Abstract 2174: MLL3 act as a tumor suppressor gene in pancreatic cancer

Abstract

Abstract Myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3) is a histone 3-lysine 4 methyltransferase, found frequently mutated in a variety of solid tumors, including pancreatic ductal adenocarcinoma where it is the fourth most common somatically mutated gene (excluding homozygous deletions). Despite various somatic mutations, the functional role of MLL3 has not been studied in pancreatic cancer. Upon careful compilation of all the known MLL3 somatic mutations in various solid tumors, no hotspots were identified. However, regardless of the mutation status, we found significantly diminished MLL3 expression in a panel of patient-derived pancreatic tumor cell lines, tumor xenografts and archived patient tumors. Examination of the MLL3 promoter region revealed a CpG island. Methylation of the promoter region was confirmed by methylation-specific PCR in majority of the tumor cell lines and xenografts. Treatment with DNA methyltransferase inhibitor relieved the promoter methylation causing increase in MLL3 transcript expression. Further, knockdown of MLL3 by siRNA in cell lines increased anchorage-independent growth, and enhanced the migration/invasion phenotype of cancer cells. Agilent microarray analysis of two pancreatic cancer cell lines subsequent to knockdown of residual MLL3 function by siRNA, revealed a battery of potential gene targets and pathways regulated by MLL3. The most common Gene Ontology (GO) categories for differentially expressed genes include those involved in cell cycle, cell migration, and DNA repair, underscoring the phenotypes observed with MLL3 siRNA. We indeed observed an increase in MLL3 expression upon DNA damage which was independent of p53 status. Using transgenic mouse model of pancreatic cancer, we are investigating whether loss of MLL3 function in exocrine pancreas cooperates with mutant Kras to accelerate the progression of pancreatic intraepithelial neoplasia (PanIN) to invasive neoplasia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2174. doi:1538-7445.AM2012-2174