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

doi:10.1016/j.isci.2023.107726

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

iScience. 2023 Aug 25;26(10):107726. doi: 10.1016/j.isci.2023.107726. eCollection 2023 Oct 20.

Authors

Julie A Johannessen^{1

2

3}, Miriam Formica^{1

2

3}, Aina Louise C Haukeland^{1

2

3}, Nora Rojahn Bråthen^{1

2}, Amani Al Outa^{1

2

3}, Miriam Aarsund^{1

2}, Marc Therrien^{4

5}, Jorrit M Enserink^{1

2

6}, Helene Knævelsrud^{1

2

3}

Affiliations

¹ Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
² Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
³ Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁴ 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.
⁵ Département de pathologie et de biologie cellulaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
⁶ Section for Biochemistry and Molecular Biology, The Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.

Abstract

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.

Keywords: Cell biology; Molecular biology; Oncology.