Grant: Operating Grant

Oncogenes have the capacity to transform cells and promote cancer. They often result from specific mutations that hyper-activate or change normal gene function and thereby force a cell to engage in a path that it normally does not follow. While a large number of oncogenes have been identified to date, we still know little about the molecular disorders they create. This is in part due to the complexity of the effects as well as the slow pace associated with mammalian-based experimental models. Several other organisms have proven invaluable to elucidate basic cellular processes. For instance, the fruit fly Drosophila has already provided seminal information regarding a large range of human afflictions, such as neurodegeneration, obesity and aging to name a few. Here, we propose to use Drosophila as a tool to speed-up the characterization of human oncogenes and to verify our findings in mouse models. Because Drosophila genetics is extremely well developed, countless tools are available to rapidly identify novel genes. We recently generated a fly model that recapitulates the ability of a human oncogene (NUP98-HOXA9) to induce proliferation and tumor-like formation. Expression of NUP98-HOXA9 during Drosophila eye development produces defects that depend on fly genes related to known mammalian collaborators of NUP98-HOXA9. Moreover, co-expression of NUP98-HOXA9 and one of these collaborators, induces strong cell proliferation behavior that produces large tumor-like formation. We now propose to use this model to identify new partners of NUP98-HOXA9 activity by genetic screening and then test the new partners in mouse leukemia models to ascertain their implication. HOX gene dysregulation is often linked to acute myeloid leukemia (AML). This project should unveil a repertoire of genes modulating the action of NUP98-HOXA9. Once validated in mouse models, each of these new genes may represent as many potential targets against HOX-dependent leukemia.