NOX2 inhibition reduces oxidative stress and prolongs survival in murine KRAS-induced myeloproliferative disease

Oncogene. 2019 Feb;38(9):1534-1543. doi: 10.1038/s41388-018-0528-1. Epub 2018 Oct 15.

Abstract

Mutations leading to constitutive RAS activation contribute in myeloid leukemogenesis. RAS mutations in myeloid cells are accompanied by excessive formation of reactive oxygen species (ROS), but the source of ROS and their role for the initiation and progression of leukemia have not been clearly defined. To determine the role of NOX2-derived ROS in RAS-driven leukemia, double transgenic LSL-KrasG12D × Mx1-Cre mice expressing oncogenic KRAS in hematopoietic cells (M-KrasG12D) were treated with Nα-methyl-histamine (NMH) that targeted the production of NOX2-derived ROS in leukemic cells by agonist activity at histamine H2 receptors. M-KrasG12D mice developed myeloid leukemia comprising mature CD11b+Gr1+ myeloid cells that produced NOX2-derived ROS. Treatment of M-KrasG12D mice with NMH delayed the development of myeloproliferative disease and prolonged survival. In addition, NMH-treated M-KrasG12D mice showed reduction of intracellular ROS along with reduced DNA oxidation and reduced occurence of double-stranded DNA breaks in myeloid cells. The in vivo expansion of leukemia was markedly reduced in triple transgenic mice where KRAS was expressed in hematopoietic cells of animals with genetic NOX2 deficiency (Nox2-/- × LSL-KrasG12D × Mx1-Cre). Treatment with NMH did not alter in vivo expansion of leukemia in these NOX2-deficient transgenic mice. We propose that NOX2-derived ROS may contribute to the progression of KRAS-induced leukemia and that strategies to target NOX2 merit further evaluation in RAS-mutated hematopoietic cancer.

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Disease Models, Animal
  • Hematopoiesis / genetics*
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / pathology
  • NADPH Oxidase 2 / genetics*
  • Oxidative Stress / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Reactive Oxygen Species / metabolism
  • Survival Analysis

Substances

  • Reactive Oxygen Species
  • NADPH Oxidase 2
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)