Hochschulschrift

Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation

Abstract: 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

Standort
Deutsche Nationalbibliothek Frankfurt am Main
Umfang
Online-Ressource
Sprache
Englisch
Anmerkungen
Nature communications. - 11 (2020) , 1659, ISSN: 2041-1723

Schlagwort
Knochenmarktransplantation

Ereignis
Veröffentlichung
(wo)
Freiburg
(wer)
Universität
(wann)
2020
Urheber

DOI
10.1038/s41467-020-15497-1
URN
urn:nbn:de:bsz:25-freidok-1657666
Rechteinformation
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Letzte Aktualisierung
14.08.2025, 10:44 MESZ

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Objekttyp

  • Hochschulschrift

Entstanden

  • 2020

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