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Matrix Combination Screening

PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability

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

(A) Potency in PAX3-FOXO1 rhabdomyosarcoma cell lines versus toxicity in normal cell lines, measured by dose response and summarized across 240 mechanistically distinct subcategories. The percent area under the dose response curve (%AUC) was averaged for all compounds within a target subcategory. The number of compounds in each category is indicated by the size of the bubble, and the difference in %AUC (normal −RMS) is indicated by color scale. (B) Differential sensitivities against molecules targeting proteins associated with SEs, compared with non-SE targets and SE signal transduction. The size of the bubble indicates the number of molecules against each target.

(A) Potency in PAX3-FOXO1 rhabdomyosarcoma cell lines versus toxicity in normal cell lines, measured by dose response and summarized across 240 mechanistically distinct subcategories. The percent area under the dose response curve (%AUC) was averaged for all compounds within a target subcategory. The number of compounds in each category is indicated by the size of the bubble, and the difference in %AUC (normal −RMS) is indicated by color scale. (B) Differential sensitivities against molecules targeting proteins associated with SEs, compared with non-SE targets and SE signal transduction. The size of the bubble indicates the number of molecules against each target. (Reprinted with permission from Gryder  BE, et al.  PAX3-FOXO1 establishes myogenic super enhancers and confers BET bromodomain vulnerability. Cancer Discov. 2017;7(8):884-99. Copyright Cancer Discov 2017.)

Publications

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.