The leucine zipper motif of the Drosophila AF10 homologue can inhibit PRE-mediated repression: implications for leukemogenic activity of human MLL-AF10 fusions.
In a screen for Drosophila genes that interfere with transcriptional repression mediated by the Polycomb group of genes, we identified a dominant mutation affecting the Alhambra (Alh) gene, the fly homologue of the human AF10 gene. AF10 has been identified as a fusion partner of both MLL and CALM in infant leukemias. Both fusion proteins retain the leucine zipper domain of AF10 but not its PHD domain. We show here that, while the full-length ALH protein has no activity on Polycomb group-responsive elements (PREs), overexpression of the isolated ALH leucine zipper domain activates several PREs. Within the ALH full-length protein, the PHD domain inhibits the PRE deregulation mediated by the leucine zipper domain. This deregulation is conserved in the human AF10 leucine zipper domain, which confers the same activity on an oncogenic MLL-AF10 fusion protein expressed in Drosophila melanogaster. These data reveal new properties for the leucine zipper domain and thus might provide new clues to understanding the mechanisms by which AF10 fusion proteins in which the PHD domain is lost might trigger leukemias in humans.
Perrin
Laurent
L
Institut de Génétique Humaine, CNRS, UPR 1142, 34396 Montpellier Cedex 5, France. perrin@ibdm.univ-mrs.fr
Bloyer
Sébastien
S
Ferraz
Conchita
C
Agrawal
Namita
N
Sinha
Pradip
P
Dura
Jean Maurice
JM
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics*; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D016350:Leucine Zippers / Q000235:genetics*; D007938:Leukemia / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011519:Proto-Oncogenes; D020218:Response Elements; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
C114359:AF10-CALM fusion protein, human; C426850:Alh protein, Drosophila; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C497422:KMT2A protein, human; C470550:MLL-AF10 fusion protein, human; C092513:MLLT10 protein, human; C096106:MLLT6 protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; C066770:Pc protein, Drosophila; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D063150:Polycomb Repressive Complex 1