About this item:

283 Views | 258 Downloads

Author Notes:

Correspondence and requests for materials should be addressed to P.J. (email: peng.jin@emory.edu) or to M.X. (email: mxx51@miami.edu).

F.P., T.S.W., Z.Z., R.G., H.M., G.Q., L.L., M.Y., J.R.O., J.W., A.Z., L.C., B.Y., C.L. and S.C. performed the experiments and analysed the data; H.N. reviewed the blood smears and histopathological sections; F.P., T.S.W., O.W., B.L.P., S.H., T.R., J.W., C.H., G.-M.L., I.A., J.P.M. and F.-C.Y. provided assistance in designing the study and revised the manuscript; P.J. and M.X. designed and supervised the studies, performed the experiments, analysed data, wrote the manuscript and are responsible for its final draft.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by grants from the NIH (HL112294 to M.X., CA172408 to M.X. and F.-C.Y., NS05163, NS079625 and HD073162 to P.J. and DK110108 to S.M.), the Department of Veterans Affairs (BX001820 to T.S.W.), and national natural science foundation of China (81629001 and 81670102 to Z.Z.)

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • ACUTE LYMPHOBLASTIC-LEUKEMIA
  • ACTIVE DNA DEMETHYLATION
  • MYELOID MALIGNANCIES
  • METHYLATION PATTERNS
  • MAMMALIAN DNA
  • STEM-CELLS
  • B-CELL
  • MUTATIONS
  • 5-CARBOXYLCYTOSINE
  • 5-METHYLCYTOSINE

Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells

Show all authors Show less authors

Journal Title:

Nature Communications

Volume:

Volume 8

Publisher:

, Pages 15102-15102

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2017, The Author(s)

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Export to EndNote