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

TY - JOUR

T1 - Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis

AU - Rasmussen, Kasper D

AU - Jia, Guangshuai

AU - Johansen, Jens V

AU - Pedersen, Marianne T

AU - Rapin, Nicolas

AU - Bagger, Frederik O

AU - Porse, Bo T

AU - Bernard, Olivier A

AU - Christensen, Jesper

AU - Helin, Kristian

N1 - © 2015 Rasmussen et al.; Published by Cold Spring Harbor Laboratory Press.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - DNAmethylation is tightly regulated throughout mammalian development, and alteredDNAmethylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in haematological 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 showthat 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.

AB - DNAmethylation is tightly regulated throughout mammalian development, and alteredDNAmethylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in haematological 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 showthat 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.

U2 - 10.1101/gad.260174.115

DO - 10.1101/gad.260174.115

M3 - Journal article

C2 - 25886910

SN - 0890-9369

SP - 910

EP - 922

JO - Genes & Development

JF - Genes & Development

M1 - 29

ER -