PU.1 is essential for MLL leukemia partially via crosstalk with the MEIS/HOX pathway

被引：36

作者：

Zhou, J. ^{[1
]}

Wu, J. ^{[1
]}

Li, B. ^{[1
,2
,3
]}

Liu, D. ^{[1
,2
]}

Yu, J. ^{[4
]}

Yan, X. ^{[3
]}

Zheng, S. ^{[1
,2
]}

Wang, J. ^{[1
,5
,6
]}

Zhang, L. ^{[1
,2
]}

He, F. ^{[1
]}

Li, Q. ^{[1
]}

Chen, A. ^{[1
,2
,3
]}

Zhang, Y. ^{[3
]}

Zhao, X. ^{[1
,3
]}

Guan, Y. ^{[7
]}

Zhao, X. ^{[1
,3
]}

Yan, J. ^{[1
]}

Ni, J. ^{[8
]}

Nobrega, M. A. ^{[9
]}

Loewenberg, B. ^{[10
]}

Delwel, R. ^{[10
]}

Valk, P. J. M. ^{[10
]}

Kumar, A. ^{[11
]}

Xie, L. ^{[4
]}

Tenen, D. G. ^{[12
,13
]}

Huang, G. ^{[3
]}

Wang, Q-f ^{[1
]}

机构：

[1] Chinese Acad Sci, Beijing Inst Genom, Lab Genome Variat & Precis Biomed, Beijing 100101, Peoples R China

[2] Univ Chinese Acad Sci, Beijing, Peoples R China

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

[4] Shanghai Ctr Bioinformat Technol, Shanghai, Peoples R China

[5] Columbia Univ, Dept Biomed Informat, New York, NY USA

[6] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY USA

[7] Jilin Univ, Hosp 1, Branch 2, Resp Dept, Changchun 130023, Peoples R China

[8] Huazhong Univ Sci & Technol, Tongji Med Coll, Wuhan 430074, Peoples R China

[9] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[10] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands

[11] Cincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplant & Immune Deficiency, Cincinnati, OH 45229 USA

[12] Canc Sci Inst Singapore, Singapore, Singapore

[13] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA USA

来源：

LEUKEMIA | 2014年 / 28卷 / 07期

基金：

中国国家自然科学基金;

关键词：

PU.1; MEIS1; MLL leukemia; transcription regulation; ACUTE MYELOID-LEUKEMIA; TRANSCRIPTIONAL ELONGATION; SELF-RENEWAL; MEIS1; GENES; HOXA9; DIFFERENTIATION; TRANSLOCATIONS; CHROMATIN; TARGETS;

D O I：

10.1038/leu.2013.384

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Mixed lineage leukemia (MLL) fusion proteins directly activate the expression of key downstream genes such as MEIS1, HOXA9 to drive an aggressive form of human leukemia. However, it is still poorly understood what additional transcriptional regulators, independent of the MLL fusion pathway, contribute to the development of MLL leukemia. Here we show that the transcription factor PU.1 is essential for MLL leukemia and is required for the growth of MLL leukemic cells via the promotion of cell-cycle progression and inhibition of apoptosis. Importantly, PU.1 expression is not under the control of MLL fusion proteins. We further identified a PU.1-governed 15-gene signature, which contains key regulators in the MEIS-HOX program (MEIS1, PBX3, FLT3, and c-KIT). PU.1 directly binds to the genomic loci of its target genes in vivo, and is required to maintain active expression of those genes in both normal hennatopoietic stem and progenitor cells and in MLL leukemia. Finally, the clinical significance of the identified PU.1 signature was indicated by its ability to predict survival in acute myelogenous leukemia patients. Together, our findings demonstrate that PU.1 contributes to the development of MLL leukemia, partially via crosstalk with the MEIS/HOX pathway.

引用

页码：1436 / 1448

页数：13

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