Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Chromosome translocations involving the mixed lineage leukemia gene MLL are associated with aggressive acute leukemias in both children and adults. Leukemogenic MLL fusion proteins delete the MLL SET domain Lys(4) methyltransferase activity and fuse MLL to 1 of >40 different translocation partners. Some MLL fusion proteins involve nuclear proteins that are transcriptional activators, whereas others have transcriptional activating activity but instead dimerize the truncated MLL molecule. Both types of MLL fusion proteins enforce persistent expression of Hox a9 and Meis1, which is pivotal for leukemogenesis through mechanisms that remain obscure. Here, we show that nuclear and dimerizable forms of MLL bind with a similar pattern to the Hox a9 locus that overlaps the distribution of wild-type MLL and deregulate transcription of three isoforms of Hox a9. Induction of MLL fusion protein activity is associated with increased levels of histone acetylation and Lys(4) methylation at Hox target genes. In addition, the MLL-ENL-ER protein, but not dimerized MLL, also induces dimethylation of histone H3 at Lys(79), suggesting alternative mechanisms for transcriptional activation.

Original publication

DOI

10.1158/0008-5472.CAN-05-1041

Type

Journal article

Journal

Cancer Res

Publication Date

15/12/2005

Volume

65

Pages

11367 - 11374

Keywords

Dimerization, Gene Expression Regulation, Histone-Lysine N-Methyltransferase, Histones, Homeodomain Proteins, Humans, Lysine, Methylation, Myeloid-Lymphoid Leukemia Protein, Neoplasm Proteins, Oncogene Proteins, Fusion, Promoter Regions, Genetic, Protein Binding, Transcription, Genetic