Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

Wong, Yan Fung; Micklem, Chris N.; Taguchi, Masataka; Itonaga, Hidehiro; Sawayama, Yasushi; Imanishi, Daisuke; Nishikawa, Shin‐Ichi; Miyazaki, Yasushi; Jakt, Lars Martin

doi:10.5966/sctm.2014-0035

Cited by 8 publications

(8 citation statements)

References 52 publications

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“…In addition, it is important to note that our analyses did not detect the emergence of acquired genetic and/or cytogenetic abnormalities when sPAP was identified. Based on the findings of a previous study describing changes in the clonal composition under azacitidine (29)(30)(31), the disease progression of our case may also have been due to clonal changes. Further studies are warranted in order to clarify the pathogenesis of the development of MDS/sPAP.…”

Section: Discussionsupporting

confidence: 69%

Secondary Pulmonary Alveolar Proteinosis Following Treatment with Azacitidine for Myelodysplastic Syndrome

et al. 2020

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Secondary pulmonary alveolar proteinosis (sPAP) is a complication of myelodysplastic syndrome (MDS). A 60-year-old woman was diagnosed with MDS with excess blasts-1. Fifty-four months after the initial diagnosis, treatment with azacitidine was initiated. Seventy-three months after the diagnosis, a bone marrow examination revealed increased myeloblasts, at which time computed tomography showed diffuse ground-glass opacities and interlobular septal thickening in the bilateral lower lung fields. A lung biopsy revealed the presence of PAP; therefore, the clinical diagnosis of MDS/sPAP was confirmed. Careful attention should be paid to the development of sPAP in MDS patients with pulmonary lesions during azacitidine treatment.

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Section: Discussionsupporting

confidence: 69%

Secondary Pulmonary Alveolar Proteinosis Following Treatment with Azacitidine for Myelodysplastic Syndrome

et al. 2020

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“…Aza treatment results in reduced DNA methylation as demonstrated by several studies in vivo and in vitro , although the degree of demethylation seems to be limited [4, 11–15]. A plethora of in vitro studies have investigated the in vitro effects of Aza, however, only a limited number of these have used primary MDS cells in the experiments [16].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease

et al. 2017

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Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median β-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.

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“…In addition to genetic alterations, epigenetic modi cations especially in DNA methylation have been shown involved in cancer progression including MDS [24][25][26]. Previous studies almost focused on the single gene change during MDS progression, such as CDKN2B, SOCS1, NR4A2, ABAT, ID4, GPX3, SOX30, and etc [9][10][11][27][28][29][30]. However, little studies showed the whole-genome DNA methylation alterations during MDS progression.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Methylation Sequencing Identifies Progression-Related Epigenetic Drivers in Myelodysplastic Syndromes

Zhou

Zhang²,

Xu³

et al. 2020

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Background: The mechanism underlying disease progression of myelodysplastic syndromes (MDS) to acute myeloid leukemia (AML) remains poorly elucidated. Epigenetic alterations are increasingly implicated in the pathogenesis of cancer progression including MDS. However, little studies explored the whole-genome methylation alterations during MDS progression.Methods: We conducted reduced representation bisulfite sequencing in four paired MDS/secondary AML (MDS/sAML) patients and intended to discover methylation-associated epigenetic drivers in MDS progression.Results: In four paired MDS/sAML patients, cases at sAML stage showed significantly increased methylation level when compared with their matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involved in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were identified involved in MDS progression. Further targeted bisulfite sequencing identified aberrant GFRA1, IRX1, NPY, and ZNF300 methylation was frequent events in additional de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Moreover, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was further confirmed by real-time quantitative methylation-specific PCR. Clinical studies showed that ZNF300 methylation could act as a potential biomarker helpful for the diagnosis and prognosis in MDS and AML patients. In in vitro experiments, overexpression of ZNF300 exhibited anti-proliferative and pro-apoptotic effects in MDS-derived AML cell line SKM-1.Conclusions: Genome-wide DNA hypermethylation was a frequent event during MDS progression. Among these changes, ZNF300 methylation through the regulation of ZNF300 expression acted as an epigenetic driver in MDS progression. These findings give a theoretical basis for investigating and using the efficacy of DNMT inhibitors in MDS patients against disease progression, and provide new insights for targeted therapy in MDS.

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Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

Cited by 8 publications

References 52 publications

Secondary Pulmonary Alveolar Proteinosis Following Treatment with Azacitidine for Myelodysplastic Syndrome

Secondary Pulmonary Alveolar Proteinosis Following Treatment with Azacitidine for Myelodysplastic Syndrome

Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease

Genome-Wide Methylation Sequencing Identifies Progression-Related Epigenetic Drivers in Myelodysplastic Syndromes

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