Effects of mixed lineage leukaemia, the human homologue of Trithorax, and its leukaemic fusion proteins in Drosophila melanogaster

Muyrers-Chen, Inhua Taveira (2002). Effects of mixed lineage leukaemia, the human homologue of Trithorax, and its leukaemic fusion proteins in Drosophila melanogaster. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000fbda

Abstract

Mixed Lineage Leukaemia (MLL) refers to the protein implicated in translocating with over 30 partner genes to form fusion proteins that lead to the development of acute leukaemia. MLL mediated leukaemia predominantly afflicts children under 5 years of age or younger, and is associated with very poor survival rates. Although MLL shares limited homology with the Drosophila Trithorax (TRX) protein, both MLL and TRX are speculated to alter gene expression profiles by modulating higher order chromatin structures.
The work presented here introduces Drosophila melanogaster as a supplementary model system for understanding how MLL leukaemic fusion proteins can contribute to leukemogenesis. The expression in the Drosophila system of the two most widely generated fusion proteins in leukaemic patients, MLL-AF9 and MLL-AF4, has defined pathway(s) through which the proteins may interfere with to induce fly lethality. Both fusion proteins were found to affect higher order chromatin structure by modifying the méthylation pattern of histone H3 at lysine 9. Modified higher order chromatin modulates pathways targeted by specific MLL fusion protein, suggesting that the C-terminal portion of the fusion proteins triggers this step in cell cycle deregulation. Finally, the finding that late trx lethals are also associated with similar modified higher order chromatin structures displayed by MLL fusion proteins uncovered an additional role for TRX in the late development of Drosophila.
The results provide guidance in understanding why so many PcG and trxG members cause cancer when mutated, and suggest the existence of additional and distinct functions by PcG and trxG proteins at late development. The expression of MLL fusion proteins in Drosophila unveils relevant and concrete pathways through which particular MLL fusion proteins may act to prevent proper cell cycle progression. Put simply, this study links the targeting by MLL fusion proteins to TRX functions required for completion of late Drosophila development.