Authors

Feng Pan, University of Miami Miller School of Medicine;Indiana University; Department of Biological Sciences, Florida International UniversityFollow
Thomas S. Wingo, Emory University; Division of Neurology, Department of Veterans Affairs Medical Center
Zhigang Zhao, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, KeyLaboratory of Cancer Prevention and Therapy
Rui Gao, University of Miami Miller School of Medicine
Hideki Makishima, Taussig Cancer Institute
Guangbo Qu, University of Miami Miller School of Medicine; Indiana University School of Medicine
Li Lin
Miao R. Yu, University of Chicago
Janice Ortega, University of Southern California Keck School of Medicine
Jiapeng Wang, Indiana University School of Medicine
Aziz Nazha, Taussig Cancer Institute
Li Chen, Emory University School of Medicine
Bing Yao, Emory University School of Medicine
Can Liu, University of Miami Miller School of Medicine
Shi Chen, University of Miami Miller School of Medicine
Ophelia Weeks, Department of Biological Sciences, Florida International UniversityFollow
Hongyu Ni, University of Illinois at Chicago
Brittany Lynn Phillips, Emory University School of Medicine
Suming Huang, University of Florida
Jianlong Wang, Icahn School of Medicine at Mount Sinai
Chuan He, University of Chicago
Guo-Min Li, University of Southern California Keck School of Medicine
Tomas Radivoyevitch, Taussig Cancer Institute
Iannis Aifantis, NYU School of Medicine
Jaroslaw P. Maciejewski, Taussig Cancer Institute
Feng-Chun Yang, University of Miami Miller School of Medicine; Indiana University School of Medicine
Peng Jin, Emory University School of Medicine
Mingjiang Xu, University of Miami Miller School of Medicine; Indiana University School of Medicine

Date of this Version

4-25-2017

Document Type

Article

Abstract

TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2?/? mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2?/? tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2?/? Lin?c-Kit+ cells shows higher mutation frequencies in Tet2?/? cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis.

Originally Published In

Nature Communications

PMID

28440315

DOI

10.1038/ncomms15102

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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