scholarly journals The mysterious human epidermal cell cycle, or an oncogene-induced differentiation checkpoint

Cell Cycle ◽  
2012 ◽  
Vol 11 (24) ◽  
pp. 4507-4516 ◽  
Author(s):  
Alberto Gandarillas
Keyword(s):  
Cell Cycle ◽  
Epidermal Cell ◽  
Induced Differentiation

The epidermal cell cycle during the last larval instar ofPieris brassicae (Lepidoptera)

1980 ◽  
Vol 136 (1) ◽  
pp. 11-20 ◽  
Author(s):  
J. Lhonor� ◽  
A. Bouthier ◽  
P. Beydon ◽  
J. L. Pennetier ◽  
R. Lafont
Keyword(s):  
Cell Cycle ◽  
Epidermal Cell ◽  
Larval Instar

Cell cycle analysis during retinoic acid induced differentiation of a human embryonal carcinoma-derived cell line

1987 ◽  
Vol 20 (2-3) ◽  
pp. 153-160 ◽  
Author(s):  
Christine L. Mummery ◽  
Marga A. van Rooijen ◽  
Stieneke E. van den Brink ◽  
Siegfried W. de Laat
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
Cell Line ◽  
Embryonal Carcinoma ◽  
Cell Cycle Analysis ◽  
Induced Differentiation

scholarly journals NADPH oxidase-induced differentiation in B-cells elucidated with cell cycle analysis

2005 ◽  
Vol 45 (supplement) ◽  
pp. S260
Author(s):  
Y. Ando ◽  
T. Suzuki ◽  
W. Hiraoka
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
Nadph Oxidase ◽  
Cell Cycle Analysis ◽  
Induced Differentiation

PSL, a nuclear cell-cycle associated antigen is increased during retinoic acid-induced differentiation of HL-60 cells

1987 ◽  
Vol 147 (3) ◽  
pp. 993-999 ◽  
Author(s):  
Jean-Philippe Barque ◽  
Sylvie Lagaye ◽  
Annie Ladoux ◽  
Véronique Della Valle ◽  
Jean Pierre Abita ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Retinoic Acid ◽  
Induced Differentiation ◽  
Nuclear Cell

IRF1 Is Crucial for ATRA-Induced Differentiation By Regulating Its Multiple Functional Targets

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2220-2220
Author(s):  
Wen Jin ◽  
Huanwei Wang ◽  
Dong Shi ◽  
Kankan Wang
Keyword(s):  
Cell Cycle ◽  
Signaling Pathways ◽  
Binding Sites ◽  
Early Stage ◽  
Gene Set Enrichment Analysis ◽  
Biological Processes ◽  
Atra Treatment ◽  
Induced Differentiation ◽  
Transcriptional Regulatory ◽  
Regulatory Cascades

Abstract Correspondence: Kankan Wang, State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine; E-mail: [email protected]. Abstract Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), characterized by the accumulation of the blasts arrest at the promyelocyte stage and cytogenetically defined by the PML-RARa oncofusion gene generated by the t(15;17) translocation. All-trans retinoic acid (ATRA), as a front-line agent in the treatment of APL, can reactivate PML-RARα targets by transcriptional switch and degradation of PML-RARα fusion protein, finally induce promyelocytic blasts to terminal differentiation and elicit complete remission of APL. However, a significant amount of evidence has demonstrated that the effect of ATRA treatment is not simply a direct consequence of the reversion of pathological processes caused by PML-RARα. Furthermore, the removal of PML-RARa only has been illustrated to stimulate cell apoptosis and demonstrated to be insufficient for ATRA-mediated differentiation. There must be other important signaling pathways synergizing with ATRA to induce differentiation. And several lines of studies have indicated early ATRA-responsive genes are more important in the ATRA-induced transcriptional regulatory cascades by mediating crosstalk among various ATRA downstream pathways. Our previous studies, together with others, indicate that interferon regulator factor 1 (IRF1) is upregulated rapidly at a very early stage after ATRA treatment. It’s not only a direct target of ATRA, but also a central transducer of IFN signaling. IFN and ATRA can potentiate each other to induce gene expression and various biological responses. Gene set enrichment analysis (GSEA) showed that IRF1 was the major transcriptional factor participating in the regulation of ATRA-upregulated genes, especially at the early stage after ATRA treatment. Thus, IRF1 may play an important role in ATRA-induced transcriptional regulatory cascades by regulating its targets. To understand molecular mechanisms of IRF1 after ATRA induction, we performed ChIP-seq to identify the genome-wide binding sites of IRF1 at 4 hours after ATRA treatment. ChIP-QPCR and luciferase assays were conducted to validate the ChIP-seq enriched target genes of IRF1 and further demonstrated that IRF1 can directly transactivated its targets in 293T cells. Furthermore, the binding sites of IRF1 mainly located near the transcription start sites (TSS), especially at the proximal promoter region, and conserved. Motif analysis showed that there were two binding motifs, classical IRF1 motif (short motif) and long motif. And these differential motifs appeared at different stages during ATRA-induced differentiation and involved in different sets of biological processes. After gene ontology analysis, IRF1 targets were identified to be involved in a variety of important biological processes, such as hematopoiesis, cell cycle, apoptosis, JAK-STAT cascade, immune response, etc. Furthermore, knockdown of IRF1 with siRNA led to a significantly repression of ATRA-induced differentiation, degradation of PML-RARα, cell cycle arrest and proliferation inhibition in APL cells. These results collectively demonstrate that IRF1 plays a crucial role in ATRA-induced differentiation and mediates multiple signaling pathways by regulating its various functional targets. Thus, our results will provide a better understanding of treatment mechanisms in APL and extend the application of ATRA to the treatment of other cancers. Disclosures No relevant conflicts of interest to declare.

Elevated EGR2 Expression Provides a Potential Link Between Cell Cycle Arrest and Induced Differentiation in Myeloid Progenitor Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2733-2733
Author(s):  
Joshua B. Bland ◽  
Jose R. Peralta ◽  
William T. Tse
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Progenitor Cells ◽  
Myeloid Differentiation ◽  
Phenotypic Effect ◽  
Induced Differentiation ◽  
Hl60 Cells ◽  
Cycle Arrest ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells

Abstract Similar to many immature cell types, myeloid progenitor cells need to exit cell cycle to undergo terminal differentiation, but the mechanism linking the two is still unclear. Elucidating this mechanism could lead to the development of new differentiation therapies to treat myeloid leukemia. Recent studies have suggested that the processes regulating myeloid differentiation and cell cycle progression together constitute a positive feedback loop where each process reciprocally affects the other. To study the relationship between these processes, we examined early cellular and molecular events associated with induced differentiation of the HL60 human promyelocytic leukemia cells. We treated HL60 cells with 3 classical inducers of differentiation (vitamin D3 analog EB1089 (EB), all-trans retinoic acid (ATRA), and dimethyl sulfoxide (DMSO)), along with PD0332991 (PD), a selective cyclin D-dependent kinase 4/6 inhibitor that caused G1-phase-specific cell-cycle arrest. We evaluated differentiation of the treated cells by flow cytometric analysis of CD11b (integrin αM) and CD71 (transferrin receptor) expression. In untreated HL60 cells, a baseline subset of 3-5% of cells exhibits a differentiated, CD11b+CD71- phenotype. Exposure to the various inducers revealed a progressive increase in the percentage of CD11b+CD71- cells with time, such that by day 4 of treatment, it has increased to 50-90% in the treated samples, indicating that all 4 agents tested were effective in inducing myeloid differentiation. To understand how differentiation induced by each agent affects cell cycle progression, the cell cycle status of the induced cells were evaluated by a BrdU-incorporation assay after a 30-minute pulse of BrdU labeling. Uninduced cells exhibited a baseline cell cycle phase distribution of 64%-28%-8% (G1-S-G2/M phases). After 1 day of induction, EB-treated sample showed no changes in the distribution (58%-33%-9%), but ATRA, DMSO and PD-treated samples showed significant changes, with an increase of cell numbers in G1 phase and decrease in S phase (74%-18%-8%, 79%-13%-8%, and 93%-4%-3%, respectively). These results reveal that an early induction of G1 arrest was caused by treatment with ATRA, DMSO and PD, but not EB, and that the cell cycle arrest occurred before major changes in the myeloid phenotype were observed. To determine how the cell cycle perturbation relates to changes in the underlying genetic regulatory network, we examined by quantitative RT-PCR analysis the expression of several transcription factors associated with myeloid differentiation. PU.1 and CEBPA were found to be expressed at high levels but these levels did not change upon treatment with the inducing agents. Similarly, the expression levels of GFI1 and EGR1 did not change significantly with induction. In contrast, the expression level of EGR2 (Early Growth Response 2) was found to be low initially but became elevated upon treatment with 3 of the 4 inducers. EGR2 is a zinc finger transcription factor implicated in the control of a switch between pro- and anti-proliferation pathways. EGR2 has been shown to regulate the transition between differentiation states of Schwann cells, induction of anergic and regulatory T cells, growth and survival of osteoclasts, and proliferation and apoptosis of acute myeloid leukemia blasts. We found that EGR2 expression, after 1 day of treatment with ATRA, DMSO or PD, was increased by 5.2 ± 0.9, 7.6 ± 1.9, 5.8 ± 0.9 folds, respectively, whereas treatment with EB led to no significant change (1.5 ± 0.2 fold). We evaluated whether simultaneous treatment of the cells with 2 inducers would result in an additive effect. Treatment of HL60 cells with a combination of ATRA/DMSO, ATRA/PD, or DMSO/PD increased the percentage of CD11b+CD71- cells to 55%, 70% and 25% after just 1 day of treatment. In line with the enhanced phenotypic effect, the expression level of EGR2 was further elevated to 7.7 ± 1.4, 15.4 ± 3.5, and 11.3 ± 3.4 folds, respectively, when the cells were treated with the above inducer combinations, indicating a tight association between EGR2 expression and the phenotypic effect. In summary, our data suggest that elevated expression of EGR2 is an early event in the induction of myeloid differentiation in HL60 cells. Because of its known role in cell cycle regulation, EGR2 could function as a mechanistic link between cell cycle arrest and induced differentiation in myeloid progenitor cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Repressed Chromatin Drives Leukaemogenesis in Mutant IDH2 Acute Myeloid Leukaemia Via Inhibition of Granulocyte Differentiation and Cell Cycle Progression

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3467-3467
Author(s):  
Douglas RA Silveira ◽  
Prodromos Chatzikyriakou ◽  
Olena Yavorska ◽  
Sarah Mackie ◽  
Roan Hulks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Research Funding ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Induced Differentiation ◽  
Effector Genes ◽  
Acute Myeloid

Abstract Differentiation arrest in acute myeloid leukaemia (AML) results in accumulation of leukaemic progenitors (L-Prog) and bone marrow failure. Mutant isocitrate dehydrogenase enzyme produces d-2-hydroxyglutarate (2HG), which inhibits α-ketoglutarate-dependent dioxygenases, including Jumonji histone demethylases (JKDM) and TET2, but how this causes AML is unclear. Inhibitors of mutant IDH enzyme (mIDHi) restore differentiation in IDH-mutant (mIDH) AML (Amatangelo et al., 2018). Here, we studied transcriptional networks involved using single-cell (SC) gene expression (GEX) and transcription factor (TF) motif accessibility in primary AML treated with the mIDH2 inhibitor enasidenib (ENA) and found that ENA activates cell cycle (CC) and pro-differentiation programmes through increased promoter accessibility of granulocyte-monocyte (GM)-TF targets. We treated patient L-Prog in vitro with ENA or vehicle, and performed SC RNA-seq (Chromium 10x) in 4 responsive (R), and one non-responsive (NR) patient samples in early, mid and late timepoints. GEX signatures were used to annotate cells according to function (undifferentiated [U], early and late GM [EGM and LGM]) and CC states. In R samples, ENA yielded more dividing late-GM at mid-late timepoints than DMSO (18% vs 6.5%), and more terminally differentiated neutrophils at late timepoints (46% vs 16%). Using SCENIC (Aibar et al., 2017) to assign highly differentially-expressed genes to TF motifs, we computed regulatory networks (regulons, 'R'). Expression of the SP1 R was strongly correlated with active proliferation and ENA conditions led to generation of more cells that co-expressed CEBPA R or CEBPE R with SP1 R, emphasising simultaneous engagement of CC and GM programmes. SP1 function is associated with CC and GM differentiation, and silencing of its binding to its targets contributes to AML pathogenesis (Maiques-Diaz et al., 2012). Control and NR samples failed to produce neutrophils, had reduced co-expression of CEBPE/SP1 R and yielded more poorly differentiated cells expressing GATA2 R. At the individual gene level, ENA stimulated downregulation of GATA2, GFI1B, IKZF1/2, and RUNX3 together with upregulation of immediate early genes which respond to cytokine and mitogenic stimuli (EGR1, IER2, AP-1) in early-mid phase. Later there is upregulation of CEBP TFs and effector genes FUT4, ELANE, AZU1 and PRTN3. Interestingly, expression of some GM-TFs (RUNX1, SPI1/PU.1, GFI1) was similar between ENA and DMSO, indicating that gene expression alone was insufficient for GM differentiation. Given the effects of 2-HG on JKDM, we assessed chromatin accessibility and TF binding using SC ATAC-seq. Overall, we had 25% of differentially accessible (DA) peaks, from which 75% were more accessible in ENA than in DMSO. ENA DA peaks were highly enriched in promoters. Using ArchR (Granja et al., 2021), we clustered cells and used ELANE expression levels to compute trajectories in parallel with SC RNA-seq data. ENA peaks were sequentially enriched for CBF/RUNX and GATA families, followed by AP-1 (JUN/FOS) and EGR/CEBP/KLF motifs. Footprinting analysis showed sequential decrease and increase of TF binding for GATA2 and CEBPA/E respectively during ENA-induced differentiation. Although it did not cause higher expression of SPI1/PU.1, ENA induced increased accessibility of its target binding sites at promoters, which included CEBPA/E and GM effectors (MPO, FUT4, PRTN3). This provides a novel mechanism by which ENA induces differentiation of L-prog. Regulatory network analysis around active, differentially expressed TFs at different phases of ENA-induced differentiation showed a switch from a repressive transcriptional landscape driven by stem-progenitor TFs, to one where AP-1 and GM-TFs activate expression of GM-effector genes. We postulate a model where MYC, E2F8 and EGR1 upregulate the CEBP family in early-mid differentiation. In addition to stimulation of promoter accessibility of TFBS, we find that ENA increases accessibility of cis-regulatory elements of CEBP TFs, adding another mechanism by which differentiation of L-Prog occurs. Our data on the mechanism of action of ENA suggest that differentiation arrest in IDHm AML involves suppression of CC and GM differentiation programs in a repressive chromatin landscape, likely via inhibition of KDM6A and demethylation of repressive H3K27me3 marks. Disclosures Silveira: Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Servier/Agios: Research Funding; BMS/Celgene: Research Funding. Hasan: Bristol Myers Squibb: Current Employment. Thakurta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Vyas: Gilead: Honoraria; Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Daiichi Sankyo: Honoraria; Jazz: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Quek: BMS/Celgene: Research Funding; Servier/Agios: Research Funding.

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