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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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165188 | 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

2022-06-01 | GSE165064 | GEO

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

Project description: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

| PRJNA693514 | ENA

| PRJNA693518 | ENA

| PRJNA693173 | ENA

| PRJNA693510 | ENA

Epigenetic Silencing of <i>PTEN</i> and Epi-Transcriptional Silencing of <i>MDM2</i> Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents.

Project description:In myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sublines were evaluated comparatively with transcriptomic and methylomic analyses. Expression profiling and genome-wide methylation microarray showed downregulation of PTEN associated with DNA hypermethylation in P39 cell lines resistant to azacitidine and decitabine. This pattern of PTEN dysregulation was also confirmed in a cohort of patients failing treatment with HMA. DNA hypomethylation of MDM2 was detected with downregulation of MDM2 in HMA resistant cell lines. Long-read sequencing revealed significant RNA hypomethylation of MDM2 resulting in alternative splicing and production of a truncated MDM2 transcript in azacitidine-resistant P39 cells. The expression of this MDM2 truncated transcript was also significantly increased in HMA-resistant patients compared with HMA-responsive patients. In conclusion, epigenetic and epi-transcriptomic dysregulation of PTEN and MDM2 were associated with resistance to hypomethylating agents.

| S-EPMC9144309 | biostudies-literature

Integrating genetics and epigenetics in myelodysplastic syndromes: advances in pathogenesis and disease evolution.

Project description:The myelodysplastic syndromes (MDS) are a group of clonal diseases characterized by inefficient haematopoiesis, increased apoptosis and risk of evolution to acute myeloid leukaemia. Alterations in epigenetic processes, including DNA methylation, histone modifications, miRNA and splicing machinery, are well known pathogenical events in MDS. Although many advances have been made in determining the mutational frequency, distribution and association affecting these epigenomic regulators, functional integration to better understand pathogenesis of the disease is a challenging and expanding area. Recent studies are shedding light on the molecular basis of myelodysplasia and how mutations and epimutations can induce and promote this neoplastic process through aberrant transcription factor function (RUNX1, ETV6, TP53), kinase signalling (FLT3, NRAS, KIT, CBL) and epigenetic deregulation (TET2, IDH1/2, DNMT3A, EZH2, ASXL1, SF3B1, U2AF1, SRSF2, ZRSR2). In this review we will try to focus on the description of these mutations, their impact on prognosis, the functional connections between the different epigenetic pathways, and the existing and future therapies targeting these processes.

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MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia.

Project description:Failure of hypomethylation agent (HMA) treatments is an important issue in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Recent studies indicated that function of wildtype TP53 positively impacts outcome of HMA treatments. We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. In TP53 wildtype myeloid cell line, combinational effects of DS-3032b or DS-5272 with AZA were observed. In Tet2-knockout mouse model of MDS and CMML, DS-5272 and AZA combination ameliorated disease-like phenotype. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML.

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