Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells

Feng Pan, Thomas S. Wingo, Zhigang Zhao, Rui Gao, Hideki Makishima, Guangbo Qu, Li Lin, Miao Yu, Janice R. Ortega, Jiapeng Wang, Aziz Nazha, Li Chen, Bing Yao, Can Liu, Shi Chen, Ophelia Weeks, Hongyu Ni, Brittany Lynn Phillips, Suming Huang, Jianlong Wang, Chuan He, Guo-Min Li, Tomas Radivoyevitch, Iannis Aifantis, Jaroslaw P. Maciejewski, Feng-Chun Yang, Peng Jin () and Mingjiang Xu ()
Additional contact information
Feng Pan: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Thomas S. Wingo: Emory University School of Medicine
Zhigang Zhao: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy
Rui Gao: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Hideki Makishima: Taussig Cancer Institute, Cleveland Clinic
Guangbo Qu: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Li Lin: Emory University School of Medicine
Miao Yu: University of Chicago
Janice R. Ortega: Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine
Jiapeng Wang: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine
Aziz Nazha: Taussig Cancer Institute, Cleveland Clinic
Li Chen: Emory University School of Medicine
Bing Yao: Emory University School of Medicine
Can Liu: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Shi Chen: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Ophelia Weeks: Florida International University
Hongyu Ni: University of Illinois at Chicago
Brittany Lynn Phillips: Emory University School of Medicine
Suming Huang: University of Florida
Jianlong Wang: Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai
Chuan He: University of Chicago
Guo-Min Li: Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine
Tomas Radivoyevitch: Taussig Cancer Institute, Cleveland Clinic
Iannis Aifantis: NYU School of Medicine
Jaroslaw P. Maciejewski: Taussig Cancer Institute, Cleveland Clinic
Feng-Chun Yang: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine
Peng Jin: Emory University School of Medicine
Mingjiang Xu: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15102

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