The leukemogenic fusion of MLL with ENL creates a novel transcriptional transactivator.
Translocations affecting the chromosomal locus 11q23 are hallmarks of infant leukemias. These events disrupt the MLL gene (also ALL-1 or HRX) and fuse the MLL amino terminus in frame with a variety of unrelated proteins. The ENL gene on 19p13.1 is a recurrent fusion partner of MLL. Whereas potential functions have been suggested for isolated domains of either MLL or ENL no experimental data exist for the biological properties of the complete chimeric MLL-ENL protein. We show here that the fusion of MLL with ENL creates a novel molecule that is a potent general transcriptional transactivator in transient reporter gene assays. MLL-ENL strongly transactivated several unrelated promoters including the promoter of Hoxa7 a potential target gene for the unaltered MLL protein. This transactivation capability was cell type specific and it was critically dependent on the contributions of the methyltransferase-homology (MT) region of MLL in combination with the C-terminus of ENL. Squelching experiments and gel retardation studies identified the ENL C-terminus as a binding partner for an unknown factor and the MLL MT region as a unique general DNA binding motif. The potential implications of these findings for the leukemogenesis by MLL-ENL are discussed.
Schreiner
S A
SA
Department of Genetics, University of Erlangen, Staudtstrasse 5, 91058 Erlangen, Germany.
García-Cuéllar
M P
MP
Fey
G H
GH
Slany
R K
RK
D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011519:Proto-Oncogenes; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis*; D015534:Trans-Activators; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C115962:HOXA7 protein, human; D018398:Homeodomain Proteins; C492047:Hoxa7 protein, mouse; C497422:KMT2A protein, human; C081448:MLLT1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse