TET1 plays an essential oncogenic role in MLL-rearranged leukemia

被引：178

作者：

Huang, Hao ^{[1
]}

Jiang, Xi ^{[1
]}

Li, Zejuan ^{[1
]}

Li, Yuanyuan ^{[1
]}

Song, Chun-Xiao ^{[2
,3
]}

He, Chunjiang ^{[1
]}

Sun, Miao

Chen, Ping ^{[1
]}

Gurbuxani, Sandeep ^{[4
]}

Wang, Jiapeng ^{[5
]}

Hong, Gia-Ming ^{[1
]}

Elkahloun, Abdel G. ^{[6
]}

Arnovitz, Stephen ^{[1
]}

Wang, Jinhua ^{[1
]}

Szulwach, Keith ^{[7
]}

Lin, Li

Street, Craig ^{[7
]}

Wunderlich, Mark ^{[8
]}

Dawlaty, Meelad ^{[9
,10
]}

Neilly, Mary Beth ^{[1
]}

Jaenisch, Rudolf ^{[9
,10
]}

Yang, Feng-Chun ^{[5
]}

Mulloy, James C.

Jin, Peng

Liu, Paul P. ^{[6
]}

Rowley, Janet D. ^{[1
]}

Xu, Mingjiang ^{[5
]}

He, Chuan ^{[2
,3
]}

Chen, Jianjun ^{[1
]}

机构：

[1] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[2] Univ Chicago, Dept Chem, Chicago, IL 60637 USA

[3] Univ Chicago, Inst Biophys Dynam, Chicago, IL 60637 USA

[4] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA

[5] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA

[6] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA

[7] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA

[8] Univ Cincinnati, Coll Med, Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[9] MIT, Whitehead Inst, Cambridge, MA 02142 USA

[10] MIT, Dept Biol, Cambridge, MA 02142 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 29期

基金：

美国国家卫生研究院;

关键词：

ACUTE MYELOID-LEUKEMIA; MIXED-LINEAGE LEUKEMIA; EMBRYONIC STEM-CELLS; POSTNATAL-DEVELOPMENT; HEMATOPOIETIC-CELLS; GENE-EXPRESSION; DOWN-REGULATION; MAMMALIAN DNA; SELF-RENEWAL; 5-HYDROXYMETHYLCYTOSINE;

D O I：

10.1073/pnas.1310656110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：11994 / 11999

页数：6

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