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The human leukemic oncogene MLL-AF4 promotes hyperplastic growth of hematopoietic tissues in Drosophila larvae

Julie A Johannessen1,2,3, Miriam Formica1,2,3, Aina Louise C Haukeland1,2,3

  • 1Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.

Iscience
|September 18, 2023
PubMed

Insights

A new Drosophila model for MLL-rearranged (MLL-r) leukemia reveals DOT1L as a key therapeutic target. Inhibiting DOT1L reversed leukemia development in this model, offering hope for improved MLL-r leukemia treatments.

Area of Science:

  • Hematology
  • Oncology
  • Genetics

Background:

  • MLL-rearranged (MLL-r) leukemias have poor survival rates with limited treatment advancements.
  • Despite molecular insights, translating this knowledge into clinical applications for MLL-r leukemia remains a challenge.

Purpose of the Study:

  • To establish a Drosophila melanogaster model for investigating MLL-r leukemia pathways.
  • To identify potential therapeutic targets for MLL-r leukemia.

Main Methods:

  • Expression of human MLL-AF4 oncogene in Drosophila hematopoietic system.
  • Depletion of Drosophila orthologs of MLL-AF4 interactors, including DOT1L.
  • Treatment with small-molecule inhibitors of DOT1L.

Main Results:

  • MLL-AF4 expression in Drosophila caused increased hemocytes and lymph gland enlargement, mimicking leukemia.
  • Depleting DOT1L or inhibiting it with small molecules rescued the MLL-AF4-induced leukemia phenotype.
  • The Drosophila model successfully recapitulated key aspects of MLL-r leukemia.

Conclusions:

  • The Drosophila model provides a valuable in vivo system for studying MLL-r leukemogenesis.
  • DOT1L is a critical interactor in MLL-r leukemogenesis and a promising therapeutic target.
  • This model can facilitate the discovery of novel genetic interactors and improve biological understanding of MLL-r leukemia.
Keywords:
Cell biologyMolecular biologyOncology

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