Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation

Nat Commun. 2020 Apr 3;11(1):1659. doi: 10.1038/s41467-020-15497-1.


Oncogenic Ras mutations occur in various leukemias. It was unclear if, besides the direct transforming effect via constant RAS/MEK/ERK signaling, an inflammation-related effect of KRAS contributes to the disease. Here, we identify a functional link between oncogenic KrasG12D and NLRP3 inflammasome activation in murine and human cells. Mice expressing active KrasG12D in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in KrasG12D mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, KrasG12D-RAC1 activation induces reactive oxygen species (ROS) production causing NLRP3 inflammasome-activation. In agreement with our observations in mice, patient-derived myeloid leukemia cells exhibit KRAS/RAC1/ROS/NLRP3/IL-1β axis activity. Our findings indicate that oncogenic KRAS not only act via its canonical oncogenic driver function, but also enhances the activation of the pro-inflammatory RAC1/ROS/NLRP3/IL-1β axis. This paves the way for a therapeutic approach based on immune modulation via NLRP3 blockade in KRAS-mutant myeloid malignancies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Gene Expression
  • Hematopoiesis
  • Humans
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism
  • Interleukin-1beta / metabolism
  • Leukemia, Myeloid / etiology
  • Leukemia, Myeloid / genetics
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • Myeloid Cells / metabolism
  • Myeloproliferative Disorders / genetics*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • NLR Proteins / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction


  • Inflammasomes
  • Interleukin-1beta
  • KRAS protein, human
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLR Proteins
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Reactive Oxygen Species
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)