TY - JOUR
T1 - Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells
AU - Pan, Feng
AU - Wingo, Thomas S.
AU - Zhao, Zhigang
AU - Gao, Rui
AU - Makishima, Hideki
AU - Qu, Guangbo
AU - Lin, Li
AU - Yu, Miao
AU - Ortega, Janice R.
AU - Wang, Jiapeng
AU - Nazha, Aziz
AU - Chen, Li
AU - Yao, Bing
AU - Liu, Can
AU - Chen, Shi
AU - Weeks, Ophelia
AU - Ni, Hongyu
AU - Phillips, Brittany Lynn
AU - Huang, Suming
AU - Wang, Jianlong
AU - He, Chuan
AU - Li, Guo Min
AU - Radivoyevitch, Tomas
AU - Aifantis, Iannis
AU - MacIejewski, Jaroslaw P.
AU - Yang, Feng Chun
AU - Jin, Peng
AU - Xu, Mingjiang
N1 - Funding Information:
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.)
Publisher Copyright:
© The Author(s) 2017.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms15102
DO - 10.1038/ncomms15102
M3 - Article
C2 - 28440315
AN - SCOPUS:85028922056
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 15102
ER -