[KoMG]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-offunction
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.

Authors : Jungeun An1,w, Edahı´ Gonza´lez-Avalos1, Ashu Chawla1, Mira Jeong2, Isaac F. Lo´pez-Moyado1, Wei Li3,Margaret A. Goodell2,3, Lukas Chavez1,4, Myunggon Ko1,5 & Anjana Rao1,6,7