The human leukemic oncogene MLL-AF4 promotes hyperplastic growth of hematopoietic tissues inDrosophilalarvae

Abstract

AbstractMLL-rearranged leukemias are among the leukemic subtypes with poorest survival, and treatment options have barely improved over the last decades. Furthermore, despite increasing molecular understanding of the mechanisms behind these hematopoietic malignancies, this knowledge has had poor translation into the clinic. Identification of novel treatment methods is hampered by the lack of relevantin vivomodels that allow for rapid identification of actionable drug targets and small molecule inhibitors. Here, we report aDrosophila melanogastermodel system to explore the pathways affected inMLL-rearranged leukemia. We show that expression of the human leukemic oncogene MLL-AF4 in theDrosophilahematopoietic system resulted in increased levels of circulating hemocytes and an enlargement of the larval hematopoietic organ, the lymph gland. Strikingly, depletion ofDrosophilaorthologs 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 anin vivosystem to unravel the genetic interactors involved in leukemogenesis and offers a strategy for a prompt identification of potential therapeutic options for treatment ofMLL-rearranged leukemia.