Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice
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Zhao-2015-Combined Loss of Tet.pdf
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Author(s)
Zhao, Zhigang
Chen, Li
Dawlaty, Meelad M.
Pan, Feng
Weeks, Ophelia
Zhou, Yuan
Cao, Zeng
Shi, Hui
Wang, Jiapeng
Lin, Li
Date Issued
November 2015
Journal
Cell Reports
Publisher
Elsevier
Citation
Zhao, Zhigang, Li Chen, Meelad M. Dawlaty, Feng Pan, Ophelia Weeks, Yuan Zhou, Zeng Cao, et al. “Combined Loss of Tet1 and Tet2 Promotes B Cell, but Not Myeloid Malignancies, in Mice.” Cell Reports 13, no. 8 (November 2015): 1692–1704.
Version
Final published version
Abstract
TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2 deletion in mice causes myeloid malignancies, while Tet1-null mice develop B cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 using Tet1/2 double-knockout (DKO) mice. DKO and Tet2[superscript −/−] HSC/HPCs show overlapping and unique 5hmC and 5mC profiles. DKO mice exhibit strikingly decreased incidence and delayed onset of myeloid malignancies in comparison to Tet2[superscript −/−] mice and in contrast develop lethal B cell malignancies. Transcriptome analysis of DKO tumors reveals expression changes in many genes dysregulated in human B cell malignancies, including LMO2, BCL6, and MYC. These results highlight the critical roles of TET1/2 individually and together in the pathogenesis of hematological malignancies.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
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DOI of Published Version
https://doi.org/10.1016/j.celrep.2015.10.037
