scholarly journals ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia

Nature ◽  
2017 ◽  
Vol 543 (7644) ◽  
pp. 265-269 ◽  
Author(s):  
Liling Wan ◽  
Hong Wen ◽  
Yuanyuan Li ◽  
Jie Lyu ◽  
Yuanxin Xi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukaemia ◽  
Histone Acetylation ◽  
Myeloid Leukaemia ◽  
Oncogenic Gene ◽  
Acute Myeloid

Gene Expression Profiling of Polycomb and Polycomb-Regulated Genes in Patients with Acute Myeloid Leukaemia - Significance and Relationship to Other Molecular Aberrations.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3165-3165
Author(s):  
Lykke C. Grubach ◽  
Caroline Juhl-Christensen ◽  
Anita Rethmeier ◽  
Lene H. Olesen ◽  
Peter Hokland ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multidrug Resistance ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Expression Profile ◽  
Expression Profiles ◽  
The Other ◽  
Expression Levels ◽  
Healthy Donors ◽  
Acute Myeloid

Abstract The Polycomb group (PcG) of genes is important for differentiation and X-chromosome silencing. Recently much attention has been afforded to the role of its aberrant expression in cancer, especially in relation to the inactivation of tumor suppressor genes. We hypothesized that a deregulation in the expression profile may contribute to the development of acute myeloid leukaemia (AML). To address this, we determined the RNA levels by RQ-PCR in diagnostic bone marrow samples from 126 patients and 20 healthy donors to delineate their expression profile of the PcG genes BMI-1, MEL18, SCML2, YY1 and EZH2. To address the interplay with downstream targets of PcG proteins, we also determined the expression of HOXA4, HOXA9 and MEIS1. These data were compared not only to the demographic and clinical data of the patients, but also to a large number of molecular assays already performed in these patients (Olesen LH et al. Br.J. Haematol. 2005 131(4):457–467; Rethmeier et al. Br.J. Haematol. 2006 133(3):276–283.). At first we noticed a striking heterogeneity in the expression profiles of the AML patients (Fig. 1). We also observed that HOXA9, MEIS1, SCML2, YY1, BMI-1 and EZH2 were significantly (p≤0.003) higher expressed in the patients compared to the healthy donors. Moreover, when patients were analyzed according to the three cytogenetic prognostic groups (normal, core-binding factor positive and complex), the expression profile of patients with the t(8,21) aberration was characterized by a significantly decreased expression of HOXA9 and MEIS1 and a higher one of SCML2, YY1 and BMI-1 than AML patients in general (p<0.003). When evaluating the impact of cytogenetic subgrouping, the expression levels of MEL18 and EZH2 significantly (p< 0.025) reflected highest expression in patients with adverse prognosis and lowest expression with patients exhibiting the most favourable prognosis. While the expression levels of the genes in focus did not correlate to course of disease, we observed that a direct relationship between transcript levels of PcG and PcG-related on the one hand and the DNA methyl transferases (DNMT’s), apoptosis and multidrug-resistance genes (p<0.001) on the other. In conclusion, in this study, which is the first to systematically analyze a series of PcG genes and genes regulated by PcG, we failed to demonstrate a correlation to the clinical outcome of patients with AML. On the other hand, our data strongly suggest that these genes might be involved in the leukaemogenic process by virtue of their relations to DNA methylation (DNMT1, DNMT3B), apoptosis (BAX, CASPASE 3) and multidrug resistance (MDR1, MRP1). Figure 1. Expression profiles of PcG or PcG-regulated genes in AML patients and healthy controls. A. Gene expression profile of all 126 AML patients included (black lines) compared to 20 healthy donors. B. Patients with CBF aberrations, t(8,21), n =7, or inv(16), n =12. The expression is calculated as 2−ΔCt *100), where ΔCt = CtTG−CtCG, CtTG is the Ct value of the target gene, and CtCG is the mean Ct value of the two control genes (B2M and ABL). Figure Figure

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.

Multiplex Quantum Dot ISH Measurement of Gene Expression in Tissue Microarrays Identifies HOXA9 and DNMT3A as Markers of Poor Response to Chemotherapy in Patients with Acute Myeloid Leukaemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2530-2530
Author(s):  
Eleni Tholouli ◽  
Sara A MacDermott ◽  
Judith A Hoyland ◽  
Caroline Glennie ◽  
Ric Swindell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multivariate Analysis ◽  
Quantum Dot ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Poor Response ◽  
Tissue Microarrays ◽  
High Expression ◽  
Response To Chemotherapy ◽  
Acute Myeloid

Abstract Microarray-based expression profiling has identified prognostic gene signatures for many cancers and validation is required in clinical samples. However, most clinical material is in the form of formalin fixed and paraffin embedded tissue (FFPET) in which gene expression analysis is problematic. We have developed a generic quantum dot (QD) based multiplexed in-situ hybridization (ISH) method enabling quantitative localization of multiple mRNA targets in FFPET. We expand on our previous work introducing a method for standardization of ISH signal, enabling comparative measurement of gene expression across multiple samples. This was applied to tissue microarrays (TMAs) using archived trephine biopsies from patients with acute myeloid leukaemia (AML) to identify prognostic genes. A total of 15 TMAs were prepared using FFPET samples from 240 patients with AML diagnosed and treated between 1994 and 2005 at Manchester Royal Infirmary (Manchester, UK). For the analysis, 192 patients were included as the remainder either died before, during or immediately after one course of chemotherapy or there was incomplete data collection. The median age was 52 years (range 17–77) and all patients received intensive chemotherapy according to standard UK MRC AML protocols. Three cores were taken from each sample for TMA preparation. A standard was prepared using a cell pellet obtained from whole blood white cells which was embedded, in triplicate, in each TMA. QD-ISH was performed for nine genes recognized to be of prognostic value in AML. Triplex QD-ISH using QD labeled anti-sense cDNA oligonucleotides was performed for the following targets: Bcl2, survivin and XIAP; DNMT1, DNMT3A and DNMT3B; HOXA4, HOXA9 and Meis1. Signal intensity for each gene was measured using spectral imaging. Scrambled sense cDNA oligonucleotides were used to measure the level of background staining for each gene in each core. Background noise was corrected for by dividing expression levels of anti-sense probes by that of the scrambled probe, for both samples and standards. This enabled direct comparison between TMAs as gene expression values of samples were normalized against the standard. The mean expression of each gene was calculated for each patient, divided into quartiles and correlated with clinical outcome data. Statistical analysis was performed using contingency tables, the chi-square test and Mann Whitney-U. Overall survival (OS) and disease free survival (DFS) were displayed using the Kaplan-Meier method and Cox regression was performed for univariate and multivariate analysis. The OS in this cohort of patients was 43% at 5 years with 80% achieving complete remission (CR) after induction chemotherapy. Patient age (&lt;60 years), WCC (&lt;100×109/l) at diagnosis, cytogenetics (good and intermediate risk) and low HOXA4 expression (median 577 [95%CI 325–828]) were all associated with improved OS (p&lt;0.0001; p=0.02; p&lt;0.0001; p=0.013) and DFS (p&lt;0.0001; p=0.013; p&lt;0.0001; p=0.025) on univariate and multivariate analysis. High expression of HOXA9 (median 0.843 [0.145–7.479]; p&lt;0.0001) and DNMT3A (median 1.305 [0.073–5.477]; p=0.04) were associated with failure to achieve CR. High Meis1 expression was found to be of borderline significance for poor response to chemotherapy (median 0.716 [0.051–7.840]; p=0.05). Expression levels of the remaining 5 genes did not show any correlation with CR, DFS or OS. These findings are consistent with recently published data regarding the prognostic significance of various new markers. In line with others we have demonstrated low expression of HOXA4 is an independent good prognostic marker in adult AML. Although high expression of HOXA9, DNMT3A and Meis1 was associated with inferior CR rates in our study, OS and DFS were not adversely affected. This may be related to improvements and more aggressive clinical practice (eg stem cell transplantation) over recent years which can overcome potential deleterious gene effects. These results demonstrate that the application of a standardized, quantitative multiplex QD-ISH can be used for identification of prognostic markers in FFPET samples. The advantages of this method include its application to TMAs which allows high sample throughput, use of archived materials and its transferability across a spectrum of malignancies.

scholarly journals Common gene expression signatures in t(8;21)- and inv(16)-acute myeloid leukaemia

2006 ◽  
Vol 135 (3) ◽  
pp. 336-347 ◽  
Author(s):  
Hitoshi Ichikawa ◽  
Kenji Tanabe ◽  
Hiroshi Mizushima ◽  
Yasuhide Hayashi ◽  
Shuki Mizutani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Common Gene ◽  
Gene Expression Signatures ◽  
Acute Myeloid

scholarly journals MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia

2005 ◽  
Vol 128 (3) ◽  
pp. 324-332 ◽  
Author(s):  
Markus Schaich ◽  
Silke Soucek ◽  
Christian Thiede ◽  
Gerhard Ehninger ◽  
Thomas Illmer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Treatment Outcome ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Acute Myeloid

Functionally distinct roles for different miR-155 expression levels through contrasting effects on gene expression, in acute myeloid leukaemia

Leukemia ◽  
2016 ◽  
Vol 31 (4) ◽  
pp. 808-820 ◽  
Author(s):  
N Narayan ◽  
L Morenos ◽  
B Phipson ◽  
S N Willis ◽  
G Brumatti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Expression Levels ◽  
Acute Myeloid
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