Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation

Shaima’a Hamarsheh; Lena Osswald; Benedikt S. Saller; Susanne Unger; Donatella De Feo; Janaki Manoja Vinnakota; Martina Konantz; Franziska M. Uhl; Heiko Becker; Michael Lübbert; Khalid Shoumariyeh; Christoph Schürch; Geoffroy Andrieux; Nils Venhoff; Annette Schmitt-Graeff; Sandra Duquesne; Dietmar Pfeifer; Matthew A. Cooper; Claudia Lengerke; Melanie Boerries; Justus Duyster; Charlotte M. Niemeyer; Miriam Erlacher; Bruce R. Blazar; Burkard Becher; Olaf Groß; Tilman Brummer; Robert Zeiser

doi:10.1038/s41467-020-15497-1

Oncogenic Kras^G12D causes myeloproliferation via NLRP3 inflammasome activation

Shaima’a Hamarsheh, Lena Osswald, Benedikt S. Saller, Susanne Unger, Donatella De Feo, Janaki Manoja Vinnakota, Martina Konantz, Franziska M. Uhl, Heiko Becker, Michael Lübbert, Khalid Shoumariyeh, Christoph Schürch, Geoffroy Andrieux, Nils Venhoff, Annette Schmitt-Graeff, Sandra Duquesne, Dietmar Pfeifer, Matthew A. Cooper, Claudia Lengerke, Melanie BoerriesJustus Duyster, Charlotte M. Niemeyer, Miriam Erlacher, Bruce R. Blazar, Burkard Becher, Olaf Groß, Tilman Brummer, Robert Zeiser

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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 Kras^G12D and NLRP3 inflammasome activation in murine and human cells. Mice expressing active Kras^G12D in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in Kras^G12D mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, Kras^G12D-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.

Original language	English (US)
Article number	1659
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15497-1
State	Published - Dec 1 2020

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Publisher Copyright:
© 2020, The Author(s).

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Hamarsheh, S., Osswald, L., Saller, B. S., Unger, S., De Feo, D., Vinnakota, J. M., Konantz, M., Uhl, F. M., Becker, H., Lübbert, M., Shoumariyeh, K., Schürch, C., Andrieux, G., Venhoff, N., Schmitt-Graeff, A., Duquesne, S., Pfeifer, D., Cooper, M. A., Lengerke, C., ... Zeiser, R. (2020). Oncogenic Kras^G12D causes myeloproliferation via NLRP3 inflammasome activation. Nature communications, 11(1), Article 1659. https://doi.org/10.1038/s41467-020-15497-1

Hamarsheh, S, Osswald, L, Saller, BS, Unger, S, De Feo, D, Vinnakota, JM, Konantz, M, Uhl, FM, Becker, H, Lübbert, M, Shoumariyeh, K, Schürch, C, Andrieux, G, Venhoff, N, Schmitt-Graeff, A, Duquesne, S, Pfeifer, D, Cooper, MA, Lengerke, C, Boerries, M, Duyster, J, Niemeyer, CM, Erlacher, M, Blazar, BR, Becher, B, Groß, O, Brummer, T & Zeiser, R 2020, 'Oncogenic Kras^G12D causes myeloproliferation via NLRP3 inflammasome activation', Nature communications, vol. 11, no. 1, 1659. https://doi.org/10.1038/s41467-020-15497-1

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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.",

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AU - Hamarsheh, Shaima’a

AU - Osswald, Lena

AU - Saller, Benedikt S.

AU - Unger, Susanne

AU - De Feo, Donatella

AU - Vinnakota, Janaki Manoja

AU - Konantz, Martina

AU - Uhl, Franziska M.

AU - Becker, Heiko

AU - Lübbert, Michael

AU - Shoumariyeh, Khalid

AU - Schürch, Christoph

AU - Andrieux, Geoffroy

AU - Venhoff, Nils

AU - Schmitt-Graeff, Annette

AU - Duquesne, Sandra

AU - Pfeifer, Dietmar

AU - Cooper, Matthew A.

AU - Lengerke, Claudia

AU - Boerries, Melanie

AU - Duyster, Justus

AU - Niemeyer, Charlotte M.

AU - Erlacher, Miriam

AU - Blazar, Bruce R.

AU - Becher, Burkard

AU - Groß, Olaf

AU - Brummer, Tilman

AU - Zeiser, Robert

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