Abstract 3717: KMT2D loss cooperates with PTCH loss for medulloblastoma genesis

Abstract

Abstract We have previously reported that the histone H3 lysine 4 methyltransferase KMT2D (also called MLL4, MLL2, and ALR; a transcriptional coactivator) is required for neuronal differentiation of human neuron-committed NT2/D1 embryonal carcinoma stem cells. Notably, we have shown that brain-specific knockout of Kmt2d alone induces spontaneous medulloblastoma (MB) in mice and that Kmt2d loss in the brain highly upregulates several oncogenic signaling programs and downregulates tumor suppressor genes. Consistent with this, our analysis of several publicly available databases indicates that Kmt2d is the most frequently mutated epigenetic modifier (8%‒10%) in MB. In this study, we sought to assess whether Kmt2d loss cooperates with another oncogenic event in MB genesis. Particularly, PTCH (also known as PTCH1), a potent MB-signaling suppressor, is one of the most frequently mutated genes in MB, and KMT2D mutations co-occur with PTCH mutations more than with many other mutations in MB. Therefore, we determined the effect of Kmt2d loss on of Ptch+/--driven MB genesis by generating and analyzing Nestin-Cre Kmt2dfl/+ Ptch+/- mice. Our results showed that heterozygous loss of Kmt2d strongly increased the genesis and incidence of Ptch+/--driven MB. Supporting this, immunohistochemistry staining of Ki-67 (a proliferation marker) showed that heterozygous loss of Kmt2d in Ptch+/--driven MB highly increased the proliferation of MB cells. Our transcriptomic analysis showed that heterozygous Kmt2d loss upregulated tumor-promoting programs, including G-protein-coupled receptor signaling and oxidation-reduction process. In line with this, heterozygous Kmt2d loss upregulated oncogenic kinases (e.g., phospho-AKT1 and phospho-ERK) that may be downstream of G-protein-coupled receptor signaling. Mechanistically, our results indicate that these tumor-promoting programs are repressed, at least in part, by the transcription-repressive and tumor-suppressive factor (s) NCOR2, whose expression is activated by KMT2D. Our results would be the first to provide molecular insights into how co-losses of an epigenetic modifier and an MB-signaling suppressor cooperate for MB genesis. Our new mouse model would be helpful in future preclinical therapeutic experiments for MB treatment. Our findings suggest that targeting oncogenic effectors downstream of KMT2D loss can be considered a potential therapeutic strategy for MB treatment. Citation Format: Shilpa S. Dhar, Calena J. Brown, Ali S. Rizvi, Janak R. Abraham, Roy V. Sillitoe, Kaifu Chen, Min Gyu Lee. KMT2D loss cooperates with PTCH loss for medulloblastoma genesis [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 3717.