Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1 (P3F). The mechanisms by which P3F dysregulates chromatin are unknown. This study found that P3F reprograms the cis-regulatory landscape by inducing (de novo) super enhancers (SEs). P3F uses SEs to set up autoregulatory loops in collaboration with master transcription factors MYOG, MYOD and MYCN. This myogenic SE circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small molecule inhibition of protein targets induced by or bound to PAX3-FOXO1-occupied SEs. Furthermore, P3F recruits and requires BET bromodomain protein BRD4 to function at SEs, resulting in a complete dependence on BRD4 and a significant susceptibility to BRD inhibition. These results yield novel insights into the epigenetic functions of P3F and reveal a specific vulnerability that can be exploited for precision therapy.
Molecular Sensitivity Landscape of Fusion-Positive Rhabodomyosarcoma (FP-RMS) Is Enriched in SE-Associated Targets, Including BRD4
Gryder BE, Yohe ME, Chou HC, Zhang X, Marques J, Wachtel M, Schaefer B, Sen N, Song Y, Gualtieri A, Pomella S, Rota R, Cleveland A, Wen X, Sindiri S, Wei JS, Barr FG, Das S, Andresson T, Guha R, Lal-Nag M, Ferrer M, Shern JF, Zhao K, Thomas CJ, Khan J. PAX3-FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Discov. 2017;7(8):884-99.
Public Health Impact
Cancer growth is driven by various genetic mutations that cause fast growth and evasion of cell death. This study found that rhabdomyosarcoma cells have a specific mutation that alters the gene expression within the cells and makes these cancer cells sensitive to certain drugs. This knowledge can be used to do more testing of these specific drugs in patients with rhabdomyosarcoma.