Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Sertoli Cell Number Correlates with Serum Inhibin B in Infant Cryptorchid Boys

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Surgical Management of Undescended Testis - Timetable and Outcome: A Debate

    Research output: Contribution to journalReviewResearchpeer-review

  3. Mte1 interacts with Mph1 and promotes crossover recombination and telomere maintenance

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Building the mammalian testis: origins, differentiation, and assembly of the component cell populations

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Heterozygous loss of Srp72 in mice is not associated with major hematological phenotypes

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. A programmed wave of uridylation-primed mRNA degradation is essential for meiotic progression and mammalian spermatogenesis

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. The splicing factor RBM25 controls MYC activity in acute myeloid leukemia

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. BloodSpot: a database of healthy and malignant haematopoiesis updated with purified and single cell mRNA sequencing profiles

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles and hallmarks of human AML1-ETO-induced AML. Using this model, we show that the primary effect of Tet2 loss in preleukemic hematopoietic cells is progressive and widespread DNA hypermethylation affecting up to 25% of active enhancer elements. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner but increases relative to population doublings. We confirmed this specific enhancer hypermethylation phenotype in human AML patients with TET2 mutations. Analysis of immediate gene expression changes reveals rapid deregulation of a large number of genes implicated in tumorigenesis, including many down-regulated tumor suppressor genes. Hence, we propose that TET2 prevents leukemic transformation by protecting enhancers from aberrant DNA methylation and that it is the combined silencing of several tumor suppressor genes in TET2 mutated hematopoietic cells that contributes to increased stem cell proliferation and leukemogenesis.

Original languageEnglish
JournalGenes & Development
Volume29
Issue number9
Pages (from-to)910-22
Number of pages13
ISSN0890-9369
DOIs
Publication statusPublished - 1 May 2015

ID: 45362735