Screening for Novel Genes Contributing to the Transformed Status of Alveolar Rhabdomyosarcoma (ARMS)

Alveolar rhabdomyosarcoma (ARMS) is the second most common subtype of rhabdomyosarcoma, accounting for approximately 20% of cases. ARMS is associated with the chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) resulting in the fusion proteins PAX3-FOXO1 and PAX7- FOXO1, respectively. The molecular mechanisms by which PAX3-FOXO1 contribute to ARMS formation remains to be fully determined. However the data reported in this thesis demonstrate the functional interaction of novel ARMS associated genes with PAX3-FOXO1 and their contribution to the development of ARMS. The research performed in our laboratory is focused on defining the molecular biology behind PAX3-FOXO1-induced tumorigenesis. Published and unpublished data from this laboratory shows that expression of PAX3-FOXO1 alone is not sufficient for the transformation of primary mouse myoblasts (Lagutina, Pritchard and Grosveld, unpublished data). Abrogation of both the p53 and Rb pathways is required in order to allow PAX3-FOXO1 driven transformation (Lagutina, Pritchard and Grosveld, unpublished data). My research is focused on the identification of these PAX3-FOXO1-complementing secondary events using a cDNA library screen. To this end, chapter 3 describes the identification of a novel gene named IRIZIO and its cooperation with PAX3-FOXO1 in transforming Arf-/- myoblasts in vivo. Similarly, chapter 4 illustrates the effect of lysil hydroxylase 1 (PLOD1) and its tumorigenic capacity when over expressed together with PAX3-FOXO1 in myogenic cells. Together, these results contribute to a better understanding of the mechanisms by which PAX3-FOXO1 and its cooperating proteins mediate myogenic cell transformation. Hopefully our findings will eventually contribute to improve the treatment of ARMS.