Abstract LB-064: Characterization of the tumor suppressor function of the lysine-specific methyltransferase KMT2D in follicular lymphoma

Abstract

Abstract Follicular lymphoma (FL) is a common and incurable form indolent B-cell lymphoma. Genomic studies have now catalogued many recurrent mutations in FL. Epigenetic regulators have emerged as the most common targets of somatic point mutations. For example, the histone methyltransferase KMT2D (MLL4/MLL2) is the most frequently mutated gene in FL with reported mutational frequencies of up to 84%. However, the transcriptional and biological consequences of KMT2D loss of function are currently unknown. Using a well-described murine model of FL, we showed that deficiency of KMT2D promotes the initiation of indolent FL in vivo. To explore the mechanism of KMT2D-mediated tumor suppression we used cross species comparisons of gene expression, histone H3K4 methylation marks and KMT2D genomic occupancy. These analyses converge on a relatively small group of conserved target genes. Strikingly, they include bona fide tumor suppressors and regulators of B-cell proliferation (e.g. TNFAIP3/A20, SOCS3, ARID1A, and TNFRSF14). Our results indicate that KMT2D restrains FL development through simultaneous effects on multiple key regulators of B-cell behavior. Note: This abstract was not presented at the meeting. Citation Format: Ana Ortega-Molina, Isaac Boss, Heng Pan, Yanwen Jiang, Deqing Hu, Xin Gao, Rita Shaknovich, Ali Shilatifard, Ari M. Melnick, Hans-Guido Wendel. Characterization of the tumor suppressor function of the lysine-specific methyltransferase KMT2D in follicular lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-064. doi:10.1158/1538-7445.AM2015-LB-064