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

Jungeun An, Edahí González-Avalos, Ashu Chawla, Mira Jeong, Isaac F. López-Moyado, Wei Li, Margaret A. Goodell, Lukas Chavez (), Myunggon Ko () and Anjana Rao ()
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Jungeun An: La Jolla Institute for Allergy and Immunology
Edahí González-Avalos: La Jolla Institute for Allergy and Immunology
Ashu Chawla: La Jolla Institute for Allergy and Immunology
Mira Jeong: Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Isaac F. López-Moyado: La Jolla Institute for Allergy and Immunology
Wei Li: Baylor College of Medicine
Margaret A. Goodell: Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
Lukas Chavez: La Jolla Institute for Allergy and Immunology
Myunggon Ko: La Jolla Institute for Allergy and Immunology
Anjana Rao: La Jolla Institute for Allergy and Immunology

Nature Communications, 2015, vol. 6, issue 1, 1-14

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.

Date: 2015
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DOI: 10.1038/ncomms10071

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