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Expression of leukemic MLL fusion proteins in Drosophila affects cell cycle control and chromosome morphology

Oncogene volume 23, pages 8639–8648 (2004)Cite this article

Abstract

The Mixed Lineage Leukemia (MLL) gene is involved in lymphoblastic and myeloid leukemia through chromosome translocations leading to fusion of MLL to partner genes, or through internal MLL rearrangements. MLL is the mammalian counterpart of the Drosophila trithorax (trx) gene, involved in maintaining active gene expression states. We have used transgenic Drosophila to assess the molecular targets and cellular processes affected by MLL and two of its leukemic fusion proteins. We find that whereas expression of normal human MLL in flies does not result in phenotypic alterations, overexpressing the human MLL-AF9 and MLL-AF4 proteins causes larval to pupal lethality, which interestingly resembles the phenotypes displayed by certain Drosophila trx mutant alleles. MLL-AF9 and MLL-AF4 transgenic flies exhibit antagonistic alterations in cell cycle progression. Additionally, flies expressing MLL-AF9 display impairment in higher order chromatin integrity, evidenced in decondensation of mitotic figures. The effects of MLL fusion proteins in Drosophila suggest that alteration of chromatin structure by MLL fusion proteins may contribute to the lethal phenotype. Our results indicate that the mode(s) of action of MLL-AF9 in Drosophila varies from that of MLL-AF4. Taken together, the expression of MLL fusion proteins in Drosophila provides a new and powerful system to reveal and characterize biological activities associated with MLL fusion proteins.

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Acknowledgements

We thank Isolde Riede for fruitful discussions and to Leonie Ringrose, Joep Muijrers, and Dirk Lankenau for critical reading of the manuscript. This project was supported by a grant to RP and EC from the German-Israeli Cooperative Project in Cancer Research, by grants to RP from the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie, and by a grant to EC from the Israeli Academy of Science. IMC was further supported by a National Science Foundation Graduate Fellowship.

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Authors and Affiliations

  1. ZMBH, University of Heidelberg, Heidelberg, D-69120, Germany

    Inhua Muyrers-Chen, Nara Lee & Renato Paro

  2. Weizmann Institute of Science, Rehovot, Israel

    Tatiana Rozovskaia & Eli Canaani

  3. University of Minnesota Cancer Center, Minneapolis, 55455, MN, USA

    John H Kersey

  4. Thomas Jefferson University, Philadelphia, USA

    Tatsuya Nakamura

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  1. Inhua Muyrers-Chen
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Correspondence to Renato Paro.

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Muyrers-Chen, I., Rozovskaia, T., Lee, N. et al. Expression of leukemic MLL fusion proteins in Drosophila affects cell cycle control and chromosome morphology. Oncogene 23, 8639–8648 (2004). https://doi.org/10.1038/sj.onc.1207904

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