title: 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-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.
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Jungeun
authors.initials: J
authors.lastname: An
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Edahí
authors.initials: E
authors.lastname: González-Avalos
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Ashu
authors.initials: A
authors.lastname: Chawla
authors.affiliation: Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Mira
authors.initials: M
authors.lastname: Jeong
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
authors.forename: Isaac F
authors.initials: IF
authors.lastname: López-Moyado
authors.affiliation: Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.|Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.|Computational Oncoepigenomics Group, Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Chavez
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.|School of Life Sciences, Ulsan National Institute of Science and Technology, UNIST-gil 50, Ulju-gun, Ulsan 689-798, Republic of Korea.
authors.forename: Myunggon
authors.initials: M
authors.lastname: Ko
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.|Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, California 92037, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
mesh_terms: D000818:Animals; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C551915:Tet3 protein, mouse