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Title:
Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation | Nature Communications
Description:
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. Oncogenic Ras mutations are common drivers in myeloid leukemia. Here, the authors show in patient cells and in mice that oncogenic K-Ras activates NLRP3 inflammasome to drive myeloproliferation, which can be reversed by genetic or pharmacologic NLRP3 blockade.
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krasgd, mice, nlrp, cells, fig, bmdcs, ilβ, article, pubmed, krasmut, activation, patients, data, google, scholar, inflammasome, kras, cell, freiburg, increased, expression, caspase, production, leukemia, compared, normalized, cas, analysis, oncogenic, shown, ros, myeloid, cmml, supplementary, experiments, university, shows, representative, nature, blood, nonkrasmut, jmml, generated, mutations, observed, blot, treated, stimulation, change, isolated,
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nature portfolio pro-inflammatory rac1/ros/nlrp3/il-1β axis privacy policy reduced kras/nlrp3/il-1β axis rac1/ros/nlrp3/il-1β axis kras/ros/nlrp3/il-1β axis advertising sequencing libraries graft-versus-host disease social media kras/rac1/ros/nlrp3 axis ras/extracellular-signal-regulated kinase kras/nlrp3/il-1β axis constant ras/mek/erk signaling pro-il-1β rna transcription reactive oxygen species nature nature 445 nlrp3/caspase-1/il-1β axis language reprints memory stage-dependent manner strain termed rosa26-cre-ert2 access id gse131885 hbss/ca2+/mg2+ solution supplementary tables s1–s3 bio-rad laboratories gmbh pro-il-1β maturation19 rac1/ros/nlrp3 axis bd cytofix/cytoperm kit nlrp3/il-1β axis single-channel array normalization bone marrow transplantation multiparameter high-dimensional data blocking il-1β reverses inflammation-related molecules il-1514 direct pro-proliferative effect kras-mutant myeloid malignancies enzyme-linked immunosorbent assay linked anti-rabbit igg promoting cell death z-score log2 intensity tlr4/myd88/triff signaling therapeutic il-1-receptor blockade kras-driven hematological malignancies cell research rosa26-cre-ert2 transgenic36 visualizing single-cell data multiple inflammation-related genes kras-mutant myeloid neoplasms
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- Juvenile myelomonocytic leukemia: who’s the driver at the wheel?
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headline:Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation
description: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. Oncogenic Ras mutations are common drivers in myeloid leukemia. Here, the authors show in patient cells and in mice that oncogenic K-Ras activates NLRP3 inflammasome to drive myeloproliferation, which can be reversed by genetic or pharmacologic NLRP3 blockade.
datePublished:2020-04-03T00:00:00Z
dateModified:2020-04-03T00:00:00Z
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Bone marrow transplantation
Myeloproliferative disease
NOD-like receptors
Targeted therapies
Science
Humanities and Social Sciences
multidisciplinary
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headline:Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation
description: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. Oncogenic Ras mutations are common drivers in myeloid leukemia. Here, the authors show in patient cells and in mice that oncogenic K-Ras activates NLRP3 inflammasome to drive myeloproliferation, which can be reversed by genetic or pharmacologic NLRP3 blockade.
datePublished:2020-04-03T00:00:00Z
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Bone marrow transplantation
Myeloproliferative disease
NOD-like receptors
Targeted therapies
Science
Humanities and Social Sciences
multidisciplinary
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url:http://orcid.org/0000-0002-1541-7867
affiliation:
name:University of Zurich
address:
name:Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
type:PostalAddress
type:Organization
name:Olaf GroÃ
affiliation:
name:University Medical Center Freiburg, Faculty of Medicine, University of Freiburg
address:
name:Institute of Neuropathology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
type:PostalAddress
type:Organization
name:University of Freiburg
address:
name:Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
type:PostalAddress
type:Organization
name:Tilman Brummer
affiliation:
name:German Cancer Research Center (DKFZ)
address:
name:German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
type:PostalAddress
type:Organization
name:University of Freiburg
address:
name:Comprehensive Cancer Centre Freiburg (CCCF), University of Freiburg, Freiburg, Germany
type:PostalAddress
type:Organization
name:University of Freiburg
address:
name:Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany
type:PostalAddress
type:Organization
name:University of Freiburg
address:
name:Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany
type:PostalAddress
type:Organization
name:Robert Zeiser
affiliation:
name:Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
address:
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
type:PostalAddress
type:Organization
name:German Cancer Research Center (DKFZ)
address:
name:German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
type:PostalAddress
type:Organization
name:University of Freiburg
address:
name:Comprehensive Cancer Centre Freiburg (CCCF), University of Freiburg, Freiburg, Germany
type:PostalAddress
type:Organization
name:University of Freiburg
address:
name:Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Faculty of Biology, University of Freiburg, Freiburg, Germany
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Faculty of Biology, University of Freiburg, Freiburg, Germany
name:Institute of Neuropathology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
name:Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Faculty of Biology, University of Freiburg, Freiburg, Germany
name:Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Faculty of Biology, University of Freiburg, Freiburg, Germany
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
name:Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Clinic for Rheumatology and Clinical Immunology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:University of Freiburg, Freiburg, Germany
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
name:Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
name:Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
name:Comprehensive Cancer Centre Freiburg (CCCF), University of Freiburg, Freiburg, Germany
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
name:Comprehensive Cancer Centre Freiburg (CCCF), University of Freiburg, Freiburg, Germany
name:German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
name:Comprehensive Cancer Centre Freiburg (CCCF), University of Freiburg, Freiburg, Germany
name:Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
name:Comprehensive Cancer Centre Freiburg (CCCF), University of Freiburg, Freiburg, Germany
name:Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, USA
name:Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
name:Institute of Neuropathology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
name:German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
name:Comprehensive Cancer Centre Freiburg (CCCF), University of Freiburg, Freiburg, Germany
name:Institute of Molecular Medicine and Cell Research (IMMZ), Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:Centre for Biological Signalling Studies (BIOSS), University of Freiburg, Freiburg, Germany
name:Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
name:German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
name:Comprehensive Cancer Centre Freiburg (CCCF), University of Freiburg, Freiburg, Germany
name:Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
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