Drosophila Hox genes induce melanised pseudo-tumours when misexpressed in hemocytes
Background: Hox genes are key early determinants of cell identity along the anterior-posterior body axis across bilaterians. Recently, several late non-homeotic functions of Hox genes have emerged in a variety of processes involved in organogenesis in several organisms, including mammals. Being crucial factors in determining cell identity and organogenesis, the misregulation of Hox genes is likely to be associated with defects in these processes. Several studies have reported the misexpression
... the misexpression of Hox genes in a variety of malignancies including acute myeloid leukaemia. Methods: The Hox genes Dfd, Ubx, abd-A and Abd-B were overexpressed via the UAS-Gal4 system using Cg-Gal4, Lsp2-Gal4, He-Gal4 and HmlD3-Gal4 as specific drivers. Genetic interaction was tested by bringing overexpression lines in heterozygous mutant backgrounds of Polycomb and trithorax group factors. Larvae were visually scored for melanised bodies. Hemocytes were quantified by dissecting larvae for lymph in 4mm wells and staining nuclei with DAPI and tested for differentiation by staining them with anti-myospheroid and for proliferation with anti-PH3. Pupal lethality was carried out by letting pupae eclose and scoring those that failed after the time point. Results: Expression of Dfd, Ubx and abd-A, but not Abd-B in the hematopoietic compartment of Drosophila led to the appearance of circulating melanised bodies, and increase in cell numbers, cell-autonomous proliferation and differentiation of hemocytes. Pupal lethality and the melanised pseudo-tumor phenotype were suppressed by the mutations in Psc1 and esc2 background while polycomb group member mutations Pc1 and Su(z)123 and trithorax group member mutation TrlR85 increased the phenotype.Conclusions: Dfd, Ubx and abd-A are leukemogenic. Mutations in Polycomb and trithorax group members, which are responsible for maintaining the expression state of the Hox genes, modulate the leukemogenic phynotype. Drosophila, widely used as a model for myeloid leukemias, can serve as a testbed for Hox expression induced leukemias.