DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3

Thompson, Benjamin J.; Bhansali, Rahul S.; Diebold, Lauren; Cook, Daniel E.; Stolzenburg, Lindsay R.; Casagrande, Anne-Sophie; Besson, Thierry; Leblond, Bertrand; Désiré, Laurent; Malinge, Sébastien; Crispino, John D.

doi:10.1083/jcb.2095oia105

Cited by 7 publications

(9 citation statements)

References 31 publications

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“…The relative contribution of either DYRK1A or DYRK1B to cell cycle regulation appears to depend on the specific experimental system. In aggregate, knockdown experiments suggest that many tumor cell lines with high expression levels of DYRK1B depend on the activity of this kinase to maintain quiescence (see Table 1), while DYRK1A has been shown to regulate cell cycle exit in terminal differentiation of neurons and lymphocytes [22,26,27].…”

Section: Cell Cycle Function Of Dyrk1bmentioning

confidence: 99%

A wake‐up call to quiescent cancer cells – potential use of DYRK1B inhibitors in cancer therapy

Becker

2017

The FEBS Journal

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Nondividing cancer cells are relatively resistant to chemotherapeutic drugs and environmental stress factors. Promoting cell cycle re-entry of quiescent cancer cells is a potential strategy to enhance the cytotoxicity of agents that target cycling cells. It is therefore important to elucidate the mechanisms by which these cells are maintained in the quiescent state. The protein kinase dual specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) is overexpressed in a subset of cancers and maintains cellular quiescence by counteracting G 0 /G 1 -S phase transition. Specifically, DYRK1B controls the S phase checkpoint by stabilizing the cyclin-dependent kinase (CDK) inhibitor p27Kip1 and inducing the degradation of cyclin D. DYRK1B also stabilizes the DREAM complex that represses cell cycle gene expression in G 0 arrested cells. In addition, DYRK1B enhances cell survival by upregulating antioxidant gene expression and reducing intracellular levels of reactive oxygen species (ROS). Substantial evidence indicates that depletion or inhibition of DYRK1B drives cell cycle re-entry and enhances apoptosis of those quiescent cancer cells with high expression of DYRK1B. Furthermore, small molecule DYRK1B inhibitors sensitize cells to the cytotoxic effects of anticancer drugs that target proliferating cells. These encouraging findings justify continued efforts to investigate the use of DYRK1B inhibitors to disrupt the quiescent state and overturn chemoresistance of noncycling cancer cells.

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Section: Cell Cycle Function Of Dyrk1bmentioning

confidence: 99%

A wake‐up call to quiescent cancer cells – potential use of DYRK1B inhibitors in cancer therapy

Becker

2017

The FEBS Journal

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“…One of the most dose sensitive chromosome 21 genes known for multiple pathway de-regulations when copy number is increased, is DYRK1A. Increased DYRK1A-dose could promote both AML and ALL pathogenesis (55,56). Interestingly, both DYRK1A, and another chromosome 21 gene ITSN also play a role in activating RAS, in specific cellular contexts (57,58).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, both DYRK1A, and another chromosome 21 gene ITSN also play a role in activating RAS, in specific cellular contexts (57,58). It will be important to unravel the mechanisms behind the actions of these chromosome 21 genes, as their specific inhibition may be an additional component to consider in combinatorial therapy approaches (56). This is highlighted by very frequent observations of extra copies of chromosome 21 as acquired changes in DS and non-DS ALL, both at diagnosis, and at relapse (20,59).…”

Section: Discussionmentioning

confidence: 99%

RAS activation via CRLF2 signaling is a widespread mechanism in Down syndrome acute lymphoblastic leukemia regardless of RAS mutations

Koschut

Ray

et al. 2020

Preprint

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Background: Down syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by the high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices.Results: Here we show that in primary leukemic cells from DS-ALL, in the absence of RAS-mutations, wild-type (wt)RAS is active, and/or can be induced by the physiological ligand TSLP of the transmembrane-receptor CRLF2. We show active/inducible RAS in 14/20 (70%) of primary DS-ALL samples analyzed, 8 of which had no RAS-mutations, but 75% of those had either mutated or hyperphosphorylated JAK2. No wtRAS cases with mutated/hyperphosphorylated JAK2 were observed that lacked activated RAS protein. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. We show that TSLP boosts the direct binding of active PTPN11 to wtRAS. Pre-inhibition of RAS or PTPN11, but not of PI3K or JAK signaling, prevented TSLP-induced RAS-GTP boost.Using multivariate-clustering based on RAS-activity/inducibility we show significant separation between standard-risk and high-risk DS-ALL groups. Cox proportional-hazards model showed proteinactivity (but not mutation status) as independently predictive of outcome. Conclusions:Our data indicate that RAS protein activity levels (and not JAK2/RAS mutation profiles), are predictive of outcome. Importantly, our data suggest that inhibition of RAS and direct RASpathway components should be combined with PI3K/mTOR and/or JAK2 inhibitors for high-risk cases.Therapeutically this is relevant for >75% of DS-ALL and our additional data suggest that it warrants further investigation in high-risk non-DS-ALL.wtRAS activation is frequent in DS-ALL

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“…Several factors have been identified that suppress proliferation in late-pre-B cells and allow Igl recombination. These include B cell translocation gene 2 (BTG2) and protein arginine methyl transferase 1 (PRMT1) (Dolezal et al, 2017), the signal transducers RAS (Mandal et al, 2009) and dual specificity tyrosine-regulated kinase 1A (DYRK1A) (Thompson et al, 2015) and the transcription factors interferon regulatory factor-4 and -8 (IRF4, IRF8) (Lu et al, 2003), IKAROS and AIOLOS (Ma et al, 2010), BCL-6 (Nahar et al, 2011) and FOXO3a (Herzog et al, 2008). In pro-B cells, IL-7 promotes cell cycle progression (Clark et al, 2014) and the RNA-binding proteins (RBPs) ZFP36L1 and ZFP36L2 suppress proliferation, allowing Igh chain recombination and B cell development (Galloway et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Polypyrimidine Tract Binding Proteins are essential for B cell development

Monzón-Casanova

Matheson

Tabbada

et al. 2019

Preprint

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During B cell development, recombination of immunoglobulin loci is tightly coordinated with the cell cycle to avoid unwanted rearrangements of other genomic locations. Several factors have been identified that suppress proliferation in late-pre-B cells to allow light chain recombination. By comparison, our knowledge of factors limiting proliferation during heavy chain recombination at the pro-B cell stage is very limited. Here we identify an essential role for the RNA-binding protein Polypyrimidine Tract Binding Protein 1 (PTBP1) in B cell development. Absence of PTBP1 and the paralog PTBP2 results in a complete block in development at the pro-B cell stage. PTBP1 promotes the fidelity of the transcriptome in pro-B cells. In particular, PTBP1 controls a cell cycle mRNA regulon, suppresses entry into S-phase and promotes progression into mitosis. Our results highlight the importance of S-phase entry suppression and post-transcriptional gene expression control by PTBP1 in pro-B cells for proper B cell development.

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DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3

Cited by 7 publications

References 31 publications

A wake‐up call to quiescent cancer cells – potential use of DYRK1B inhibitors in cancer therapy

A wake‐up call to quiescent cancer cells – potential use of DYRK1B inhibitors in cancer therapy

RAS activation via CRLF2 signaling is a widespread mechanism in Down syndrome acute lymphoblastic leukemia regardless of RAS mutations

Polypyrimidine Tract Binding Proteins are essential for B cell development

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