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 WangChuan He, Guo Min Li, Tomas Radivoyevitch, Iannis Aifantis, Jaroslaw P. MacIejewski, Feng-Chun Yang, Peng Jin, Mingjiang Xu

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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.

Original languageEnglish (US)
Article number15102
JournalNature Communications
Volume8
DOIs
StatePublished - Jan 1 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Pan, F., Wingo, T. S., Zhao, Z., Gao, R., Makishima, H., Qu, G., Lin, L., Yu, M., Ortega, J. R., Wang, J., Nazha, A., Chen, L., Yao, B., Liu, C., Chen, S., Weeks, O., Ni, H., Phillips, B. L., Huang, S., ... Xu, M. (2017). Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells. Nature Communications, 8, [15102]. https://doi.org/10.1038/ncomms15102