Evidence map›Paper›PMID 39403923›Full record

ArticleThe Journal of clinical investigation2024

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

Jonathan Bohlen, Ivan Bagarić, Taja Vatovec, Masato Ogishi, Syed F Ahmed, Axel Cederholm, Lori Buetow, Steicy Sobrino, Corentin Le Floc'h, Carlos A Arango-Franco and 54 more

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Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

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3 citing papers in PubMed.

  1. Article
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4 · The record

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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

64 authors.

Jonathan BohlenLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Ivan BagarićLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Taja VatovecLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Masato OgishiSt. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.
Syed F AhmedCancer Research UK Scotland Institute, Glasgow, United Kingdom.
Axel CederholmScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Lori BuetowCancer Research UK Scotland Institute, Glasgow, United Kingdom.
Steicy SobrinoParis Cité University, Imagine Institute, INSERM U1163, Paris, France.
Corentin Le Floc'hLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Carlos A Arango-FrancoLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Luis SeabraParis Cité University, Imagine Institute, INSERM U1163, Paris, France.
Marine MicheletUnit of Allergy and Pneumology, Children's Hospital, Toulouse, France.
Federica BarzaghiSan Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Davide LeardiniPediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Francesco SaettiniCentro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
Francesca VendeminiDepartment of Pediatrics, Fondazione IRCCS San Gerardo, Monza, Italy.
Francesco BaccelliPediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Albert CatalaPediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
Eleonora GambineriDepartment of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
Marinella VeltroniCentre of Excellence, Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy.
Yurena Aguilar de la RedPediatric Oncology and Hematology Department, Miguel Servet Hospital, Zaragoza, Spain.
Gillian I RiceDivision 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 ConsonniCentre of Excellence, Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy.
Laureline BertelootDepartment of Pediatric Imaging, Necker Hospital for Sick Children, Paris, France.
Laetitia LargeaudLaboratory of Hematology, Hospital Center of the University of Toulouse, Toulouse, France.
Francesca ContiPediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Cécile RoullionParis Cité University, Imagine Institute, INSERM U1163, Paris, France.
Cécile MassonParis Cité University, Imagine Institute, INSERM U1163, Paris, France.
Boris BessotParis Cité University, Imagine Institute, INSERM U1163, Paris, France.
Yoann SeeleuthnerLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Tom Le VoyerLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Darawan RinchaiSt. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.
Jérémie RosainLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Anna-Lena NeehusLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Lucia Erazo-BorrásLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Hailun LiLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Zarah JandaLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
En-Jui ChoLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Edoardo MuratorePediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Camille SoudéeLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Candice LainéLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Eric DelabesseDepartment of Hematology, CHU and Centre de Recherche de Cancérologie de Toulouse, Paul-Sabatier University, Toulouse, France.
Claire GoulvestreLaboratory of Immunology, Cochin Hospital, Paris, France.
Cindy S MaGarvan Institute of Medical Research, New South Wales, Australia.
Anne PuelLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Stuart G TangyeGarvan Institute of Medical Research, New South Wales, Australia.
Isabelle AndréParis Cité University, Imagine Institute, INSERM U1163, Paris, France.
Christine Bole-FeysotParis Cité University, Imagine Institute, INSERM U1163, Paris, France.
Laurent AbelLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Miriam ErlacherDivision of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Shen-Ying ZhangLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Vivien BéziatLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Chantal Lagresle-PeyrouParis Cité University, Imagine Institute, INSERM U1163, Paris, France.
Emmanuelle SixParis Cité University, Imagine Institute, INSERM U1163, Paris, France.
Marlène PasquetDepartment of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.
Laia AlsinaClinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
Alessandro AiutiSan Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Peng ZhangSt. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.
Yanick J CrowParis Cité University, Imagine Institute, INSERM U1163, Paris, France.
Nils LandegrenScience for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Riccardo MasettiUnit of Allergy and Pneumology, Children's Hospital, Toulouse, France.
Danny T HuangCancer Research UK Scotland Institute, Glasgow, United Kingdom.
Jean-Laurent CasanovaLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
Jacinta BustamanteLaboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.

Funding

Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational SuccessUL1TR001866 · NCATS · ROCKEFELLER UNIVERSITY · PI COLLER, BARRY, KRUEGER, JAMES G · 2016 to 2025
$40.6M
Genome-Wide Dissection of Mendelian Susceptibility to Mycobacterial DiseaseR01AI095983 · NIAID · ROCKEFELLER UNIVERSITY · PI BUSTAMANTE, JACINTA, CASANOVA, JEAN-LAURENT · 2021 to 2025
$2.5M
Cancer Research UK 29256NCATS NIH HHS UL1 TR001866NIAID NIH HHS R01 AI095983uk medical research council MC_UU_00035/11
6 · The paper itself

Abstract

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.

Indexed as

Loss of HeterozygosityMAP Kinase Signaling SystemMonocytesProto-Oncogene Proteins c-cblAdultCytokinesFemaleHeterozygoteHumansInflammationMaleCBL protein, humanCytokinesProto-Oncogene Proteins c-cblAutoimmunityImmunologyInnate immunityMonocytes

Identifiers

PMID39403923
PMCPMC11475086

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.