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AF4p12, a Human Homologue to the furry Gene of Drosophila, as a Novel MLL Fusion Partner

¹ Laboratoire d'Hématologie et de Cytogénétique, Centre Hospitalier Lyon Sud and EA 3737, Pierre-Benite, France; ² Institut National de la Sante et de la Recherche Medicale U590, Centre Léon Bérard, Université Claude Bernard Lyon I, Lyon, France; ³ Laboratoire d'Hématologie, CHU Robert Debré, Reims, France; and ⁴ Département d'Hématologie, Université Paris V René Descartes, Hôpital Necker, and Institut National de la Sante et de la Recherche Medicale EMI02.10, Paris, France

Requests for reprints: Ruth Rimokh, Institut National de la Sante et de la Recherche Medicale U590, Centre Léon Bérard, 69373 Lyon Cedex 08, France. Phone: 330-478-78-29-03; Fax: 330-478-78-27-20; E-mail: rimokh{at}lyon.fnclcc.fr, & Sandrine Hayette, Laboratoire d' Hématologie et de Cytogénétique, Centre Hospitalier Lyon Sud, 69495 Pierre-Bénite, France. Phone: 33-478-86-41-07; Fax: 33-478-86-41-04; E-mail: sandrine.hayette{at}chu-lyon.fr.

More than 35 different partner genes with the mixed lineage leukemia (MLL) gene have been cloned from leukemia cells with translocations involving chromosome 11 band q23. In this study, we report on a novel fusion partner of the MLL gene, AF4p12, which we have identified as the human homologue to the furry gene of Drosophila. AF4p12, highly conserved in evolution, encodes a large protein of 3,105 amino acids. The expression of AF4p12 has been preferentially detected in colon, placenta, and brain tissues and in tumor cells of lymphoid origin. We show that the t(4;11)(p12;q23) translocation results in the creation of a chimeric RNA encoding a putative fusion protein containing 1,362 amino acids from the NH₂-terminal part of MLL and 712 amino acids from the COOH-terminal part of AF4p12. FLT3 and HOXA9 genes are overexpressed in this leukemia. We found that the COOH-terminal part of AF4p12 fused to MLL contains a leucine zipper motif and exhibits transcriptional activation properties when fused to Gal4 DNA-binding domains in transient transfection assays. The AF4p12 fragment fused to MLL may contribute to the oncogenic activation of MLL, possibly through specific recruitment of the transcriptional machinery.

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