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 Blood, 15 December 2007, Vol. 110, No. 13, pp. 4445-4454.
Prepublished online as a Blood First Edition Paper on September 12, 2007; DOI 10.1182/blood-2007-05-090514.

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Submitted May 15, 2007
Accepted August 29, 2007

A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification

Dorothee Mueller, Christian Bach, Deniz Zeisig, Maria-Paz Garcia-Cuellar, Sara Monroe, Arun Sreekumar, Rong Zhou, Alexey Nesvizhskii, Arul Chinnaiyan, Jay L Hess, and Robert K. Slany*

Department of Genetics, University Erlangen, Erlangen, Germany
Department of Pathology, University Michigan Medical School, Ann Arbor, MI, United States

* Corresponding author; email: rslany{at}biologie.uni-erlangen.de.

Chimeric proteins joining the histone methyltransferase MLL with various fusion partners trigger distinctive lymphoid and myeloid leukemias. Here we immunopurified proteins associated with ENL, a protein commonly fused to MLL. Identification of these ENL associated proteins (EAP) by mass spectrometry revealed enzymes with a known role in transcriptional elongation (RNAPolymeraseII C-terminal domain kinase pTEFb), and in chromatin modification (histone-H3 methyltransferase DOT1L) as well as other frequent MLL partners (AF4, AF5q31, LAF4), and polycomb group members (RING1, CBX8 and BCoR). The composition of EAP was further verified by coimmunoprecipitation, two-hybrid analysis, pulldown and colocalization experiments. Purified EAP showed a histone H3 Lysine79-specific methylase activity, displayed a robust RNAPolII CTD kinase function and counteracted the effect of the pTEFb inhibitor 5,6-Dichloro-benzimidazole-riboside. In vivo an ENL knockdown diminished genome-wide as well as gene-specific H3K79 dimethylation, reduced global run-on elongation and inhibited transient transcriptional reporter activity. According to structure-function data DOT1L recruitment was important for transformation by the MLL-ENL fusion derivative. These results suggest a function of ENL in histone modification and transcriptional elongation.


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