KMT2D depletion promotes KRAS-induced pancreatic carcinogenesis independent of TP53.

Despite extensive efforts identifying disease drivers, therapeutics developed against them have so far failed to improve patient outcomes in pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer. Thus, focus has turned to the characterization of molecules contributing to the drivers' ability to promote the development of this disease. Here, we demonstrate a novel role for KMT2D, a histone methyltransferase, in PDAC biology. Analysis of exome-seq and RNA-Seq data shows that KMT2D is highly mutated and significantly downregulated in human PDAC. Further, low KMT2D expression associates with lower survival in human PDAC. Next, we examined the role of Kmt2d in PDAC development using two independent genetically engineered mouse models driven by mutant Kras in the presence and absence of the tumor suppressor Tp53. Loss of Kmt2d increases tumor incidence mostly with a poorly differentiated phenotype and reduces survival in both models even in the absence of Tp53. Similarly, in human PDAC, the loss of TP53 does not affect the survival of KMT2D low cases. Of note, the sole Kmt2d depletion did not affect normal pancreas development or mice survival. RNA-Seq analysis demonstrates the enrichment of pathways controlling cell growth in Kmt2df/+ PDAC cells. Interestingly, inactivation of Kmt2d resulted in increased levels of Ki67-positive cells in vivo. Together, these findings define the role of this methyltransferase in Kras-driven PDAC biology as tumor suppressor candidate for this dismal condition.