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

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.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2024-10-14
DOI
https://doi.org/10.1172/jci181604
Citations
5
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
2.27

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article

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

Chantal Lagresle‐Peyrou, Francesco Baccelli, Yurena Aguilar de la Red, Laureline Berteloot et al.
5 citations
Journal of Clinical Investigation
Acute Myeloid Leukemia Research
2.27
article

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

Chantal Lagresle‐Peyrou, Francesco Baccelli, Yurena Aguilar de la Red, Laureline Berteloot, Z. Janda, Laëtitia Largeaud, Éric Delabesse, Davide Leardini, Miriam Erlacher, Yanick Joseph Crow, Francesca Vendemini, Albert Català, Laia Alsina, Francesca Conti, Marinella Veltroni, Darawan Rinchai, Camille Soudée, Marlène Pasquet, Christine Bôle‐Feysot, Nils Landegren, Francesco Saettini, Boris Bessot, Candice Lainé, Luís Seabra, Riccardo Masetti, Danny T. Huang, Steicy Sobrino, Jean‐Laurent Casanova, Syed Feroj Ahmed, Corentin Le Floc’h, Cécile Masson, Edoardo Muratore, S. Cindy, Jérémie Rosain, Carlos A. Arango-Franco, Alessandro Aiuti, Tom Le Voyer, Anne Puel, Eleonora Gambineri, Anna‐Lena Neehus, Lucía Victoria Erazo-Borrás, Shen‐Ying Zhang, Gillian Rice, Jonathan Bohlen, Axel Cederholm, Emmanuelle Six, Eun‐Gyung Cho, Yoann Seeleuthner, Stuart G. Tangye, Jacinta Bustamante, Federica Barzaghi, Claire Goulvestre, Masato Ogishi, Vivien Béziat, Lori Buetow, Filippo Consonni, Laurent Abel, Isabelle André‐Schmutz, Taja Vatovec, Ivan Bagarić, Peng Zhang, Hailun Li, Marine Michelet, Cécile Roullion
article en
5 citations

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.

Journal of Clinical InvestigationVol. 134(20)
Uppsala University (SE), Centre National de la Recherche Scientifique (FR), Hospital Sant Joan de Déu Barcelona (ES), Howard Hughes Medical Institute (US), Université Toulouse III - Paul Sabatier (FR), Garvan Institute of Medical Research (AU), Vita-Salute San Raffaele University (IT), Inserm (FR), University of Freiburg (DE), Université Fédérale de Toulouse Midi-Pyrénées (FR), Université Paris Cité (FR), Heidelberg University (DE), Manchester Academic Health Science Centre (GB), Science for Life Laboratory (SE), University Medical Center Freiburg (DE), Cancer Research UK (GB), Karolinska Institutet (SE), University of Manchester (GB), Centre Hospitalier Universitaire de Toulouse (FR), UNSW Sydney (AU), Universidad de Antioquia (CO), Hospital for Sick Children Pediatric Center (US), Centre de Recherches en Cancérologie de Toulouse (FR), Hôpital Cochin (FR), Assistance Publique – Hôpitaux de Paris (FR), Institut universitaire du cancer de Toulouse Oncopole (FR), Toulouse Mathematics Institute (FR), ENT and Allergy (US), Azienda Ospedaliera San Gerardo (IT), Meyer Children's Hospital (IT), Hospital Universitario Miguel Servet (ES), ID Genomics (United States) (US), Azienda USL di Bologna (IT), The San Raffaele Telethon Institute for Gene Therapy (IT), Hôpital Saint-Louis (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University Hospital Ulm (DE), Institute of Genetics and Cancer (GB), Institut des Maladies Génétiques Imagine (FR), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), University of Florence (IT), Universitat de Barcelona (ES), University of Glasgow (GB), Rockefeller University (US), University of Bologna (IT), University of Edinburgh (GB)
Rockefeller University
Zero hunger
Openalex Percentile: Top 11%
Acute Myeloid Leukemia Research
2.27
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