Leukemogenic MLL-ENL Fusions Induce Alternative Chromatin States to Drive a Functionally Dichotomous Group of Target Genes

Cell Reports

Robert K. Slany¹  Maria-Paz Garcia-Cuellar¹  Martin Dugas²  Christoph Bartenhagen²  Christian Büttner³ 

[1] Department of Genetics, Friedrich-Alexander-University Erlangen-Nürnberg, 91058 Erlangen, Germany;Department of Medical Informatics, University Münster, 48149 Münster, Germany;Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nürnberg, 91058 Erlangen, Germany;

关键词: leukemia;    chromatin;    MLL-ENL;    P-TEFb;    DOT1L;    inhibitors;   

DOI  :  10.1016/j.celrep.2016.03.018

来源: DOAJ

【 摘 要 】

MLL fusions are leukemogenic transcription factors that enhance transcriptional elongation through modification of chromatin and RNA Pol II. Global transcription rates and chromatin changes accompanying the transformation process induced by MLL-ENL were monitored by nascent RNA-seq and ChIP-seq, revealing 165 direct target genes separated into two distinct clades. ME5 genes bound MLL-ENL at the promoter, relied on DOT1L-mediated histone methylation, and coded preferentially for transcription factors, including many homeobox genes. A distinct ME3 group accumulated MLL-ENL beyond the termination site, was dependent on P-TEFb-mediated phosphorylation of RNA Pol II for transcription, and translated mainly into proteins involved in RNA biology and ribosome assembly. This dichotomy was reflected by a differential sensitivity toward small molecule inhibitors, suggesting the possibility of a combinatorial strategy for treatment of MLL-induced leukemia.

【 授权许可】

Unknown