Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.

Humans Loss of Heterozygosity Proto-Oncogene Proteins c-cbl / genetics Monocytes / metabolism MAP Kinase Signaling System / genetics Male Female Inflammation / genetics Heterozygote Cytokines / genetics Adult
Autoimmunity Immunology Innate immunity Monocytes

Journal

The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877

Informations de publication

Date de publication:
15 Oct 2024
Historique:
received: 02 04 2024
accepted: 20 08 2024
medline: 15 10 2024
pubmed: 15 10 2024
entrez: 15 10 2024
Statut: epublish

Résumé

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.

Identifiants

DOI: 10.1172/JCI181604 PMID: 39403923
pubmed: 39403923
pii: 181604
doi: 10.1172/JCI181604
doi:
pii:

Substances chimiques

Proto-Oncogene Proteins c-cbl EC 2.3.2.27
CBL protein, human EC 6.3.2.-
Cytokines 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Auteurs

Jonathan Bohlen (J)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.

Ivan Bagarić (I)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
Heidelberg University, Heidelberg, Germany.

Taja Vatovec (T)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
Heidelberg University, Heidelberg, Germany.

Masato Ogishi (M)

St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.

Syed F Ahmed (SF)

Cancer Research UK Scotland Institute, Glasgow, United Kingdom.

Axel Cederholm (A)

Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.

Lori Buetow (L)

Cancer Research UK Scotland Institute, Glasgow, United Kingdom.

Steicy Sobrino (S)

Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
Laboratory of Chromatin and Gene Regulation during Development, Paris Cité University, INSERM U1163, Imagine Institute, Paris, France.
Laboratory of Human Lymphohematopoiesis, INSERM U1163, Imagine Institute, Paris, France.

Corentin Le Floc'h (C)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.

Carlos A Arango-Franco (CA)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia.

Luis Seabra (L)

Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.

Marine Michelet (M)

Unit of Allergy and Pneumology, Children's Hospital, Toulouse, France.

Federica Barzaghi (F)

San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Davide Leardini (D)

Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Francesco Saettini (F)

Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.

Francesca Vendemini (F)

Department of Pediatrics, Fondazione IRCCS San Gerardo, Monza, Italy.

Francesco Baccelli (F)

Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Albert Catala (A)

Pediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.

Eleonora Gambineri (E)

Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
Centre of Excellence, Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy.

Marinella Veltroni (M)

Centre of Excellence, Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy.

Yurena Aguilar de la Red (Y)

Pediatric Oncology and Hematology Department, Miguel Servet Hospital, Zaragoza, Spain.

Gillian I Rice (GI)

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.

Filippo Consonni (F)

Centre of Excellence, Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy.
"Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.

Laureline Berteloot (L)

Department of Pediatric Imaging, Necker Hospital for Sick Children, Paris, France.
INSERM U1163, Paris, France.

Laetitia Largeaud (L)

Laboratory of Hematology, Hospital Center of the University of Toulouse, Toulouse, France.

Francesca Conti (F)

Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.

Cécile Roullion (C)

Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
Genomics Core Facility and.

Cécile Masson (C)

Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
Bioinformatic Plateform, INSERM U1163 and INSERM US24/CNRS UAR3633, Paris Cité University, Paris, France.

Boris Bessot (B)

Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.

Yoann Seeleuthner (Y)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.

Tom Le Voyer (T)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.
Clinical Immunology Department, Assistance Publique Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Paris, France.

Darawan Rinchai (D)

St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.

Jérémie Rosain (J)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.
Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children-AP-HP, Paris, France.

Anna-Lena Neehus (AL)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.

Lucia Erazo-Borrás (L)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia.

Hailun Li (H)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.

Zarah Janda (Z)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Heidelberg University, Heidelberg, Germany.

En-Jui Cho (EJ)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Heidelberg University, Heidelberg, Germany.

Edoardo Muratore (E)

Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Camille Soudée (C)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.

Candice Lainé (C)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.

Eric Delabesse (E)

Department of Hematology, CHU and Centre de Recherche de Cancérologie de Toulouse, Paul-Sabatier University, Toulouse, France.

Claire Goulvestre (C)

Laboratory of Immunology, Cochin Hospital, Paris, France.

Cindy S Ma (CS)

Garvan Institute of Medical Research, New South Wales, Australia.
School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, Australia.

Anne Puel (A)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.

Stuart G Tangye (SG)

Garvan Institute of Medical Research, New South Wales, Australia.
School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, Australia.

Isabelle André (I)

Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.

Christine Bole-Feysot (C)

Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
Genomics Core Facility and.

Laurent Abel (L)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.

Miriam Erlacher (M)

Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.

Shen-Ying Zhang (SY)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.

Vivien Béziat (V)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.

Chantal Lagresle-Peyrou (C)

Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.

Emmanuelle Six (E)

Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
Laboratory of Human Lymphohematopoiesis, INSERM U1163, Imagine Institute, Paris, France.

Marlène Pasquet (M)

Department of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.

Laia Alsina (L)

Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain.

Alessandro Aiuti (A)

San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Università Vita-Salute San Raffaele, Milan, Italy.

Peng Zhang (P)

St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.

Yanick J Crow (YJ)

Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.

Nils Landegren (N)

Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.

Riccardo Masetti (R)

Unit of Allergy and Pneumology, Children's Hospital, Toulouse, France.

Danny T Huang (DT)

Cancer Research UK Scotland Institute, Glasgow, United Kingdom.
School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.

Jean-Laurent Casanova (JL)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.
Department of Pediatrics, Necker Hospital for Sick Children-AP-HP, Paris, France.
Howard Hughes Medical Institute, New York, New York, USA.

Jacinta Bustamante (J)

Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.
Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children-AP-HP, Paris, France.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Autoinflammation in patients with leukocytic...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Déséquilibre allélique › Perte d'hétérozygotie › Autoinflammation in patients with leukocytic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-cbl › Autoinflammation in patients with leukocytic...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Phagocytes › Monocytes › Autoinflammation in patients with leukocytic...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Système de signalisation des MAP kinases › Autoinflammation in patients with leukocytic...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Inflammation › Autoinflammation in patients with leukocytic...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Hétérozygote › Autoinflammation in patients with leukocytic...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Cytokines › Autoinflammation in patients with leukocytic...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Autoinflammation in patients with leukocytic...