| Literature DB >> 23818607 |
Hao Huang1, Xi Jiang, Zejuan Li, Yuanyuan Li, Chun-Xiao Song, Chunjiang He, Miao Sun, Ping Chen, Sandeep Gurbuxani, Jiapeng Wang, Gia-Ming Hong, Abdel G Elkahloun, Stephen Arnovitz, Jinhua Wang, Keith Szulwach, Li Lin, Craig Street, Mark Wunderlich, Meelad Dawlaty, Mary Beth Neilly, Rudolf Jaenisch, Feng-Chun Yang, James C Mulloy, Peng Jin, Paul P Liu, Janet D Rowley, Mingjiang Xu, Chuan He, Jianjun Chen.
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.Entities:
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Year: 2013 PMID： 23818607 PMCID： PMC3718141 DOI： 10.1073/pnas.1310656110
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 12.779