Oral Presentation Advances in Neuroblastoma Research Congress 2016

Altering the MYCN/MAX ratio in a drosophila MYCN model leads to homeotic transformation of the eye to wing through deregulation of specific HOX genes (#80)

Roberto Bernardoni 1 , Giuseppe Di Candia 1 , Giorgia Giordani 1 , Ettore De Giorgio 1 , Laura De Grandis 1 , Giorgio Milazzo 1 , Daniela Erriquez 1 , Francesca Ferrucci 1 , Murray D Norris 2 , Michelle Haber 2 , Giovanni Perini 1
  1. University of Bologna, Bologna, ITALY, Italy
  2. Children’s Cancer Institute Australia for Medical Research, Sydney, New South Wales, Australia

For children with high risk neuroblastoma characterized by amplification of the MYCN oncogene survival rates are particularly poor. MYCN is a transcription factor that heterodimerises with MAX to control a large set of genes. The process of amplification invariably leads to very high levels of MYCN protein, which alters the intracellular ratio between MYCN and MAX. This suggests that at least some of MYCN’s oncogenic effects may be MAX-independent and that in turn the levels of MAX may be critical for normal MYCN function. To explore this hypothesis, we took advantage of a MYCN fly model in which it is possible to modulate the expression levels of drosophila Myc (dMyc), human MYCN or drosophila MAX (dMax) in the fly eye. Using this approach, we generated a range of drosophila lines with different combinations of dMYC, MYCN and/or dMAX expression levels. The results showed that MAX downregulation against a normal dMyc background reduced proliferation and organ growth but did not affect retina differentiation. Conversely, dMYC/MYCN overexpression with a normal dMAX background blocked eye cell differentiation with deformation of the eye structure. Surprisingly, flies with simultaneous high levels of dMYC or MYCN and concomitant silencing of dMAX showed an eye to wing homeotic transformation. Molecular and cellular investigation of this phemomenon revealed that high levels of dMyc/MYCN protein in the eye primordium leads to ectopic activation of Antennapedia, the wing HOX-specific gene, most likely through repression of Deformed, the eye HOX-specific gene. Based on these results we propose that during development, very high MYCN levels may alter regulation of a specific set of HOX genes to alter/block cell differentiation, thus predisposing cells to neoplastic transformation.