Kmt2a Cooperates With Menin to Suppress Tumorigenesis in Mouse Pancreatic Islets

Cancer Biol Ther. 2016 Dec;17(12):1274-1281. doi: 10.1080/15384047.2016.1250986. Epub 2016 Nov 1.

Abstract

The reported incidence of pancreatic neuroendocrine tumors (PanNETs) has increased, due in large part to improvements in detection and awareness. However, therapeutic options are limited and a critical need exists for understanding a more thorough characterization of the molecular pathology underlying this disease. The Men1 knockout mouse model recapitulates the early stage of human PanNET development and can serve as a foundation for the development of advanced mouse models that are necessary for preclinical testing. Menin, the product of the MEN1 gene, has been shown to physically interact with the KMT2A and KMT2B histone methyltransferases. Both the KMT2A and MEN1 genes are located on chromosome 11q, which frequently undergoes loss of heterozygosity (LOH) in PanNETs. We report herein that inactivation of Kmt2a in Men1-deficient mice accelerated pancreatic islet tumorigenesis and shortened the average life span. Increases in cell proliferation were observed in mouse pancreatic islet tumors upon inactivation of both Kmt2a and Men1. The Kmt2a/Men1 double knockout mouse model can be used as a mouse model to study advanced PanNETs.

Keywords: Kmt2a; Men1; PanNETs; methyltransferase; tumorigenesis.

MeSH terms

  • Animals
  • Carcinogenesis / metabolism*
  • Cell Proliferation
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Islets of Langerhans / physiopathology
  • Loss of Heterozygosity
  • Mice
  • Mice, Knockout
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Neoplasms, Experimental
  • Neuroendocrine Tumors / genetics
  • Neuroendocrine Tumors / pathology*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*

Substances

  • Men1 protein, mouse
  • Proto-Oncogene Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse