Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes

Rey, Benjamin; O'Hagan, Kathleen; Dellett, Margaret; Aibar, Sara; Colyer, Hilary A. A.; Alonso, M. Eva; Díez-Campelo, María; Armstrong, Richard N.; Sharpe, Daniel; Gutiérrez, Norma C.; García, José María Sánchez; Rivas, Javier De Las; Mills, Ken I.; Hernández-Rivas, Jesús M.

doi:10.1038/leu.2012.253

Cited by 33 publications

(21 citation statements)

References 50 publications

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“…However, analysis of this site using bone marrow cell DNA from 30 MDS patients failed to detect any methylated cytosines, indicating that DNA methylation is not a frequent mechanism for MYBL2 downregulation in MDS (JP Issa, personal communication, 2012). This finding is supported by a recently published study that did not identify methylation affecting the MYBL2 gene in cells from 83 MDS cases (Del Rey et al, 2012). …”

Section: Resultssupporting

confidence: 72%

MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy

Heinrichs

Conover

Bueso‐Ramos

et al. 2013

eLife

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A common deleted region (CDR) in both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) affects the long arm of chromosome 20 and has been predicted to harbor a tumor suppressor gene. Here we show that MYBL2, a gene within the 20q CDR, is expressed at sharply reduced levels in CD34+ cells from most MDS cases (65%; n = 26), whether or not they harbor 20q abnormalities. In a murine competitive reconstitution model, Mybl2 knockdown by RNAi to 20–30% of normal levels in multipotent hematopoietic progenitors resulted in clonal dominance of these ‘sub-haploinsufficient’ cells, which was reflected in all blood cell lineages. By 6 months post-transplantation, the reconstituted mice had developed a clonal myeloproliferative/myelodysplastic disorder originating from the cells with aberrantly reduced Mybl2 expression. We conclude that downregulation of MYBL2 activity below levels predicted by classical haploinsufficiency underlies the clonal expansion of hematopoietic progenitors in a large fraction of human myeloid malignancies.DOI: http://dx.doi.org/10.7554/eLife.00825.001

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Section: Resultssupporting

confidence: 72%

MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy

Heinrichs

Conover

Bueso‐Ramos

et al. 2013

eLife

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“…And after a series of inclusion and exclusion screening, a total of 8 and 10 microarray datasets were selected for MDS (GSE19429, GSE2779, GSE30195, GSE41130, GSE4619, GSE51757, GSE58831 and GSE81173) (8,13–17) and AML (GSE24395, GSE30029, GSE33223, GSE37307, GSE68172, GSE70284, GSE79605, GSE84881, GSE9476 and GSE983) (18–25) respectively, as indicated in Materials and methods (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, approximately 30% of the patients with MDS would progress into AML (7). Thus, a number of approaches have been developed to compare MDS and AML in the cytogenetic and molecular aspects, and some hallmark genes or phenotypes being established (8). However, the molecular mechanisms and biological events underlying MDS and AML development and their transition remain to be addressed.…”

Section: Introductionmentioning

confidence: 99%

Integrated bioinformatic analysis of microarray data reveals shared gene signature between MDS and AML

et al. 2018

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Myeloid disorders, especially myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), cause significant mobility and high mortality worldwide. Despite numerous attempts, the common molecular events underlying the development of MDS and AML remain to be established. In the present study, 18 microarray datasets were selected, and a meta-analysis was conducted to identify shared gene signatures and biological processes between MDS and AML. Using NetworkAnalyst, 191 upregulated and 139 downregulated genes were identified in MDS and AML, among which, PTH2R, TEC, and GPX1 were the most upregulated genes, while MME, RAG1, and CD79B were mostly downregulated. Comprehensive functional enrichment analyses revealed oncogenic signaling related pathway, fibroblast growth factor receptor (FGFR) and immune response related events, ‘interleukine-6/interferon signaling pathway, and B cell receptor signaling pathway’, were the most upregulated and downregulated biological processes, respectively. Network based meta-analysis ascertained that HSP90AA1 and CUL1 were the most important hub genes. Interestingly, our study has largely clarified the link between MDS and AML in terms of potential pathways, and genetic markers, which shed light on the molecular mechanisms underlying the development and transition of MDS and AML, and facilitate the understanding of novel diagnostic, therapeutic and prognostic biomarkers.

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“…Comparing low-risk MDS cases with a control group, 552 differentially methylated CpG loci were identified, while hypermethylated genes were more frequent than hypomethylated genes [71]. In another study, patients with higher levels of methylation, compared with patients with lower levels, had a shorter median overall survival (12.3 v 17.5 months, respectively) and shorter median progression-free survival (6.4 v 14.9 months, respectively) [72].…”

Section: Epigeneticsmentioning

confidence: 99%

Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia

Vajen

Thomay

Schlegelberger

2013

Cancers

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Chromosomal instability (CIN) is a characteristic feature of cancer. In this review, we concentrate on mechanisms leading to CIN in myeloid neoplasia, i.e., myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The pathogenesis of myeloid neoplasia is complex and involves genetic and epigenetic alterations. Chromosome aberrations define specific subgroups and guide clinical decisions. Genomic instability may play an essential role in leukemogenesis by promoting the accumulation of genetic lesions responsible for clonal evolution. Indeed, disease progression is often driven by clonal evolution into complex karyotypes. Earlier studies have shown an association between telomere shortening and advanced MDS and underlined the important role of dysfunctional telomeres in the development of genetic instability and cancer. Several studies link chromosome rearrangements and aberrant DNA and histone methylation. Genes implicated in epigenetic control, like DNMT3A, ASXL1, EZH2 and TET2, have been discovered to be mutated in MDS. Moreover, gene-specific hypermethylation correlates highly significantly with the risk score according to the International Prognostic Scoring System. In AML, methylation profiling also revealed clustering dependent on the genetic status. Clearly, genetic instability and clonal evolution are driving forces for leukemic transformation. Understanding the mechanisms inducing CIN will be important for prevention and for novel approaches towards therapeutic interventions.

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Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes

Cited by 33 publications

References 50 publications

MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy

MYBL2 is a sub-haploinsufficient tumor suppressor gene in myeloid malignancy

Integrated bioinformatic analysis of microarray data reveals shared gene signature between MDS and AML

Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia

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