KMT2D depletion promote KRAS-induced pancreatic carcinogenesis independent of TP53

We examined the role 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 Kmt2d reduces survival and promotes disease progression in both models even in absence of Tp53. Similarly, in human PDAC the loss of TP53 does not affect the prognosis value 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.