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

Oncogene. 2004 Nov 11;23(53):8639-48. doi: 10.1038/sj.onc.1207904.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Brain / cytology
  • Brain / metabolism
  • Cell Cycle*
  • Chromosomes / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drosophila / cytology*
  • Drosophila / embryology
  • Drosophila / growth & development
  • Drosophila / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / embryology
  • Embryo, Nonmammalian / metabolism
  • Gene Expression
  • Gene Expression Regulation, Developmental
  • Larva / genetics
  • Larva / growth & development
  • Larva / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Myeloid-Lymphoid Leukemia Protein
  • Protein Binding
  • Proto-Oncogenes / genetics
  • Pupa / genetics
  • Pupa / growth & development
  • Pupa / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Survival Rate
  • Thioredoxins / genetics
  • Thioredoxins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DHD protein, Drosophila
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Membrane Proteins
  • Recombinant Proteins
  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • Thioredoxins