Acute loss of TET function results in aggressive myeloid cancer in mice [RNA-Seq]

TET-family dioxygenases oxidize 5-methylcytosine (5mC) in DNA, and exert tumor 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. We show that acute elimination of TET function induces the rapid development of an aggressive, fully-penetrant and cell-autonomous myeloid leukemia in mice, pointing to a causative role for TET-loss-of-function in this myeloid malignancy. Phenotypic and transcriptional profiling showed aberrant differentiation of hematopoietic 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 observed progressive accumulation of DNA damage and strong impairment of DNA break repair, suggesting a key role for TET proteins in maintaining genomic integrity.