Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies

Stomper, Julia; Rotondo, John Charles; Greve, Gabriele; Lübbert, Michael

doi:10.1038/s41375-021-01218-0

Cited by 121 publications

(116 citation statements)

References 138 publications

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“…Despite the success of hypomethylating agents, approximately 50% of patients fail to respond to these drugs [69]. The majority of patients that respond to hypomethylating agents eventually relapse due to the development of primary and secondary resistances to this treatment [69,70]. Moreover, the aberrant DNA methylation pattern observed in the present study reinforces the role of epigenetics in MDS development.…”

Section: Discussionsupporting

confidence: 66%

DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome—Relevance as Complementary Prognostic Biomarkers

Gonçalves

Alves

Baldeiras

et al. 2021

Cancers

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Oxidative stress and abnormal DNA methylation have been implicated in cancer, including myelodysplastic syndromes (MDSs). This fact leads us to investigate whether oxidative stress is correlated with localized and global DNA methylations in the peripheral blood of MDS patients. Sixty-six MDS patients and 26 healthy individuals were analyzed. Several oxidative stress and macromolecule damage parameters were analyzed. Localized (gene promotor) and global DNA methylations (5-mC and 5-hmC levels; LINE-1 methylation) were assessed. MDS patients had lower levels of reduced glutathione and total antioxidant status (TAS) and higher levels of peroxides, nitric oxide, peroxides/TAS, and 8-hydroxy-2-deoxyguanosine compared with controls. These patients had higher 5-mC levels and lower 5-hmC/5-mC ratio and LINE-1 methylation and increased methylation frequency of at least one methylated gene. Peroxide levels and peroxide/TAS ratio were higher in patients with methylated genes than those without methylation and negatively correlated with LINE-1 methylation and positively with 5-mC levels. The 5-hmC/5-mC ratio was significantly associated with progression to acute leukemia and peroxide/TAS ratio with overall survival. This study points to a relationship between oxidative stress and DNA methylation, two common pathogenic mechanisms involved in MDS, and suggests the relevance of 5-hmC/5-mC and peroxide/TAS ratios as complementary prognostic biomarkers.

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Section: Discussionsupporting

confidence: 66%

DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome—Relevance as Complementary Prognostic Biomarkers

Gonçalves

Alves

Baldeiras

et al. 2021

Cancers

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“…In the respiratory tract, it is expressed in human epithelial alveolar cells, where it favors the SARS-CoV-2 infection [48]. Furthermore, similarly to other genes [50][51][52][53], the hACE2 gene is under epigenetic regulation by DNA methylation [54]. Recent findings indicate that its improper methylation might increase SARS-CoV-2 susceptibility [54].…”

Section: Sars-cov-2 Spike Protein Structure and Functionsmentioning

confidence: 99%

SARS-CoV-2 Infection: New Molecular, Phylogenetic, and Pathogenetic Insights. Efficacy of Current Vaccines and the Potential Risk of Variants

Rotondo

Martini

Maritati

et al. 2021

Viruses

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly discovered coronavirus responsible for the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 has rapidly become a public health emergency of international concern. Although remarkable scientific achievements have been reached since the beginning of the pandemic, the knowledge behind this novel coronavirus, in terms of molecular and pathogenic characteristics and zoonotic potential, is still relatively limited. Today, there is a vaccine, or rather several vaccines, which, for the first time in the history of highly contagious infectious diseases that have plagued mankind, has been manufactured in just one year. Currently, four vaccines are licensed by regulatory agencies, and they use RNA or viral vector technologies. The positive effects of the vaccination campaign are being felt in many parts of the world, but the disappearance of this new infection is still far from being a reality, as it is also threatened by the presence of novel SARS-CoV-2 variants that could undermine the effectiveness of the vaccine, hampering the immunization control efforts. Indeed, the current findings indicate that SARS-CoV-2 is adapting to transmission in humans more efficiently, while further divergence from the initial archetype should be considered. In this review, we aimed to provide a collection of the current knowledge regarding the molecular, phylogenetic, and pathogenetic insights into SARS-CoV-2. The most recent findings obtained with respect to the impact of novel emerging SARS-CoV-2 variants as well as the development and implementation of vaccines are highlighted.

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“…In recent years, a number of studies have focused on the role of epigenetics in spermatogenesis and male infertility (Seisenberger et al, 2012;Laurentino et al, 2015;Stuppia et al, 2015;Urdinguio et al, 2015;Laqqan et al, 2017b;Nasri et al, 2017;McSwiggin and O'Doherty, 2018). Epigenetics refers to the gene regulation process without changes in DNA sequence and includes DNA methylation, posttranslational histone modifications and microRNA (miRNA) regulation (Giacone et al, 2019;Stomper et al, 2021). Several specific epigenomic/epigenetic modifications are established during spermatogenesis to form highly specialized mature sperm cells, allowing significant reorganizations of sperm chromatin structure (Jenkins and Carrell, 2011).…”

Section: Introductionmentioning

confidence: 99%

Epigenetics of Male Infertility: The Role of DNA Methylation

Rotondo

Lanzillotti

Mazziotta

et al. 2021

Front. Cell Dev. Biol.

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In recent years, a number of studies focused on the role of epigenetics, including DNA methylation, in spermatogenesis and male infertility. We aimed to provide an overview of the knowledge concerning the gene and genome methylation and its regulation during spermatogenesis, specifically in the context of male infertility etiopathogenesis. Overall, the findings support the hypothesis that sperm DNA methylation is associated with sperm alterations and infertility. Several genes have been found to be differentially methylated in relation to impaired spermatogenesis and/or reproductive dysfunction. Particularly, DNA methylation defects of MEST and H19 within imprinted genes and MTHFR within non-imprinted genes have been repeatedly linked with male infertility. A deep knowledge of sperm DNA methylation status in association with reduced reproductive potential could improve the development of novel diagnostic tools for this disease. Further studies are needed to better elucidate the mechanisms affecting methylation in sperm and their impact on male infertility.

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Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies

Cited by 121 publications

References 138 publications

DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome—Relevance as Complementary Prognostic Biomarkers

DNA Methylation Is Correlated with Oxidative Stress in Myelodysplastic Syndrome—Relevance as Complementary Prognostic Biomarkers

SARS-CoV-2 Infection: New Molecular, Phylogenetic, and Pathogenetic Insights. Efficacy of Current Vaccines and the Potential Risk of Variants

Epigenetics of Male Infertility: The Role of DNA Methylation

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