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Multi-omics analysis of myelodysplastic syndromes resistance to epigenetics threrary reveals PI3K/Akt activation mediated by epigenetic silencing of PTEN and epi-transcriptional silencing of MDM2 [epitranscriptome]

ABSTRACT: Myelodysplastic syndrome (MDS) is a clonal myeloid neoplasm characterized by ineffective haematopoiesis and cytopenia with frequent epigenetic modifications. Hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC) are standard therapeutic options in MDS, but drug resistance is not uncommon.To study RNA modification in particular M6A, P39-AZA-S and P39-AZA-R native RNA libraries were prepared using the direct RNA sequencing kit (Oxford Nanopore) following the manufacturer’s protocol (SQK-RNA002). Differential methylated RNA signal called from raw fast5 files were used as input for basecalling and downstream mapping and methylated transcript detection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165064 | GEO | 2022/06/01

REPOSITORIES: GEO

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Multi-omics analysis of myelodysplastic syndromes resistance to epigenetics threrary reveals PI3K/Akt activation mediated by epigenetic silencing of PTEN and epi-transcriptional silencing of MDM2 [methylome]

Project description:Myelodysplastic syndrome (MDS) is a clonal myeloid neoplasm characterized by ineffective haematopoiesis and cytopenia with frequent epigenetic modifications. Hypomethylating agents (HMA) such as azacitidine (AZA) and decitabine (DEC) are standard therapeutic options in MDS, but drug resistance is not uncommon. Herein, multi-omic analysis is used to identify signaling pathways during MDS HMA resistance using MDS cell line P39 and validated in P39 and Kasumi-1. The Illumina Infinium Methylation EPIC BeadChip (850k) was used for comparison of P39-AZA-S and P39-DEC-S (control group) and P39-AZA-R and P39-DEC-R (resistant group). Sampple was prepared following the manufacturer protocol and final chip imaging was performed on Illumina iScan System (Illumina). Bioinformatic analysis of Methylation EPIC data utilized the Illumina GenomeStudio Methylation module V2011. Only CpG sites passed quality controls were filtered and normalized for differential methylation calculation.

2022-06-01 | GSE165185 | GEO

2022-06-01 | GSE165187 | GEO

A methylation signature at diagnosis in patients with high-risk Myelodysplastic Syndromes and secondary Acute Myeloid Leukemia predicts azacitidine response but not relapse

Project description:Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response. We performed global methylation analysis of 75 patients with high risk MDS and secondary AML (sAML) who were included in CETLAM MDS-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetics. At diagnosis, no global methylation pattern allowed us to differentiate patients according to the cytological subtype, cytogenetics or treatment response. But we found a methylation signature defined by 200 probes, which allowed us to distinguish between responding and non-responding patients to azacitidine (AZA) treatment. Studying follow-up samples, we have confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to determine a methylation pattern predictive of progression or relapse. In conclusion, altered DNA methylation patterns at diagnosis, in a subset of determined CpGs, may serve as biomarker for predicting AZA response.

2021-01-27 | GSE152710 | GEO

Inhibition of CBP synergizes with the RNA-dependent mechanisms of azacitidine by limiting protein translation

Project description:The nucleotide analogue azacitidine (AZA) interferes with RNA and DNA metabolism and is currently the best treatment option for a subset of patients with high-risk myelodysplastic syndromes. However, only half of treated patients respond and almost all patients that initially respond eventually relapse. Thus, response-predicting biomarkers and new treatment options are urgently needed to improve the clinical management of these patients. Here, we performed a loss-of-function shRNA screen in combination with AZA treatment in a MDS-derived AML cell line to identify chromatin regulators affecting drug response. We identified the histone acetyl transferase and transcriptional co-activator CBP as a major regulator of AZA sensitivity. Compounds inhibiting the enzymatic activity of CBP synergistically reduced viability of MDS-derived AML cell lines when combined with AZA. Surprisingly, this affect was specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is limited to DNA incorporation. The identification of immediate target genes suggested that the effect of CBP inhibition is mediated by downregulation of genes encoding the translational machinery, which could be confirmed in proteomic analysis of nascent proteins. Furthermore, proteins most affected by CBP inhibition include key drivers of cycle progression. Taken together, our results identify a novel synergistic interaction between CBP inhibitors and specifically AZA that warrants further evaluation for the combinatorial treatment of high-risk MDS patients. Beyond the scope of MDS and AZA, we provide novel insight in the function of clinically promising CBP inhibitors that is related to unexpected interference with the translational machinery.

2021-09-22 | PXD021738 | Pride

Single-cell transcriptomes of CD8+ T cells from patients with HR-MDS and AML

Project description:Treatment with hypomethylating agents (HMA), and specifically azacitidine (AZA), is the standard of care for patients with higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) that are not eligible to receive intensive chemotherapy. Despite research efforts, it is not possible to predict response to treatment with HMA. In this study, we aimed to identify immune cell signatures in the bone marrow (BM) associated with treatment outcomes. By employing mass cytometry, we performed an in-depth immunophenotypic analysis in BM samples deriving from patients with myeloid neoplasms prior to treatment initiation. We identified an increased pre-treatment frequency of a CD8+ T cell subset, characterized as CD57+CXCR3+CCR7-CD45RA+, in patients with MDS and AML who did not respond to treatment with AZA, compared to responders. Furthermore, a baseline frequency of more than 29% of CD57+CXCR3+CD8+ T cells was correlated with poor overall survival. We further engaged scRNA-seq to assess the transcriptional profile of BM CD8+ T cells from treatment-naïve patients with MDS and AML, to identify molecular signatures in CD8+ T subpopulations associated with favorable outcomes. Response to treatment was positively associated with enrichment of IFN-mediated pathways coupled with enhanced cytotoxic signature, whereas enrichment of the TGF-β signaling pathway was observed in cell clusters from non-responders. Together, this study identified a specific CD57+CXCR3+ CD8+ T cell population with predictive value in patients with MDS and AML treated with AZA, and characterized molecular signatures in CD8+ T cells linked to cytokine signaling that were associated with treatment outcomes.

2024-01-12 | GSE250077 | GEO

Non-canonical immune response to inhibition of DNA methylation via stabilization of dsRNAs from endogenous retroviruses

Project description:5-Aza-2'-deoxycytidine, also known as decitabine, is a DNA hypomethylating agent (HMA) used to treat acute myeloid leukemia (AML) and pre-leukemic disorder myelodysplastic syndrome (MDS). Decitabine activates the transcription of endogenous retroviruses (ERV), which can induce immune response by acting as cellular double-stranded RNAs. Here, we employ an image-based screening system to identify dsRNA-binding factors that mediate the downstream effect of ERV induction. We find that STAUFEN1 (STAU1) knockdown decreases the interferon signature and rescues decitabine-mediated cell death. Our subsequent analyses reveal that STAU1 directly binds to ERV RNAs and stabilizes the RNAs together with a long noncoding RNA, TINCR. Analysis of a clinical patient cohort further supports that MDS and AML patients with low STAU1 and TINCR expressions exhibited poor response to the HMA therapy. Our study reveals that decitabine-mediated cell death is a consequence of complex interactions among different dsRNA binding proteins for access to their common dsRNA targets.

2021-04-14 | GSE152258 | GEO

LC-MSMS of the MHC-I immunopeptidome of AML cell line, THP-1

Project description:The hypomethylating agent 5-azacytidine (AZA) is the first-line induction therapy for AML patients unsuitable for intensive chemotherapy. The anti-tumor effect of AZA results in part from T-cell cytotoxic responses against MHC-I-associated peptides (MAPs) deriving from hypermethylated genomic regions such as cancer-testis antigens (CTAs), or endogenous retroelements (EREs). However, clear evidence supporting higher ERE MAPs presentation after AZA treatment in AML is lacking. Interestingly, we find that AZA-mediated DNMT2 inhibition leads to autophagy induction, which is responsible for mitigating ERE MAPs generation. To validate our findings, we examined the immunopeptidome of THP-1 cells treated with AZA combined with autophagy inhibitor, Spautin-1 or decitabine (DAC, non-DNMT2 inhibiting HMA) through a proteogenomic approach.

2024-04-17 | PXD046853 | Pride

A hypermethylated ALOX12 gene is highly susceptible to 5-azacytidine treatment in myelodysplastic syndromes

Project description:5-azacytidine (AZA) is widely used for treatment of myelodysplastic syndromes (MDS). However, identifying predictive factors for response to AZA remains challenging. The aim in present study was to identify the genes which are susceptible to AZA in MDS and investigate the possibility of the gene for predictor for response to AZA therapy. To identify AZA-susceptible genes, we compared the gene expression changes by AZA in MDS-L cells (AZA-sensitive) with those in MDS-L/CDA cells (AZA-resistant) in culture. Of 438 AZA-susceptible genes, we searched the genes which are hypermethylated in MDS patients as compared to healthy controls by analyzing public dataset GSE152710, and found ALOX12 gene. Analysis of public dataset GSE145733 and GSE58831 revealed that ALOX12 expression was suppressed in MDS classes with excess blasts but not in other classes, and were negatively and positively correlated with bone marrow blast counts and survival, respectively, in MDS patients. Analysis of public dataset GSE152710 revealed that the methylation level of ALOX12 gene was decreased in MDS patients with complete remission but not in those with partial response and progression disease after AZA therapy. Our retrospective clinical study in which nine AZA-treated patients were enrolled suggested that ALOX12 expression was increased in patients with favorable response, while decreased in patient with poor response after AZA therapy. In conclusion, ALOX12 gene could be tumor suppressive and promising marker for predicting the response to AZA therapy in MDS.

2023-05-31 | GSE233764 | GEO

Next-generation sequencing analysis to compare expression pattern of relapse and baseline "GMP pattern" MDS samples

Project description:Transcriptional changes occurring in the expanding LMPP population of "GMP pattern" MDS patients with blast expansion post-HMA failure were compared with the transcriptional profile of untreated (baseline) "GMP pattern" MDS patients.

2022-01-03 | GSE136812 | GEO

Myelodysplastic syndrome marrow stroma shows widespread aberrant hypermethylation that is abrogated by treatment with DNMT inhibitors

Project description:The marrow microenvironment contributes to the pathogenesis of ineffective hematopoiesis in Myelodysplastic Syndromes (MDS). Since mutations and cytogenetic alterations are generally not present in marrow stromal cells, we hypothesized that epigenetic alterations may be responsible for altered stroma functionin MDS. Global DNA methylation of MDS marrow-derived stroma was analyzed by HELP assay and compared to healthy controls. MDS stroma showed aberrant hypermethylation that preferentially occurred outside of CpG islands and involved important signaling pathways.Comparison with stroma derived from 5-Azacytidine (5-Aza) treated MDS patients revealed abrogation of aberrant methylation in treated samples. Integrative expression analysis revealed that the WNT pathway was epigenetically dysregulated in MDS stroma, and the WNT antagonists FRZB and SFRP1 were aberrantly hypermethylated and underexpressed. These epigenetic changes were validated ina co-culture model of stroma and leukemic cells and in an independent set of MDS samples. Importantly, 5-Aza treatment of MDS stroma enhanced hematopoietic activity and erythroid differentiationfrom co-cultured healthy CD34+ cells. These results reveal widespread aberrant epigenetic changes in the MDS marrow microenvironment and demonstrate that DNA methyl transferase inhibitors alter the epigenomic profiles of stromal cells, potentiallycontributing to theirtherapeutic efficacy. The study population consisted of 6 MDS patients and 3 healthy controls. Individual HpaII restriction digest profiles were compared to an internal MspI digest control, to yield differentially methylated fragments for every sample.

2015-05-20 | E-GEOD-60233 | biostudies-arrayexpress

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