Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERIC-mediated monocyte activation
Por:
Bohlen J, Bagaric I, Vatovec T, Ogishi M, Ahmed SF, Cederholm A, Buetow L, Sobrino S, Le Floc'h C, Arango-Franco CA, Seabra L, Michelet M, Barzaghi F, Leardini D, Saettini F, Vendemini F, Baccelli F, Català-Temprano A, Gambineri E, Veltroni M, Aguilar de la Red Y, Rice GI, Consonni F, Berteloot L, Largeaud L, Conti F, Roullion C, Masson C, Bessot B, Seeleuthner Y, Le Voyer T, Rinchai D, Rosain J, Neehus AL, Erazo-Borrás L, Li H, Janda Z, Cho EJ, Muratore E, Soudée C, Lainé C, Delabesse E, Goulvestre C, Ma CS, Puel A, Tangye SG, André I, Bole-Feysot C, Abel L, Erlacher M, Zhang SY, Béziat V, Lagresle-Peyrou C, Six E, Pasquet M, Alsina L, Aiuti A, Zhang P, Crow YJ, Landegren N, Masetti R, Huang DT, Casanova JL and Bustamante J
Publicada:
15 oct 2024
Ahead of Print:
15 oct 2024
Resumen:
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. ERIC 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 UIC Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.
Filiaciones:
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
Bagaric 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
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
Ogishi M:
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA
Ahmed SF:
Cancer Research UK Scotland Institute, Glasgow, United Kingdom
Cederholm A:
Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Buetow L:
Cancer Research UK Scotland Institute, Glasgow, United Kingdom
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
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
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
Seabra L:
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France
Michelet M:
Unit of Allergy and Pneumology, Children's Hospital, Toulouse, France
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
Leardini D:
Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Saettini F:
Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
Vendemini F:
Department of Pediatrics, Fondazione IRCCS San Gerardo, Monza, Italy
Baccelli F:
Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
Català-Temprano A:
Pediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
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
Veltroni M:
Centre of Excellence, Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy
Aguilar de la Red Y:
Pediatric Oncology and Hematology Department, Miguel Servet Hospital, Zaragoza, Spain
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
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
Berteloot L:
Department of Pediatric Imaging, Necker Hospital for Sick Children, Paris, France
INSERM U1163, Paris, France
Largeaud L:
Laboratory of Hematology, Hospital Center of the University of Toulouse, Toulouse, France
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
Roullion C:
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France
Genomics Core Facility and
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
Bessot B:
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France
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
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
Rinchai D:
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA
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
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
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
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
Janda Z:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France
Heidelberg University, Heidelberg, Germany
Cho EJ:
Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France
Heidelberg University, Heidelberg, Germany
Muratore E:
Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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
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
Delabesse E:
Department of Hematology, CHU and Centre de Recherche de Cancérologie de Toulouse, Paul-Sabatier University, Toulouse, France
Goulvestre C:
Laboratory of Immunology, Cochin Hospital, Paris, France
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
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
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
André I:
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France
Bole-Feysot C:
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France
Genomics Core Facility and
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
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
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
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
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
Six E:
Paris Cité University, Imagine Institute, INSERM U1163, Paris, France
Laboratory of Human Lymphohematopoiesis, INSERM U1163, Imagine Institute, Paris, France
Pasquet M:
Department of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France
Alsina L:
Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain
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
Zhang P:
St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA
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
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
Masetti R:
Unit of Allergy and Pneumology, Children's Hospital, Toulouse, France
Huang DT:
Cancer Research UK Scotland Institute, Glasgow, United Kingdom
School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
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
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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