Hydroxycarbamide effects on DNA methylation and gene expression in myeloproliferative neoplasms

Castillo, Stephania Contreras; Montibus, Bertille; Rocha, Azucena; Duke, Will; Meyenn, Ferdinand von; McLornan, Donal; Harrison, Claire; Mullally, Ann; Schulz, Reiner; Oakey, Rebecca J.

doi:10.1101/gr.270066.120

Cited by 3 publications

(2 citation statements)

References 80 publications

(90 reference statements)

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“…These studies should include concomitant molecular, genomic, and immune cell studies to decipher in depth the impact of combination therapy with HU and IFN upon circulating CD34+ cells and progenitors. 41 , 42 , 43 , 44 , 45 , 46 …”

Section: Discussionmentioning

confidence: 99%

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A novel integrated biomarker index for the assessment of hematological responses in MPNs during treatment with hydroxyurea and interferon‐alpha2

et al. 2022

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Background Conventional cytoreductive therapy for patients with chronic Philadelphia‐negative myeloproliferative neoplasms (MPNs) includes hydroxyurea (HU), interferon‐alpha2 (IFN), and anagrelide. HU is worldwide the most used cytoreductive agent, which lowers elevated blood cell counts within days in the large majority of patients. However, some patients may experience rebound cytosis when HU is reduced due to cytopenia, thereby potentially giving rise to fluctuating cell counts during therapy. Such rapid oscillations may be harmful and potentially elicit thrombosis. Treatment with IFN gradually lowers elevated cell counts within weeks and when the dosage is reduced, the cell counts do not rapidly increase but are sustained within the normal range in the large majority of patients. Conventional hematological response criteria are among others based upon single absolute cell count values and do not take into account the relative decreases toward normal for each cell count. Materials, Methods & Results Using serial data from the Danish DALIAH trial, we herein describe a novel integrated biomarker index for the assessment of hematological and molecular (JAK2V617F) responses in patients with MPNs during treatment with IFN or HU. Discussion This novel tool convincingly displays the superiority of IFN versus HU in normalizing elevated cell counts. Our results need to be validated in larger studies but already now call for studies of the safety and efficacy of combination therapy during the initial treatment of patients with MPNs.

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Section: Discussionmentioning

confidence: 99%

“…Our data support future studies on the safety and efficacy of combination therapy with IFN and HU. These studies should include concomitant molecular, genomic, and immune cell studies to decipher in depth the impact of combination therapy with HU and IFN upon circulating CD34+ cells and progenitors 41–46 …”

Section: Discussionmentioning

confidence: 99%

A novel integrated biomarker index for the assessment of hematological responses in MPNs during treatment with hydroxyurea and interferon‐alpha2

et al. 2022

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Weighted gene co-expression network analysis identifies key hub genes and pathways in acute myeloid leukemia

Wang

Bajpai²,

Gu³

et al. 2023

Front. Genet.

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Introduction: Acute myeloid leukemia (AML) is the most common type of leukemia in adults. However, there is a gap in understanding the molecular basis of the disease, partly because key genes associated with AML have not been extensively explored. In the current study, we aimed to identify genes that have strong association with AML based on a cross-species integrative approach.Methods: We used Weighted Gene Co-Expression Network Analysis (WGCNA) to identify co-expressed gene modules significantly correlated with human AML, and further selected the genes exhibiting a significant difference in expression between AML and healthy mouse. Protein-protein interactions, transcription factors, gene function, genetic regulation, and coding sequence variants were integrated to identify key hub genes in AML.Results: The cross-species approach identified a total of 412 genes associated with both human and mouse AML. Enrichment analysis confirmed an association of these genes with hematopoietic and immune-related functions, phenotypes, processes, and pathways. Further, the integrated analysis approach identified a set of important module genes including Nfe2, Trim27, Mef2c, Ets1, Tal1, Foxo1, and Gata1 in AML. Six of these genes (except ETS1) showed significant differential expression between human AML and healthy samples in an independent microarray dataset. All of these genes are known to be involved in immune/hematopoietic functions, and in transcriptional regulation. In addition, Nfe2, Trim27, Mef2c, and Ets1 harbor coding sequence variants, whereas Nfe2 and Trim27 are cis-regulated, making them attractive candidates for validation. Furthermore, subtype-specific analysis of the hub genes in human AML indicated high expression of NFE2 across all the subtypes (M0 through M7) and enriched expression of ETS1, LEF1, GATA1, and TAL1 in M6 and M7 subtypes. A significant correlation between methylation status and expression level was observed for most of these genes in AML patients.Conclusion: Findings from the current study highlight the importance of our cross-species approach in the identification of multiple key candidate genes in AML, which can be further studied to explore their detailed role in leukemia/AML.

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Hydroxyurea—The Good, the Bad and the Ugly

Musiałek

Rybaczek

2021

Genes

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Hydroxyurea (HU) is mostly referred to as an inhibitor of ribonucleotide reductase (RNR) and as the agent that is commonly used to arrest cells in the S-phase of the cycle by inducing replication stress. It is a well-known and widely used drug, one which has proved to be effective in treating chronic myeloproliferative disorders and which is considered a staple agent in sickle anemia therapy and—recently—a promising factor in preventing cognitive decline in Alzheimer’s disease. The reversibility of HU-induced replication inhibition also makes it a common laboratory ingredient used to synchronize cell cycles. On the other hand, prolonged treatment or higher dosage of hydroxyurea causes cell death due to accumulation of DNA damage and oxidative stress. Hydroxyurea treatments are also still far from perfect and it has been suggested that it facilitates skin cancer progression. Also, recent studies have shown that hydroxyurea may affect a larger number of enzymes due to its less specific interaction mechanism, which may contribute to further as-yet unspecified factors affecting cell response. In this review, we examine the actual state of knowledge about hydroxyurea and the mechanisms behind its cytotoxic effects. The practical applications of the recent findings may prove to enhance the already existing use of the drug in new and promising ways.

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Hydroxycarbamide effects on DNA methylation and gene expression in myeloproliferative neoplasms

Cited by 3 publications

References 80 publications

A novel integrated biomarker index for the assessment of hematological responses in MPNs during treatment with hydroxyurea and interferon‐alpha2

A novel integrated biomarker index for the assessment of hematological responses in MPNs during treatment with hydroxyurea and interferon‐alpha2

Weighted gene co-expression network analysis identifies key hub genes and pathways in acute myeloid leukemia

Hydroxyurea—The Good, the Bad and the Ugly

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