Targeting MMSET in t(4;14)+ tumors prolongs survival.

<p>(A) Mouse xenograft model using t(4;14)+ KMS11 cells harboring a luciferase gene and a doxycycline-inducible MMSET-specific shRNA. Animals that were not administered doxycycline (−Dox) are shown on the top and animals that were given doxycycline are shown on the bottom (+Dox). Two representative animals are shown from each group (n = 5) at the following timepoints: 2 weeks after treatment; 4 weeks after treatment; 2 weeks after release from Dox; and 4 weeks after release from Dox. –Dox animals were sacrificed 26 days after treatment initiation due to tumor size. The same two animals are shown at each time points. (B) Kaplan-Meier curve of the xenograft mouse experiment from A. (C) Measurement of the luciferin signal in treated (black) and untreated (red) mice over time. (D) Immunoblot for H3K36me2 and H3K27me3 using nuclear extracts from tumors isolated from the untreated or doxycycline-treated mice (E) Proposed model for explaining how MMSET overexpression alters the epigenetic landscape of myeloma cells. Methylation of H3K36 by MMSET induces a global decrease of H3K27me3, leading to activation of gene expression (bottom). Additionally, an overabundance of K36 methylation alters genome-wide EZH2 binding, inducing focal increases in H3K27 methylation and gene repression.