Abstract PR12: Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape

Several types of bone/cartilage tumors reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. We find that the H3 lysine 36 to methionine (H3K36M) mutation, identified in >90% of chondroblastomas, impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases, resulting in globally diminished H3K36 methylation. Depletion of H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy H3K36M mutation. Following the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of polycomb target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas where novel K36M/I mutations in H3.1 are identified in rare pediatric cases. This abstract is also being presented as Poster A12. Citation Format: Chao Lu, Siddhant Jain, Dominik Hoelper, Denise Bechet, Leili Ran, Irene Andrulis, Brendan Dickson, Jacek Majewski, Craig Thompson, Ping Chi, Benjamin Garcia, Nada Jabado, Peter Lewis, C. David Allis. Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR12.