RRC ID 67565
Author Gavory G, Baril C, Laberge G, Bidla G, Koonpaew S, Sonea T, Sauvageau G, Therrien M.
Title A genetic screen in Drosophila uncovers the multifaceted properties of the NUP98-HOXA9 oncogene.
Journal PLoS Genet
Abstract Acute myeloid leukemia (AML) underlies the uncontrolled accumulation of immature myeloid blasts. Several cytogenetic abnormalities have been associated with AML. Among these is the NUP98-HOXA9 (NA9) translocation that fuses the Phe-Gly repeats of nucleoporin NUP98 to the homeodomain of the transcription factor HOXA9. The mechanisms enabling NA9-induced leukemia are poorly understood. Here, we conducted a genetic screen in Drosophila for modifiers of NA9. The screen uncovered 29 complementation groups, including genes with mammalian homologs known to impinge on NA9 activity. Markedly, the modifiers encompassed a diversity of functional categories, suggesting that NA9 perturbs multiple intracellular events. Unexpectedly, we discovered that NA9 promotes cell fate transdetermination and that this phenomenon is greatly influenced by NA9 modifiers involved in epigenetic regulation. Together, our work reveals a network of genes functionally connected to NA9 that not only provides insights into its mechanism of action, but also represents potential therapeutic targets.
Volume 17(8)
Pages e1009730
Published 2021-8-1
DOI 10.1371/journal.pgen.1009730
PMID 34383740
PMC PMC8384169
MeSH Animals Cell Differentiation / genetics Drosophila melanogaster / genetics Epigenesis, Genetic / genetics Gene Expression / genetics Gene Expression Regulation / genetics Gene Regulatory Networks / genetics Homeodomain Proteins / genetics* Homeodomain Proteins / metabolism Humans Leukemia, Myeloid, Acute / genetics Myeloid Cells / metabolism Myeloid Cells / physiology Nuclear Pore Complex Proteins / genetics* Nuclear Pore Complex Proteins / metabolism Oncogene Proteins, Fusion / genetics Oncogene Proteins, Fusion / metabolism Oncogenes / genetics Transcription Factors / genetics Translocation, Genetic / genetics
IF 5.175