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Cancer specific cha...
Cancer specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia
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- Qu, Ying (author)
- Karolinska Institutet
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- Siggens, Lee (author)
- Karolinska Institutet
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- Cordeddu, Lina (author)
- Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden
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- Gaidzik, Verena I (author)
- Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany
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- Karlsson, Kasper (author)
- Karolinska Institutet
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- Bullinger, Lars (author)
- Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany
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- Döhner, Konstanze (author)
- Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany
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- Ekwall, Karl (author)
- Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden
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- Lehmann, Sören (author)
- Karolinska Institutet,Uppsala universitet,Hematologi,Ctr Hematol & Regenerat Med, Dept Med Huddinge, Huddinge, Sweden; Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden
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- Lennartsson, Andreas (author)
- Karolinska Institutet
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(creator_code:org_t)
- American Society of Hematology, 2017
- 2017
- English.
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 129:7, s. e13-e25
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Abstract
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- Acute myeloid leukemia (AML) is characterized by an impaired differentiation process leading to an accumulation of immature blasts in the blood. One feature of cytogenetically normal AML is alterations to the DNA methylome. Here we have analyzed 57 AML patients with normal karyotype using Illuminas 450 k array and show that aberrant DNA methylation is significantly altered at enhancer regions and that the methylation levels at specific enhancers predict overall survival of AML patients. The majority of sites that become differentially methylated in AML occur in regulatory elements of the human genome. Hypermethylation associates with enhancer silencing. In addition, ChIP-seq analyses showed that a subset of hypomethylated sites correlate with enhancer activation, indicated by increased H3K27 acetylation. DNA hypomethylation is not therefore sufficient for enhancer activation. Some sites of hypomethylation occur at weak / poised enhancers marked with H3K4 monomethylation in hematopoietic progenitor cells. Other hypomethylated regions occur at sites inactive in progenitors and reflect the de novo acquisition of AML specific enhancers. Altered enhancer dynamics are reflected in the gene expression of enhancer target genes including genes involved in oncogenesis and blood cell development. This study demonstrates that histone variants and different histone modifications interact with aberrant DNA methylation, causing perturbed enhancer activity in CN-AML that contributes to a leukemic transcriptome.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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- ref (subject category)
- art (subject category)
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Blood
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To the university's database
- By the author/editor
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Qu, Ying
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Siggens, Lee
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Cordeddu, Lina
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Gaidzik, Verena ...
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Karlsson, Kasper
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Bullinger, Lars
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show more...
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Döhner, Konstanz ...
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Ekwall, Karl
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Lehmann, Sören
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Lennartsson, And ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Hematology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Blood
- By the university
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Uppsala University
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Karolinska Institutet