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Molecular and Cellular Biology, January 2003, p. 119-130, Vol. 23, No. 1
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.1.119-130.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Leucine Zipper Motif of the Drosophila AF10 Homologue Can Inhibit PRE-Mediated Repression: Implications for Leukemogenic Activity of Human MLL-AF10 Fusions

Laurent Perrin,{dagger}* Sébastien Bloyer, Conchita Ferraz, Namita Agrawal,{ddagger} Pradip Sinha,2{ddagger} and Jean Maurice Dura

Institut de Génétique Humaine, CNRS, UPR 1142, 34396 Montpellier Cedex 5, France

Received 18 April 2002/ Returned for modification 25 June 2002/ Accepted 1 October 2002

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.

* Corresponding author. Mailing address: Institut de Génétique Humaine, CNRS, UPR 1142, 141 rue de la Cardonille, 34396 Montpellier Cedex 5, France. Phone: (33) 4 91 26 96 11. Fax: (33) 4 91 82 06 82. E-mail: perrin{at}ibdm.univ-mrs.fr.

{dagger} Present address: Laboratoire de Génétique et Physiologie du Développement, Campus de Luminy, CNRS Case 907, 13288 Marseille Cedex 9, France.

{ddagger} Present address: Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 20 80 16, India.

Molecular and Cellular Biology, January 2003, p. 119-130, Vol. 23, No. 1
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.1.119-130.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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