DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia

Álvarez, Sara; Suela, Javier; Valencia, Ana; Fernández, Agustín F.; Wunderlich, Mark; Agirre, Xabier; Prósper, Felipe; Martín‐Subero, José I.; Maiques, Alba; Acquadro, Francesco; Rodríguez-Perales, Sandra; Calasanz, Marı́a José; Román‐Gómez, José; Siebert, Reiner; Mulloy, James C.; Cervera, José; Sanz, Miguel Á.; Esteller, Manel; Cigudosa, Juan C.

doi:10.1371/journal.pone.0012197

Cited by 78 publications

(63 citation statements)

References 38 publications

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“…Interestingly, we and others have previously identified aberrant DNA methylation of Wnt antagonists as being responsible for the activation of the Wnt/b-catenin pathway required for the development of leukemic stem cells and for the maintenance of self-renewal on AML1-ETO patients. 37 This study reveals another level of complexity identifying the H3K9me3 modification as an initial event targeting this pathway (TCF3, SOX18 or FZD7) in the HSPC-AE model. SUV39H1 is the only member of the mammalian H3K9 histone methyltransferases known to interact with AML1 and DNA methyltransferase 1.…”

Section: Discussionmentioning

confidence: 78%

“…36 We recently showed that the AML1-ETO fusion protein was not sufficient to induce the specific DNA methylation pattern observed in primary patient samples. 37 The AML1-ETO fusion protein is known to repress transcription by recruiting chromatin modifiers such as the NCoR/SMRT/HDAC complex, 10 thus leading to histone H4 deacetylation and recruitment of the SUV39H1 protein, a histone H3 lysine 9 methyltransferase at DNA binding sites. 38 Using ChIP-chip, we identified 1168 AML1-ETO target genes involved in functions such as hematopoietic differentiation and self-renewal, the main features reported in the HSPC-AE.…”

Section: Discussionmentioning

confidence: 99%

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Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

et al. 2012

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The AML1-ETO fusion protein, which is present in 10 --15% of cases of acute myeloid leukemia, is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. ChIP-chip analysis of human hematopoietic stem/progenitor cells transduced with the AML1-ETO fusion gene enabled us to identify 1168 AML1-ETO target genes, 103 of which were co-occupied by histone deacetylase 1 (HDAC1) and had lost the hyperacetylation mark at histone H4, and 264 showed a K9 trimethylation at histone H3. Enrichment of genes involved in hematopoietic differentiation and in specific signaling pathways was observed in the presence of these epigenetic modifications associated with an 'inactive' chromatin status. Furthermore, AML1-ETO target genes had a significant correlation between the chromatin marks studied and transcriptional silencing. Interestingly, AML1 binding sites were absent on a large number of selected AML1-ETO promoters and an Sp1 binding site was found in over 50% of them. Reversible silencing induced by the fusion protein in the presence of AML1 and/or Sp1 transcription factor binding site was confirmed. Therefore, this study provides a global analysis of AML1-ETO functional chromatin modifications and identifies the important role of Sp1 in the DNA binding pattern of AML1-ETO, suggesting a role for Sp1-targeted therapy in this leukemia subtype.Leukemia ( Keywords: AML1-ETO; myeloid leukemia ; histone deacetylation; H3K9me3; Sp1 INTRODUCTIONThe presence of the AML1-ETO fusion protein indicates acute myeloid leukemia (AML) with t(8;21)(q22;q22), which accounts for B10 --15% of all AML cases.1,2 This product is the consequence of a reciprocal translocation that fuses the DNA binding domain of the AML1 transcription factor essential for transcriptional activation of genes involved in normal hematopoiesis in frame with nearly the entire ETO protein, a transcriptional repressor molecule expressed in a variety of tissues.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

et al. 2012

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“…2 Previous studies showed associations of certain methylation patterns with specific chromosome abnormalities and gene mutations and suggested a prognostic significance to these patterns. [3][4][5][6][7][8][9][10][11][12] However, it remains unclear if DNA methylation profiles differ according to AML cytogenetic risk group, the principal predictor of outcome in AML.…”

Section: Introductionmentioning

confidence: 99%

Identification of differentially methylated markers among cytogenetic risk groups of acute myeloid leukemia

Davison

et al. 2015

Epigenetics

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Abbreviations: AML, acute myeloid leukemia; CHARM, comprehensive high-throughput array-based relative methylation analysis; DMR, differentially methylated region; TCGA, The Cancer Genome Atlas Research NetworkAberrant DNA methylation is known to occur in cancer, including hematological malignancies such as acute myeloid leukemia (AML). However, less is known about whether specific methylation profiles characterize specific subcategories of AML. We examined this issue by using comprehensive high-throughput array-based relative methylation analysis (CHARM) to compare methylation profiles among patients in different AML cytogenetic risk groups. We found distinct profiles in each group, with the high-risk group showing overall increased methylation compared with low-and midrisk groups. The differentially methylated regions (DMRs) distinguishing cytogenetic risk groups of AML were enriched in the CpG island shores. Specific risk-group associated DMRs were located near genes previously known to play a role in AML or other malignancies, such as MN1, UHRF1, HOXB3, and HOXB4, as well as TRIM71, the function of which in cancer is not well characterized. These findings were verified by quantitative bisulfite pyrosequencing and by comparison with results available at the TCGA cancer genome browser. To explore the potential biological significance of the observed methylation changes, we correlated our findings with gene expression data available through the TCGA database. The results showed that decreased methylation at HOXB3 and HOXB4 was associated with increased gene expression of both HOXB genes specific to the mid-risk AML, while increased DNA methylation at DCC distinctive to the high-risk AML was associated with increased gene expression. Our results suggest that the differential impact of cytogenetic changes on AML prognosis may, in part, be mediated by changes in methylation.

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“…For the PCSs, the risk of bias assessments ranged from low 24,30,101,193,395 to low to moderate. 34,127,394 None of those studies were found to have methodological flaws that would raise concerns about the studies' findings. Refer to Supplemental Table 19 for the quality-assessment results of studies included for statement 20.…”

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confidence: 99%

“…398 target genes was associated with better progression-free survival and OS in cytogenetically normal AML. 399 Within our SR, 2 studies were identified for gene-specific methylation, one finding no significant prognostic effect of BMP/ retinoic acid inducible neural specific 1 (BRINP1/DBC1) methylation in AML 394 and one of which found that methylation status of any of 9 specific genes adversely affected OS in ALL (P , .05). 34 In our SR, 5 studies found a significant effect of miRNA expression levels on outcome in adult AML (P , .05), 24,30,127,193,395 including one in which miRNA expression patterns were correlated with expression of other prognostic markers, 127 whereas one study found no significant effect on outcome.…”

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confidence: 99%

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

Arber¹,

Borowitz²,

Cessna³

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

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Context.-A complete diagnosis of acute leukemia requires knowledge of clinical information combined with morphologic evaluation, immunophenotyping and karyotype analysis, and often, molecular genetic testing. Although many aspects of the workup for acute leukemia are well accepted, few guidelines have addressed the different aspects of the diagnostic evaluation of samples from patients suspected to have acute leukemia.Objective.-To develop a guideline for treating physicians and pathologists involved in the diagnostic and prognostic evaluation of new acute leukemia samples, including acute lymphoblastic leukemia, acute myeloid leukemia, and acute leukemias of ambiguous lineage.Design.-The College of American Pathologists and the American Society of Hematology convened a panel of experts in hematology and hematopathology to develop recommendations. A systematic evidence review was conducted to address 6 key questions. Recommendations were derived from strength of evidence, feedback received during the public comment period, and expert panel consensus.Results.-Twenty-seven guideline statements were established, which ranged from recommendations on what clinical and laboratory information should be available as part of the diagnostic and prognostic evaluation of acute leukemia samples to what types of testing should be performed routinely, with recommendations on where such testing should be performed and how the results should be reported.Conclusions.-The guideline provides a framework for the multiple steps, including laboratory testing, in the evaluation of acute leukemia samples. Some aspects of the guideline, especially molecular genetic testing in acute leukemia, are rapidly changing with new supportive literature, which will require on-going updates for the guideline to remain relevant.

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DNA Methylation Profiles and Their Relationship with Cytogenetic Status in Adult Acute Myeloid Leukemia

Cited by 78 publications

References 38 publications

Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs

Identification of differentially methylated markers among cytogenetic risk groups of acute myeloid leukemia

Initial Diagnostic Workup of Acute Leukemia: Guideline From the College of American Pathologists and the American Society of Hematology

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