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 4 publications

(8 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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“…Castillo and colleagues examined HU-induced methylation changes in cells derived from individuals with myeloproliferative neoplasms. 43 This group used the Illumina Infinium MethylationEPIC Array, which uses sequence-specific probes targeting individual CpGs to quantify cytosine methylation at over 850 000 distinct CpG sites. In CD34 + hematopoietic stem and progenitor cells (HSPCs) from these patients, HU treatment resulted in 60 828 differentially methylated probes (DMPs) and 690 differentially methylated regions (DMRs), which were defined as having at least four differentially methylated CpGs within a 1000 base pair segment.…”

Section: Genome-wide Analysis Of Hydroxyurea-induced Dna Methylation ...mentioning

confidence: 99%

“…Minimal DNA methylation changes were detected in patient neutrophils, suggesting that these local epigenetic changes are cell-and tissue-specific. 43 Studies of DNA methylation in SCD patients are few but indicate that changes do exist between the methylomes of SCD individuals and healthy non-SCD controls. Gil et al investigated DNA methylation changes in the placentas of pregnant women with SCD.…”

Section: Genome-wide Analysis Of Hydroxyurea-induced Dna Methylation ...mentioning

confidence: 99%

“…39 The overall pattern of DNA methylation is cell-and tissue-specific and stable long term, but can be altered due to different disease pathologies and their treatments as well as environmental factors, sometimes leading to aberrant gene expression. [36][37][38][40][41][42][43][44][45][46] Epigenetics could both provide insight into the mechanisms of action of HU and provide insight into how HU treatment could be optimized for all patients. Since changes in DNA methylation can F I G U R E 1 Top row: Sickle hemoglobin (HbS) is a mutated form of adult hemoglobin (HbA), in which glutamate (Glu) 6 of the β-globin chain is mutated to valine (Val).…”

Section: Introductionmentioning

confidence: 99%

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Reviewing the impact of hydroxyurea on DNA methylation and its potential clinical implications in sickle cell disease

Lewis,

Guilcher,

Greenway

2024

European J of Haematology

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Hydroxyurea (HU) is the most common drug therapy for sickle cell disease (SCD). The clinical benefits of HU derive from its upregulation of fetal hemoglobin (HbF), which reduces aggregation of the mutated sickle hemoglobin protein (HbS) and reduces SCD symptoms and complications. However, some individuals do not respond to HU, or stop responding over time. Unfortunately, current understanding of the mechanism of action of HU is limited, hindering the ability of clinicians to identify those patients who will respond to HU and to optimize treatment for those receiving HU. Given that epigenetic modifications are essential to erythropoiesis and HbF expression, we hypothesize that some effects of HU may be mediated by epigenetic modifications, specifically DNA methylation. However, few studies have investigated this possibility and the effects of HU on DNA methylation remain relatively understudied. In this review, we discuss the evidence linking HU treatment to DNA methylation changes and associated gene expression changes, with an emphasis on studies that were performed in individuals with SCD. Overall, although HU can affect DNA methylation, research on these changes and their clinical effects remains limited. Further study is likely to contribute to our understanding of hematopoiesis and benefit patients suffering from SCD.

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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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Hydroxycarbamide effects on DNA methylation and gene expression in myeloproliferative neoplasms

Cited by 4 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

Reviewing the impact of hydroxyurea on DNA methylation and its potential clinical implications in sickle cell disease

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

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