Clinical update on hypomethylating agents

Duchmann, Matthieu; Itzykson, Raphaël

doi:10.1007/s12185-019-02651-9

Cited by 52 publications

(31 citation statements)

References 98 publications

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“…Different types of epigenetic inhibitors are currently being applied for cancer treatment. Decitabine inhibits DNMTs, producing DNA hypomethylation (43). It is approved for treatment of haematological malignancies, such as myelodysplastic syndrome, chronic myelomonocitic leukaemia and acute myeloid leukaemia.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long‑term BRAF inhibition

et al. 2020

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It is estimated that ~50% of patients with melanoma harbour B-Raf (BRAF)V600 driver mutations, with the most common of these being BRAFV600E, which leads to the activation of mitogen-activated protein kinase proliferative and survival pathways. BRAF inhibitors are used extensively to treat BRAF-mutated metastatic melanoma; however, acquired resistance occurs in the majority of patients. The effects of long-term treatment with PLX4032 (BRAFV600 inhibitor) were studied in vitro on sensitive V600E BRAF-mutated melanoma cell lines. After several weeks of treatment with PLX4032, the majority of the melanoma cells died; however, a proportion of cells remained viable and quiescent, presenting senescent cancer stem cell-like characteristics. This surviving population was termed SUR cells, as discontinuing treatment allowed the population to regrow while retaining equal drug sensitivity to that of parental cells. RNA sequencing analysis revealed that SUR cells exhibit changes in the expression of 1,415 genes (P<0.05) compared with parental cells. Changes in the expression levels of a number of epigenetic regulators were also observed. These changes and the reversible nature of the senescence state were consistent with epigenetic regulation; thus, it was investigated as to whether the senescent state could be reversed by epigenetic inhibitors. It was found that both parental and SUR cells were sensitive to different histone deacetylase (HDAC) inhibitors, such as SAHA and MGCD0103, and to the cyclin-dependent kinase (CDK)9 inhibitor, CDKI-73, which induced apoptosis and reduced proliferation both in the parental and SUR populations. The results suggested that the combination of PLX4032 with HDAC and CDK9 inhibitors may achieve complete elimination of SUR cells that persist after BRAF inhibitor treatment, and reduce the development of resistance to BRAF inhibitors.

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Section: Discussionmentioning

confidence: 99%

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long‑term BRAF inhibition

et al. 2020

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“…The main features of MDS are myeloid cell cytopenias, morphologic dysplasia, ineffective hematopoiesis and a high risk of transformation to acute myeloid leukemia (AML) (Weinberg & Hasserjian, 2019). Although there are many new drugs for the treatment of MDS in recent years, about one-third of patients with MDS experience transformation to AML and the overall survival (OS) of MDS remains not ideal (Duchmann & Itzykson, 2019). There is accumulating evidence that MDS are associated with abnormal genetic mutations (Ogawa, 2019).…”

Section: Introductionmentioning

confidence: 99%

Screening and identification of key candidate genes and pathways in myelodysplastic syndrome by bioinformatic analysis

Ying¹

2019

PeerJ

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Myelodysplastic syndrome (MDS) is a heterogeneous hematologic malignancy derived from hematopoietic stem cells and the molecular mechanism of MDS remains unclear. This study aimed to elucidate potential markers of diagnosis and prognosis of MDS. The gene expression profiles GSE19429 and GSE58831 were obtained and downloaded from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) in MDS were screened using GEO2R and overlapped DEGs were obtained with Venn Diagrams. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway functional enrichment analyses, protein–protein interaction network establishment and survival analyses were performed. Functional enrichment analysis indicated that these DEGs were significantly enriched in the interferon signaling pathway, immune response, hematopoietic cell lineage and the FOXO signaling pathway. Four hub genes and four significant modules including 25 module genes were obtained via Cytoscape MCODE. Survival analysis showed that the overall survival of MDS patients having BLNK, IRF4, IFITM1, IFIT1, ISG20, IFI44L alterations were worse than that without alterations. In conclusion, the identification of these genes and pathways helps understand the underlying molecular mechanisms of MDS and provides candidate targets for the diagnosis and prognosis of MDS.

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“…In our study, we found that the expression level of HAL was significantly correlated with the degree of gene methylation. However, as a demethylation agent, hypomethylating agent (HMA) alone has difficulty achieving the intended effect in the clinical treatment of AML (Duchmann & Itzykson, 2019). We speculated that the combination of methotrexate and HMA may achieve better efficacy when changes in HAL expression are detected.…”

Section: Discussionmentioning

confidence: 99%

Construction of a solid Cox model for AML patients based on multiomics bioinformatic analysis

Cai

Liu

et al. 2021

Preprint

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Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy. The bone marrow (BM) microenvironment in AML plays an important role in leukemogenesis, drug resistance and leukemia relapse. In this study, we aimed to identify reliable immune-related biomarkers for AML prognosis by multiomics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and constructed a LASSO-Cox regression model to predict the prognosis of AML using multiomics bioinformatic analysis data. This was followed by independent validation of the model in the GSE106291 (n=251), GSE12417 (n=163) and GSE37642 (n=137) datasets and mutated genes in clinical samples for predicting overall survival (OS). Molecular docking was performed to predict the most optimal ligands to these hub genes. The single-cell RNA sequence dataset GSE116256 was used to clarify the expression of the hub genes in different immune cell types. According to their significant differences in immune gene signatures and survival trends, we concluded that the immune infiltration-lacking subtype (IL type) is associated with better prognosis than the immune infiltration-rich subtype (IR type). Using the LASSO model, we built a classifier based on 5 hub genes to predict the prognosis of AML (risk score = -0.086×ADAMTS3 + 0.180×CD52 + 0.472×CLCN5 - 0.356×HAL + 0.368×ICAM3). In summary, we constructed a prognostic model of AML using integrated multiomics bioinformatic analysis that could serve as a therapeutic classifier.

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Clinical update on hypomethylating agents

Cited by 52 publications

References 98 publications

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long‑term BRAF inhibition

Epigenetic inhibitors eliminate senescent melanoma BRAFV600E cells that survive long‑term BRAF inhibition

Screening and identification of key candidate genes and pathways in myelodysplastic syndrome by bioinformatic analysis

Construction of a solid Cox model for AML patients based on multiomics bioinformatic analysis

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