Abstract 3719: Loss of Kmt2c, of the COMPASS-like complex, cooperates with oncogenic signaling in cancer

Abstract

Abstract In mammals, the histone methyltransferase KMT2C is one of the major regulators of gene expression and is one of the most commonly lost epigenetic regulators across all cancers. Studies in mice demonstrated that Kmt2c is a haploinsufficient tumor suppressor in AML and inoculation of mammary fat pads with breast cancer cells that lack KMT2C had significantly larger tumor growth and reduced survival compared to mice injected with isogenic wild-type cells. Analysis of cBioportal’s curated set of non-redundant cancer patient studies indicates that loss of function KMT2C mutations significantly co-occur with RAS gain of function mutations. Our lab previously discovered that cells expressing oncogenic RAS displayed altered activation of enhancer gene regulator elements. We will test how loss of KMT2C cooperates with oncogenic Ras by: 1) characterizing the impact of KMT2C loss, with or without expression of oncogenic RAS, on biological properties of cells and global chromatin architecture and 2) characterizing how KMT2C loss may cooperate with oncogenic RAS to alter hematopoiesis and the global enhancer landscape in animal models. MEFs expressing heterozygous loss of Kmt2c have a proliferative advantage relative to WT littermate controls. Interestingly, WT MEFs demonstrate enhanced migration in a wound assay, but heterozygotes demonstrate an advantage in a transwell membrane assay. Heterozygotes further display greater EdU incorporation, indicating a greater propensity for entering S-phase and undergoing cell-division. RNA-seq experiments have indicated an upregulation of MAPK & Ras signaling pathway genes in heterozygotes, whilst simultaneously downregulating gene pathways critical for proper extra-cellular matrix organization. Therefore, loss of Kmt2c disrupts biological cell phenotypes, in a manner relatable to the hallmarks of cancer, demonstrating how Kmt2c loss may promote malignancy. Further studies must now be performed to elucidate the molecular mechanisms altered by loss of KMT2C and how they cause changes in cellular phenotypes. Citation Format: Gabriel Prado, Richard L. Bennett, Jonathan D. Licht. Loss of Kmt2c, of the COMPASS-like complex, cooperates with oncogenic signaling in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3719.