Abstract 1431: A novel tumor-suppressor role of MyoD, a muscle differentiation factor, in mouse models of medulloblastoma

Medulloblastoma, an embryonal tumor of the cerebellum, is the most common pediatric brain cancer. For decades, it has been known that a small subset of medulloblastomas present with myogenic differentiation. However, the mechanistic basis and significance of this biological anomaly remain to be determined. We have identified hitherto unknown expression of muscle differentiation factor, MyoD in cerebellar tumors from mouse models of medulloblastoma as well as in a subset of human medulloblastomas. At a cellular level, MyoD is expressed in mitotically active cells and intriguingly, in mouse tumors does not activate its canonical targets involved in the muscle differentiation program. To understand the functional consequence of this finding in medulloblastoma genesis, we have conducted genetic studies to assess tumor formation in the SmoA1 and SmoA2 medulloblastoma models, on a MyoD-deficient background. We demonstrate that MyoD acts as a haploinsufficient tumor suppressor as the MyoD wt/-; SmoA1 and MyoD wt/-; SmoA2 mice have an accelerated onset of tumors compared to MyoD wt/wt; SmoA1 or MyoD wt/wt; SmoA2 mice respectively. Our findings suggest that the expression of MyoD might be an oncogene-induced compensatory response in the cerebellum to suppress tumor growth by restoring balance between proliferation and differentiation, similar to the role of some other bHLH transcription factors. Harnessing this latent tumor suppressor network to induce differentiation or cell cycle arrest holds promise for future therapeutic interventions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1431. doi:1538-7445.AM2012-1431