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 Boerries

Justus Duyster, Charlotte M. Niemeyer, Miriam Erlacher, Bruce R. Blazar, Burkard Becher, Olaf Groß, Tilman Brummer, Robert Zeiser

Research output: Contribution to journal › Article › peer-review

128 Scopus citations

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 - Apr 3 2020

Bibliographical note

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Animals
Cell Proliferation
Gene Expression
Hematopoiesis
Humans
Inflammasomes/immunology
Interleukin-1beta/metabolism
Leukemia, Myeloid/etiology
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
Reactive Oxygen Species/metabolism
Signal Transduction

PubMed: MeSH publication types

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

Publisher link

10.1038/s41467-020-15497-1

Find It

Find It at U of M Libraries

Cite this

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

@article{ccd9ee3d47d44e249fb478cc00ebf7f6,

title = "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.",

keywords = "Animals, Cell Proliferation, Gene Expression, Hematopoiesis, Humans, Inflammasomes/immunology, Interleukin-1beta/metabolism, Leukemia, Myeloid/etiology, 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, Reactive Oxygen Species/metabolism, Signal Transduction",

author = "Shaima{\textquoteright}a Hamarsheh and Lena Osswald and Saller, \{Benedikt S.\} and Susanne Unger and \{De Feo\}, Donatella and Vinnakota, \{Janaki Manoja\} and Martina Konantz and Uhl, \{Franziska M.\} and Heiko Becker and Michael L{\"u}bbert and Khalid Shoumariyeh and Christoph Sch{\"u}rch and Geoffroy Andrieux and Nils Venhoff and Annette Schmitt-Graeff and Sandra Duquesne and Dietmar Pfeifer and Cooper, \{Matthew A.\} and Claudia Lengerke and Melanie Boerries and Justus Duyster and Niemeyer, \{Charlotte M.\} and Miriam Erlacher and Blazar, \{Bruce R.\} and Burkard Becher and Olaf Gro{\ss} and Tilman Brummer and Robert Zeiser",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = apr,

day = "3",

doi = "10.1038/s41467-020-15497-1",

language = "English (US)",

volume = "11",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation

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

PY - 2020/4/3

Y1 - 2020/4/3

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Proliferation

KW - Gene Expression

KW - Hematopoiesis

KW - Humans

KW - Inflammasomes/immunology

KW - Interleukin-1beta/metabolism

KW - Leukemia, Myeloid/etiology

KW - Mice

KW - Mice, Inbred C57BL

KW - Molecular Targeted Therapy

KW - Myeloid Cells/metabolism

KW - Myeloproliferative Disorders/genetics

KW - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism

KW - NLR Proteins/metabolism

KW - Proto-Oncogene Proteins p21(ras)/genetics

KW - Reactive Oxygen Species/metabolism

KW - Signal Transduction

UR - https://www.scopus.com/pages/publications/85083041601

UR - https://www.scopus.com/pages/publications/85083041601#tab=citedBy

U2 - 10.1038/s41467-020-15497-1

DO - 10.1038/s41467-020-15497-1

M3 - Article

C2 - 32246016

AN - SCOPUS:85083041601

SN - 2041-1723

VL - 11

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 1659

ER -