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

作者：An Jungeun; Gonzalez Avalos Edahi; Chawla Ashu; Jeong Mira; Lopez Moyado Isaac F; Li Wei; Goodell Margaret A; Chavez Lukas; Ko Myunggon; Rao Anjana

来源：Nature Communications, 2015, 6(1): 10071.

DOI：10.1038/ncomms10071

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.

• 出版日期2015-11