jean Pierre; Malinge, Sébastien; Crispino, John D.

doi:10.1172/jci135937

Cited by 54 publications

(52 citation statements)

References 84 publications

(115 reference statements)

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“…40 In addition, DYRK1A inhibition or deletion can reduce the phosphorylation level of STAT3 at both the Y705 and S727 site. 41 Similarly, DYRK1A suppression using siRNA or pharmacological inhibition can abolish STAT3 nuclear accumulation by reducing its Y705 phosphorylation. 42 In line with the studies on DYRK1A, Gao et al showed that STAT3 may harbor a canonical DYRK1B phosphorylation site and that DYRK1B deletion using siRNA downregulates STAT3 tyrosine phosphorylation (Y705) but not serine phosphorylation in a cell-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics

et al. 2022

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Background: Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Since kinases have been reported to modulate mitochondrial function, we investigated the effects of dual-specificity tyrosine-regulated kinase 1B (DYRK1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. Methods: We engineered DYRK1B transgenic and knock out mice and used transverse aortic constriction (TAC) to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-seq analysis and mitochondrial functional analysis. Results: We found that DYRK1B expression was clearly upregulated in failing human myocardium as well as in hypertrophic murine hearts. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated TAC-induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α. Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. Conclusions: Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.

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Section: Discussionmentioning

confidence: 99%

DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics

et al. 2022

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“…There is abundant literature linking DYRK1A with solid cancers and leukemias (reviews: [ 107 , 108 , 109 ]). The most prominent examples are pancreatic cancer, brain tumor, acute megakaryoblastic leukemia (AMKL) [ 110 ], and acute lymphoblastic leukemia (ALL) [ 111 ] ( Table 3 for more details). DYRK1A regulates DNA damage response [ 72 , 74 ].…”

Section: Dyrks and Human Diseasementioning

confidence: 99%

“…Ovarian cancer [187,188] DYRK1A Acute megakaryoblastic leukemia (AMKL) [110,189] DYRK1A Acute lymphoblastic leukemia (ALL) [111,190,191]…”

Section: Dyrk1amentioning

confidence: 99%

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

Lindberg

Meijer

2021

IJMS

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Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease.

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“…Thus, the normal mitosis-to-meiosis transition might be disrupted by the local dysregulation of transcription caused by abnormally high amounts of DYRK1A. As shown by Li et al, DYRK1A is able to activate STAT3 [17,18], which in turn promotes GDNF expression [19]. GDNF is a major factor for stem cell renewal and non-differentiation commitment [20].…”

Section: Discussionmentioning

confidence: 99%

“…DYRK1A has been found to phosphorylate STAT3 Ser-727 in a simian fibroblast (COS-7) cell line [24] and in human B cell precursor of leukemia (MUTZ-5) cells [18]. Inhibition of DYRK1A with small interfering RNAs in human epithelial lung cancer cell lines (A549 and NCI-H460 cells) [17] inhibits the expression and nuclear translocation of STAT3.…”

Section: Discussionmentioning

confidence: 99%

DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

Dard

Moreau

Parizot

et al. 2021

Genes

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Down syndrome (DS) is the most common chromosomal disorder. It is responsible for intellectual disability (ID) and several medical conditions. Although men with DS are thought to be infertile, some spontaneous paternities have been reported. The few studies of the mechanism of infertility in men with DS are now dated. Recent research in zebrafish has indicated that overexpression of DYRK1A (the protein primarily responsible for ID in DS) impairs gonadogenesis at the embryonic stage. To better ascertain DYRK1A’s role in infertility in DS, we investigated the effect of DYRK1A overexpression in a transgenic mouse model. We found that overexpression of DYRK1A impairs fertility in transgenic male mice. Interestingly, the mechanism in mice differs slightly from that observed in zebrafish but, with disruption of the early stages of spermatogenesis, is similar to that seen in humans. Unexpectedly, we observed hypogonadotropic hypogonadism in the transgenic mice.

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

Cited by 54 publications

References 84 publications

DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics

DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

DYRK1A Overexpression in Mice Downregulates the Gonadotropic Axis and Disturbs Early Stages of Spermatogenesis

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