TET1 plays an essential oncogenic role in MLL-rearranged leukemia
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Huang-2013-TET1 plays an essent.pdf
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Author(s)
Jaenisch, Rudolf
Huang, Hao
Jiang, Xi
Li, Zejuan
Li, Yuanyuan
Song, Chun-Xiao
He, Chunjiang
Chen, Ping
Gurbuxani, Sandeep
Wang, Jiapeng
Date Issued
July 2013
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Huang, H., X. Jiang, Z. Li, Y. Li, C.-X. Song, C. He, M. Sun, et al. “TET1 Plays an Essential Oncogenic Role in MLL-Rearranged Leukemia.” Proceedings of the National Academy of Sciences 110, no. 29 (July 16, 2013): 11994–11999.
Version
Final published version
Abstract
The ten-eleven translocation 1 (TET1) gene is the founding member of the TET family of enzymes (TET1/2/3) that convert 5-methylcytosine to 5-hydroxymethylcytosine. Although TET1 was first identified as a fusion partner of the mixed lineage leukemia (MLL) gene in acute myeloid leukemia carrying t(10,11), its definitive role in leukemia is unclear. In contrast to the frequent down-regulation (or loss-of-function mutations) and critical tumor-suppressor roles of the three TET genes observed in various types of cancers, here we show that TET1 is a direct target of MLL-fusion proteins and is significantly up-regulated in MLL-rearranged leukemia, leading to a global increase of 5-hydroxymethylcytosine level. Furthermore, our both in vitro and in vivo functional studies demonstrate that Tet1 plays an indispensable oncogenic role in the development of MLL-rearranged leukemia, through coordination with MLL-fusion proteins in regulating their critical cotargets, including homeobox A9 (Hoxa9)/myeloid ecotropic viral integration 1 (Meis1)/pre-B-cell leukemia homeobox 3 (Pbx3) genes. Collectively, our data delineate an MLL-fusion/Tet1/Hoxa9/Meis1/Pbx3 signaling axis in MLL-rearranged leukemia and highlight TET1 as a potential therapeutic target in treating this presently therapy-resistant disease.
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/10.1073/pnas.1310656110
