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Nat. Commun., Published 26 November 2015, 6, Article number: 10071 | doi:10.1038/ncomms10071
Acute loss of TET function results in aggressive myeloid cancer in mice
Abstract
Jungeun An1,†, Edahí González-Avalos1, Ashu Chawla1, Mira Jeong2, Isaac F. López-Moyado1, Wei Li3, Margaret A. Goodell2,3, Lukas Chavez1,4,*, Myunggon Ko1,5,* & Anjana Rao1,6,7,*
1 Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA. 2 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. 3 Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. 4 Computational Oncoepigenomics Group, Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. 5 School of Life Sciences, Ulsan National Institute of Science and Technology, UNIST-gil 50, Ulju-gun, Ulsan 689-798, Republic of Korea. 6 Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California 92093, USA. 7 Sanford Consortium for Regenerative Medicine, La Jolla, California 92037, USA.
† Present address: Center for Genomic Integrity, Institute for Basic Science (IBS), UNIST-gil 50, Ulju-gun, Ulsan 689-798, Republic of Korea.
*Correspondence to : Lukas Chavez or Myunggon Ko or Anjana Rao
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.
논문정보
- Research article
- 2015년 11월 (BRIC 등록일 2015-12-01)
- 국내(교신)+국외 연구진
- 생명과학 > 유전학
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