A genetic screen in Drosophila uncovers the multifaceted properties of the NUP98-HOXA9 oncogene

Gwenaëlle Gavory,Gawa Bidla,Gino Laberge,Surapong Koonpaew,Thomas Sonea,Caroline Baril,Guy Sauvageau,Marc Therrien,David A Wassarman

doi:10.1371/journal.pgen.1009730

Gwenaëlle Gavory, Gawa Bidla + Show 7 more

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https://doi.org/10.1371/journal.pgen.1009730

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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.

Highlights

Acute myeloid leukemia (AML) is among the most common and deadliest forms of leukemia affecting the ageing human population [1]
Acute myeloid leukemia or AML is a cancer of blood cells
A representative example is the NUP98-HOXA9 oncoprotein, which results from the fusion of the NUP98 and HOXA9 genes

Summary

Introduction

Acute myeloid leukemia (AML) is among the most common and deadliest forms of leukemia affecting the ageing human population [1]. It is a clonal disease of hematopoietic stem cells characterized by the interruption of myeloid differentiation and the relentless proliferation of abnormal progenitors accumulating in bone marrow, blood and other tissues. Molecular lesions impinging on relatively few genes have been linked to the pathogenesis of AML [2]. DNMT3A, FLT3, IDH1, IDH2, and NPM1 are among the most commonly mutated loci [3,4]. The prognosis remains bleak and a deeper understanding of the underlying mechanistic causes of AML remains absolutely necessary to accelerate the development of effective therapies

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