Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors

Tomiatti, Viktoriya; Istvànffy, Rouzanna; Pietschmann, Elke; Kratzat, Susanne; Hoellein, Alexander; Quintanilla-Fend, Leticia; Bubnoff, Nikolas von; Peschel, Christian; Oostendorp, Robert A.J.; Keller, Ulrich

doi:10.1038/onc.2014.364

Cited by 13 publications

(16 citation statements)

References 46 publications

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“…These data are in agreement with publicly available datasets, including the MILE study [46] , which also found significantly higher CKS1B and CKS2 expression in healthy bone marrow mononuclear cells compared to bulk MLLr leukaemic samples. Altogether, these analyses revealed a dysregulation of CKS expression in MLLr leukaemia, but also in BCR-ABL positive CML [47] , consistent with putative roles for CKS1B and CKS2 in leukaemogenesis. CKS expression levels might also be linked to the relative stage of maturation in normal haematopoiesis (CD34 + versus PBMC).…”

Section: Resultssupporting

confidence: 69%

“…Previous studies, describing the requirement of Cks1 [8] , [47] and Cks2 [8] , [13] in cell cycle dynamics, have postulated that targets of the Cks1/Cks2 axis may extend beyond the specific subset of Cyclins and CKIs [5] , [7] , [10] , [13] , [62] . Here, we provide the first evidence for an essential role of the Cks1/Cks2 axis in the regulation of Mll1 expression.…”

Section: Discussionmentioning

confidence: 99%

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The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability

Grey

Ivey

Milne

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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The Cdc28 protein kinase subunits, Cks1 and Cks2, play dual roles in Cdk-substrate specificity and Cdk-independent protein degradation, in concert with the E3 ubiquitin ligase complexes SCFSkp2 and APCCdc20. Notable targets controlled by Cks include p27 and Cyclin A. Here, we demonstrate that Cks1 and Cks2 proteins interact with both the MllN and MllC subunits of Mll1 (Mixed-lineage leukaemia 1), and together, the Cks proteins define Mll1 levels throughout the cell cycle. Overexpression of CKS1B and CKS2 is observed in multiple human cancers, including various MLL-rearranged (MLLr) AML subtypes. To explore the importance of MLL-Fusion Protein regulation by CKS1/2, we used small molecule inhibitors (MLN4924 and C1) to modulate their protein degradation functions. These inhibitors specifically reduced the proliferation of MLLr cell lines compared to primary controls. Altogether, this study uncovers a novel regulatory pathway for MLL1, which may open a new therapeutic approach to MLLr leukaemia.

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Section: Resultssupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability

Grey

Ivey

Milne

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Surface markers were stained using antibodies from eBioscience (eBioscience Natutec, Heidelberg Germany, http://www.ebioscience.com), except for PE‐Cy5.5‐streptavidin conjugate, which was obtained from Invitrogen (Thermo Fischer, Karlsruhe, Germany, https://www.thermofisher.com) as previously described (Supporting Information Table S1) . For bone marrow staining, 2 × 10 6 cells were used for mature population stains, and 6 × 10 6 for staining of progenitors and HSCs.…”

Section: Methodsmentioning

confidence: 99%

Loss of Sfrp2 in the Niche Amplifies Stress-Induced Cellular Responses, and Impairs the In Vivo Regeneration of the Hematopoietic Stem Cell Pool

et al. 2016

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Sfrp2 is overexpressed in stromal cells which maintain hematopoietic stem cells (HSCs) during in vitro culture. We here showed, that coculture of hematopoetic cells with stromal cells with reduced expression of Sfrp2 increases the number lineage-negative Kit 1 Sca-1 1 (LSK) and progenitor cells in vitro. The LSK cells from these cocultures showed activation of canonical Wnt signaling, higher levels of Ki-67, BrdU incorporation, and the number of cH2A.X positive foci. Total repopulating activity of these cultures was, however, diminished, indicating loss of HSC. To extend these in vitro data, we modelled stress in vivo, i.e., by aging, or 5-FU treatment in Sfrp2 2/2 mice, or replicative stress in regeneration of HSCs in Sfrp2 2/2 recipients. In all three in vivo stress situations, we noted an increase of LSK cells, characterized by increased levels of b-catenin and cyclin D1. In the transplantation experiments, the increase in LSK cells in primary recipients was subsequently associated with a progressive loss of HSCs in serial transplantations. Similar to the in vitro coculture stress, in vivo genotoxic stress in 5-FU-treated Sfrp2 2/2 mice increased cell cycle activity of LSK cells with higher levels of BrdU incorporation, increased expression of Ki-67, and canonical Wnt signaling. Importantly, as noted in vitro, increased cycling of LSKs in vivo was accompanied by a defective cH2A.X-dependent DNA damage response and depolarized localization of acetylated H4K16. Our experiments support the view that Sfrp2 expression in the niche is required to maintain the HSC pool by limiting stressinduced DNA damage and attenuating canonical Wnt-mediated HSC activation. STEM CELLS 2016;34:2381-2392 SIGNIFICANCE STATEMENTHematopoietic stress (coculture, regeneration, genotoxicity, and aging) results in reduced hematopoietic stem cell (HSC) numbers and quality. Here, we show that stromal Sfrp2 dampens the response of HSC to different forms of stress in vitro and in vivo. Without Sfrp2, the niche's ability to limit the stress response is diminished. As a result, HSC show an increased DNA damage response, do not efficiently self-renew, resulting in a defective regeneration of the HSC pool. Thus, SFRP2 secreted by the niche preserves the number of HSCs, a finding which may help to identify new ways to prevent the loss of stem cells under stress conditions.

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“…The data from this work also shows that YM-155 mediates a loss in (budding uninhibited by benzimidazoles 1) BUB1 [-5.95, p<0.001]/BUB1B which could block not only checkpoint activity leading to mitosis but also spindle assembly, kinetochore-microtubule attachment and chromosome segregation (88,108,109). Other related transcripts down-regulated by YM-155 include SKP2 [-2.23, p<0.001] which encodes for S-phase kinase-associated protein 2 which is part of SCF complex (SKp1-cullin-FBox)/ Cks1 inversely associated with concentration of p27Kip1 and p57Kip2 (CDK inhibitors) which initiate cell cycle arrest (110,111).…”

Section: Discussionmentioning

confidence: 99%

Effects of Sepantronium Bromide (YM-155) on the Whole Transcriptome of MDA-MB-231 Cells: Highlight on Impaired ATR/ATM Fanconi Anemia DNA Damage Response

Mazzio

Lewis

Elhag

et al. 2018

Cancer Genomics Proteomics

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Sepantronium bromide (YM-155) is believed to elicit apoptosis and mitotic arrest in tumor cells by reducing (BIRC5, survivin) mRNA. In this study, we monitored changes in survivin mRNA and protein after treating MDA-MB-231 cells with YM-155 concurrent with evaluation of whole transcriptomic (WT) mRNA and long intergenic non-coding RNA at 2 time points: 8 h sub-lethal (83 ng/mL) and 20 h at the LC (14.6 ng/mL). The data show a tight association between cell death and the precipitating loss of survivin protein and mRNA (-2.67 fold-change (FC), p<0.001) at 20 h, questioning if the decline in survivin is attributed to cell death or drug impact. The meager loss of survivin mRNA was overshadowed by enormous differential change to the WT in both magnitude and significance for over 2000 differentially up/down-regulated transcripts: (+22 FC to -12 FC, p<0.001). The data show YM-155 to up-regulate transcripts in control of circadian rhythm (NOCT, PER, BHLHe40, NFIL3), tumor suppression (SIK1, FOSB), histone methylation (KDM6B) and negative feedback of NF-kappa B signaling (TNFAIP3). Down-regulated transcripts by YM-155 include glucuronidase (GUSBP3), numerous micro-RNAs, DNA damage repair elements (CENPI, POLQ, RAD54B) and the most affected system was the ataxia-telangiectasia mutated (ATM)/Fanconi anemia E3 monoubiquitin ligase core complexes (FANC transcripts - A/B/E/F/G/M), FANC2, FANCI, BRCA1, BRCA2, RAD51, PALB2 gene and ATR (ATM- and Rad3-Related) pathway. In conclusion, these findings suggest that a primary target of YM-155 is the loss of replicative DNA repair systems.

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Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors

Cited by 13 publications

References 46 publications

The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability

The Cks1/Cks2 axis fine-tunes Mll1 expression and is crucial for MLL-rearranged leukaemia cell viability

Loss of Sfrp2 in the Niche Amplifies Stress-Induced Cellular Responses, and Impairs the In Vivo Regeneration of the Hematopoietic Stem Cell Pool

Effects of Sepantronium Bromide (YM-155) on the Whole Transcriptome of MDA-MB-231 Cells: Highlight on Impaired ATR/ATM Fanconi Anemia DNA Damage Response

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