PU.1 Activation Relieves GATA-1-Mediated Repression of Cebpa and Cbfb during Leukemia Differentiation

被引:21
作者
Burda, Pavel [1 ,2 ]
Curik, Nikola [1 ,2 ]
Kokavec, Juraj [1 ,2 ]
Basova, Petra [1 ,2 ]
Mikulenkova, Dana [3 ]
Skoultchi, Arthur I. [5 ]
Zavadil, Jiri [6 ,7 ]
Stopka, Tomas [1 ,2 ,4 ]
机构
[1] Charles Univ Prague, Fac Med 1, Inst Pathol Physiol, Prague 12853, Czech Republic
[2] Charles Univ Prague, Fac Med 1, Ctr Expt Hematol, Prague 12853, Czech Republic
[3] Gen Fac Hosp, Inst Hematol & Blood Transfus, Prague, Czech Republic
[4] Gen Fac Hosp, Dept Med 1, Prague, Czech Republic
[5] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10467 USA
[6] NYU, Dept Pathol, Inst Canc, New York, NY 10016 USA
[7] New York Langone Med Ctr, Ctr Hlth Informat & Bioinformat, Prague, Czech Republic
关键词
ACUTE MYELOID-LEUKEMIA; TRANSCRIPTION FACTOR; TERMINAL DIFFERENTIATION; BETA-SUBUNIT; C/EBP-ALPHA; GATA-1; CELLS; EXPRESSION; BINDING; HEMATOPOIESIS;
D O I
10.1158/1541-7786.MCR-09-0031
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Hematopoietic transcription factors GATA-1 and PU.1 bind each other on DNA to block transcriptional programs of undesired lineage during hematopoietic commitment. Murine erythroleukemia (MEL) cells that coexpress GATA-1 and PU.1 are blocked at the blast stage but respond to molecular removal (down regulation) of PU.1 or addition (upregulation) of GATA-1 by inducing terminal erythroid differentiation. To test whether GATA-1 blocks PU.1 in MEL cells, we have conditionally activated a transgenic PU.1 protein fused with the estrogen receptor ligand-binding domain (PUER), resulting in activation of a myeloid transcriptional program. Gene expression arrays identified components of the PU.1-dependent transcriptome negatively regulated by GATA-1 in MEL cells, including CCAAT/enhancer binding protein a (Cebpa) and core-binding factor, beta subunit (Cbfb), which encode two key hematopoietic transcription factors. Inhibition of GATA-1 by small interfering RNA resulted in derepression of PU.1 target genes. Chromatin immunoprecipitation and reporter assays identified PU.1 motif sequences near Cebpa and Cbfb that are co-occupied by PU.1 and GATA-1 in the leukemic blasts. Significant derepression of Cebpa and Cbfb is achieved in MEL cells by either activation of PU.1 or knockdown of GATA-1. Furthermore, transcriptional regulation of these loci by manipulating the levels of PU.1 and GATA-1 involves quantitative increases in a transcriptionally active chromatin mark: acetylation of histone H3K9. Collectively, we show that either activation of PU.1 or inhibition of GATA-1 efficiently reverses the transcriptional block imposed by GATA-1 and leads to the activation of a myeloid transcriptional program directed by PU.1. (Mol Cancer Res 2009;7(10):1693-703)
引用
收藏
页码:1693 / 1703
页数:11
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