期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 29, 页码 11994-11999出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1310656110
关键词
-
资金
- National Institutes of Health [CA127277, NS079625, HD073162, HG006827, HL112294, CA118319]
- National Human Genome Research Institute
- American Cancer Society Research Scholar grant
- Emory Genetics Discovery Fund
- Winship Cancer Institute Kennedy Seed Grant
- Winship Multi-Investigator Pilot Grant
- G. Harold and Leila Y. Mathers Charitable Foundation
- Gabrielle's Angel Foundation
- Leukemia and Lymphoma Society
- Translational Research grant
- LLS Special Fellowship
- University of Chicago Committee on Cancer Biology Fellowship Program
- Department of Defense Predoctoral Traineeship Award [W81XWH-10-1-0396]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据