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

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  • Jungeun An

    (La Jolla Institute for Allergy and Immunology
    Present address: Center for Genomic Integrity, Institute for Basic Science (IBS), UNIST-gil 50, Ulju-gun, Ulsan 689-798, Republic of Korea)

  • 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
    Baylor College of Medicine)

  • Lukas Chavez

    (La Jolla Institute for Allergy and Immunology
    Computational Oncoepigenomics Group, German Cancer Research Center (DKFZ))

  • Myunggon Ko

    (La Jolla Institute for Allergy and Immunology
    School of Life Sciences, Ulsan National Institute of Science and Technology, UNIST-gil 50)

  • Anjana Rao

    (La Jolla Institute for Allergy and Immunology
    University of California at San Diego
    Sanford Consortium for Regenerative Medicine)

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.

Suggested Citation

  • Jungeun An & Edahí González-Avalos & Ashu Chawla & Mira Jeong & Isaac F. López-Moyado & Wei Li & Margaret A. Goodell & Lukas Chavez & Myunggon Ko & Anjana Rao, 2015. "Acute loss of TET function results in aggressive myeloid cancer in mice," Nature Communications, Nature, vol. 6(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms10071
    DOI: 10.1038/ncomms10071
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    Cited by:

    1. Romain O. Georges & Hugo Sepulveda & J. Carlos Angel & Eric Johnson & Susan Palomino & Roberta B. Nowak & Arshad Desai & Isaac F. López-Moyado & Anjana Rao, 2022. "Acute deletion of TET enzymes results in aneuploidy in mouse embryonic stem cells through decreased expression of Khdc3," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Ihab Ansari & Llorenç Solé-Boldo & Meshi Ridnik & Julian Gutekunst & Oliver Gilliam & Maria Korshko & Timur Liwinski & Birgit Jickeli & Noa Weinberg-Corem & Michal Shoshkes-Carmel & Eli Pikarsky & Era, 2023. "TET2 and TET3 loss disrupts small intestine differentiation and homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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