The human leukemic oncogene MLL-AF4 promotes hyperplastic growth of hematopoietic tissues in Drosophila larvae
Julie A. Johannessen,
Miriam Formica,
Aina Louise C. Haukeland,
Nora Rojahn Bråthen,
Amani Al Outa,
Miriam Aarsund,
Marc Therrien,
Jorrit M. Enserink,
Helene Knævelsrud
Affiliations
Julie A. Johannessen
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
Miriam Formica
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
Aina Louise C. Haukeland
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
Nora Rojahn Bråthen
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Amani Al Outa
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
Miriam Aarsund
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
Marc Therrien
Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC H3C 3J7, Canada; Département de pathologie et de biologie cellulaire, Université de Montréal, Montréal, QC H3C 3J7, Canada
Jorrit M. Enserink
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Section for Biochemistry and Molecular Biology, The Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
Helene Knævelsrud
Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway; Corresponding author
Summary: 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.
