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Acute loss of TET function results in aggressive myeloid cancer in mice.

ABSTRACT: TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling shows aberrant differentiation of haematopoietic stem/progenitor cells, impaired erythroid and lymphoid differentiation and strong skewing to the myeloid lineage, with only a mild relation to changes in DNA modification. We also observe progressive accumulation of phospho-H2AX and strong impairment of DNA damage repair pathways, suggesting a key role for TET proteins in maintaining genome integrity.

SUBMITTER: An J

PROVIDER: S-EPMC4674670 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Acute loss of TET function results in aggressive myeloid cancer in mice.

An Jungeun J González-Avalos Edahí E Chawla Ashu A Jeong Mira M López-Moyado Isaac F IF Li Wei W Goodell Margaret A MA Chavez Lukas L Ko Myunggon M Rao Anjana A

Nature communications 20151126

TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumour suppressor activity in many types of cancers. Even in the absence of TET coding region mutations, TET loss-of-function is strongly associated with cancer. Here we show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukaemia in mice, pointing to a causative role for TET loss-of-function in this myeloid malignancy. Phenotypic and trans ...[more]

PMID: 26607761

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