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Grosveld Research: Alveolar Rhabdomyosarcoma

Alveolar Rhabdomyosarcoma (ARMS) is a highly malignant and often devastating skeletal muscle tumor in children. The disease typically develops during puberty, and the overall survival rate is only 50%. ARMS cells are characterized by the recurrent chromosome translocations t(2;13) or t(1;13) encoding the fusion transcription factors PAX3-FOXO1a or PAX7-FOXO1a, respectively.

PAX3, PAX7, and FOXO1a play distinct roles during muscle formation. In mouse embryos that lack PAX3, muscle precursor cells fail to populate the trunk and extremities. In those that lack PAX7, satellite cells, the progenitor cells needed for muscle expansion and regeneration after birth, fail to form. We have shown that FOXO1a regulates the rate of fusion of skeletal muscle cells.

Primary mouse myoblasts expressing PAX3-FOXO1a proliferate faster than normal myoblasts, but the expression of the fusion protein is insufficient to cause tumorigenic transformation of these cells. PAX3-FOXO1a, but not PAX3, transforms myoblasts that harbor both a compromised p53 pathway and a compromised pRb pathway.

Using extensive expression profiling of PAX3-FOXO1a–expressing myoblasts, we have identified several genes whose aberrant expression contributes to the enhanced proliferation of these cells. In addition, we have identified proteins that are part of the PAX3-FOXO1a transcription complex. Using genetic approaches, we are currently determining whether the presence of these proteins in the complex is crucial for the PAX3-FOXO1a–mediated transformation of myoblasts into ARMS cells.

A large part of our effort on this project is dedicated to the development of a versatile mouse model of ARMS in which we can test the cooperation of PAX3-FOXO1a with other mutations that occur in human ARMS. This mouse model will be used as a preclinical model to test novel therapeutic modalities that may eventually improve the cure rates for patients with this devastating disease.