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

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.

Jungeun An, Edahi Gonzalez-Avalos, Ashu Chawla, Mira Jeong, Isaac F. Lopez-Moyado, Wei Li, Margaret A. Goodell, Lukas Chavez, Myunggon Ko & Anjana Rao

 

Nat Commun. 2015 Nov 26;6:10071. doi: 10.1038/ncomms10071.