The leukemogenic AF4-MLL fusion protein causes P-TEFb kinase activation and altered epigenetic signatures

被引：61

作者：

Benedikt, A.

Baltruschat, S. ^{[2
]}

Scholz, B.

Bursen, A.

Arrey, T. N. ^{[2
]}

Meyer, B. ^{[2
]}

Varagnolo, L. ^{[3
]}

Mueller, A. M. ^{[3
]}

Karas, M. ^{[2
]}

Dingermann, T.

Marschalek, R. ^{[1
]}

机构：

[1] Goethe Univ Frankfurt, Inst Pharmaceut Biol, DCAL, ZAFES,Bioctr, D-60438 Frankfurt, Germany

[2] Goethe Univ Frankfurt, Inst Pharmaceut Chem, Bioctr, ZAFES, D-60438 Frankfurt, Germany

[3] Univ Wurzburg, Ctr Med Expt, Wurzburg, Germany

来源：

LEUKEMIA | 2011年 / 25卷 / 01期

关键词：

acute leukemia; MLL; AF4; fusion genes; fusion proteins; NF-KAPPA-B; DEPENDENT GENE-EXPRESSION; TRANSCRIPTIONAL ELONGATION; HISTONE METHYLTRANSFERASE; H3K79; METHYLATION; SET DOMAIN; MLL FAMILY; LEUKEMIA; AF4; CHROMATIN;

D O I：

10.1038/leu.2010.249

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Expression of the AF4-MLL fusion protein in murine hematopoietic progenitor/stem cells results in the development of proB acute lymphoblastic leukemia. In this study, we affinity purified the AF4-MLL and AF4 protein complexes to elucidate their function. We observed that the AF4 complex consists of 11 binding partners and exhibits positive transcription elongation factor b (P-TEFb)-mediated activation of promoter-arrested RNA polymerase (pol) II in conjunction with several chromatin-modifying activities. In contrast, the AF4-MLL complex consists of at least 16 constituents including P-TEFb kinase, H3K4(me3) and H3K79(me3) histone methyltransferases (HMT), a protein arginine N-methyltransferase and a histone acetyltransferase. These findings suggest that the AF4-MLL protein disturbs the fine-tuned activation cycle of promoter-arrested RNA Pol II and causes altered histone methylation signatures. Thus, we propose that these two processes are key to trigger cellular reprogramming that leads to the onset of acute leukemia. Leukemia (2011) 25, 135-144; doi: 10.1038/leu.2010.249; published online 29 October 2010

引用

页码：135 / 144

页数：10

共 45 条

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