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

MLL-rearranged (MLL-r) leukemias are among the leukemic subtypes with poorest survival, and treatment options have barely improved over the last decades. Despite increasing molecular understanding of the mechanisms behind these hematopoietic malignancies, this knowledge has had poor translation into the clinic. Here, we report a Drosophila melanogaster model system to explore the pathways affected in MLL-r leukemia. We show that expression of the human leukemic oncogene MLL-AF4 in the Drosophila hematopoietic system resulted in increased levels of circulating hemocytes and an enlargement of the larval hematopoietic organ, the lymph gland. Strikingly, depletion of Drosophila orthologs of known interactors of MLL-AF4, such as DOT1L, rescued the leukemic phenotype. In agreement, treatment with small-molecule inhibitors of DOT1L also prevented the MLL-AF4-induced leukemia-like phenotype. Taken together, this model provides an in vivo system to unravel the genetic interactors involved in leukemogenesis and offers a system for improved biological understanding of MLL-r leukemia.

Date de publication
20 octobre 2023
Johannessen JA, Formica M, Haukeland ALC, Bråthen NR, Al Outa A, Aarsund M, Therrien M, Enserink JM, Knævelsrud H
Référence PubMed
iScience 2023;26(10):107726
ID PubMed
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.