Tumorigenicity of Ewing sarcoma is critically dependent on the trithorax proteins MLL1 and menin
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Laurie K. Svoboda1, Natashay Bailey1, Raelene A. Van Noord2, Melanie A. Krook1, Ashley Harris1, Cassondra Cramer1, Brooke Jasman1, Rajiv M. Patel3,4, Dafydd Thomas3, Dmitry Borkin3, Tomasz Cierpicki3, Jolanta Grembecka3, Elizabeth R. Lawlor1,3
1Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109, USA
2Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
3Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
4Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Elizabeth R. Lawlor, email: [email protected]
Keywords: Ewing sarcoma, trithorax, MLL, menin, HOX
Received: August 15, 2016 Accepted: November 14, 2016 Published: November 18, 2016
Developmental transcription programs are epigenetically regulated by the competing actions of polycomb and trithorax (TrxG) protein complexes, which repress and activate genes, respectively. Ewing sarcoma is a developmental tumor that is associated with widespread de-regulation of developmental transcription programs, including HOX programs. Posterior HOXD genes are abnormally over-expressed by Ewing sarcoma and HOXD13, in particular, contributes to the tumorigenic phenotype. In MLL1 fusion-driven leukemia, aberrant activation of HOXA genes is epigenetically mediated by the TrxG complex and HOXA gene expression and leukemogenesis are critically dependent on the protein-protein interaction between the TrxG proteins MLL1 and menin. Based on these data, we investigated whether posterior HOXD gene activation and Ewing sarcoma tumorigenicity are similarly mediated by and dependent on MLL1 and/or menin. Our findings demonstrate that Ewing sarcomas express high levels of both MLL1 and menin and that continued expression of both proteins is required for maintenance of tumorigenicity. In addition, exposure of Ewing sarcoma cells to MI-503, an inhibitor of the MLL1-menin protein-protein interaction developed for MLL1-fusion driven leukemia, leads to loss of tumorigenicity and down-regulated expression of the posterior HOXD gene cluster. Together these data demonstrate an essential role for MLL1 and menin in mediating tumor maintenance and posterior HOXD gene activation in Ewing sarcoma. A critical dependency of these tumors on the MLL1-menin interaction presents a potentially novel therapeutic target.
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