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

TLDR

TET-family dioxygenases oxidize 5‑methylcytosine and act as tumor suppressors, and loss of TET function—whether by mutation or other mechanisms—is strongly linked to cancer. Acute loss of TET activity in mice triggers rapid, fully penetrant, cell‑autonomous myeloid leukemia characterized by skewed myeloid differentiation, impaired erythroid/lymphoid maturation, and defective DNA damage repair.

Abstract

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.