Bohlen, Jonathan and Bagarić, Ivan and Vatovec, Taja and Ogishi, Masato and Ahmed, Syed F. and Cederholm, Axel and Buetow, Lori and Sobrino, Steicy and Le Floc’h, Corentin and Arango-Franco, Carlos A. and Seabra, Luis and Michelet, Marine and Barzaghi, Federica and Leardini, Davide and Saettini, Francesco and Vendemini, Francesca and Baccelli, Francesco and Catala, Albert and Gambineri, Eleonora and Veltroni, Marinella and Aguilar de la Red, Yurena and Rice, Gillian I. and Consonni, Filippo and Berteloot, Laureline and Largeaud, Laetitia and Conti, Francesca and Roullion, Cécile and Masson, Cécile and Bessot, Boris and Seeleuthner, Yoann and Le Voyer, Tom and Rinchai, Darawan and Rosain, Jérémie and Neehus, Anna-Lena and Erazo-Borrás, Lucia and Li, Hailun and Janda, Zarah and Cho, En-Jui and Muratore, Edoardo and Soudée, Camille and Lainé, Candice and Delabesse, Eric and Goulvestre, Claire and Ma, Cindy S. and Puel, Anne and Tangye, Stuart G. and André, Isabelle and Bole-Feysot, Christine and Abel, Laurent and Erlacher, Miriam and Zhang, Shen-Ying and Béziat, Vivien and Lagresle-Peyrou, Chantal and Six, Emmanuelle and Pasquet, Marlène and Alsina, Laia and Aiuti, Alessandro and Zhang, Peng and Crow, Yanick J. and Landegren, Nils and Masetti, Riccardo and Huang, Danny T. and Casanova, Jean-Laurent and Bustamante, Jacinta (2024) Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation. Journal of Clinical Investigation, 134 (20): e181604. ISSN 0021-9738

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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.

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Title Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation
Creators Bohlen, Jonathan and Bagarić, Ivan and Vatovec, Taja and Ogishi, Masato and Ahmed, Syed F. and Cederholm, Axel and Buetow, Lori and Sobrino, Steicy and Le Floc’h, Corentin and Arango-Franco, Carlos A. and Seabra, Luis and Michelet, Marine and Barzaghi, Federica and Leardini, Davide and Saettini, Francesco and Vendemini, Francesca and Baccelli, Francesco and Catala, Albert and Gambineri, Eleonora and Veltroni, Marinella and Aguilar de la Red, Yurena and Rice, Gillian I. and Consonni, Filippo and Berteloot, Laureline and Largeaud, Laetitia and Conti, Francesca and Roullion, Cécile and Masson, Cécile and Bessot, Boris and Seeleuthner, Yoann and Le Voyer, Tom and Rinchai, Darawan and Rosain, Jérémie and Neehus, Anna-Lena and Erazo-Borrás, Lucia and Li, Hailun and Janda, Zarah and Cho, En-Jui and Muratore, Edoardo and Soudée, Camille and Lainé, Candice and Delabesse, Eric and Goulvestre, Claire and Ma, Cindy S. and Puel, Anne and Tangye, Stuart G. and André, Isabelle and Bole-Feysot, Christine and Abel, Laurent and Erlacher, Miriam and Zhang, Shen-Ying and Béziat, Vivien and Lagresle-Peyrou, Chantal and Six, Emmanuelle and Pasquet, Marlène and Alsina, Laia and Aiuti, Alessandro and Zhang, Peng and Crow, Yanick J. and Landegren, Nils and Masetti, Riccardo and Huang, Danny T. and Casanova, Jean-Laurent and Bustamante, Jacinta
Identification Number 10.1172/JCI181604
Date 15 October 2024
Divisions College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Publisher Americal Society for Clinical Investigation
Additional Information ALN is supported by the Bettencourt-Schueller Foundation, the International PhD program of the Imagine Institute, and the Fin de Thèse program of the FRM (FDT202204015102). J Bohlen was supported by fellowships from the European Molecular Biology Organization and Marie Curie Research. NL was supported by the Swedish Research Council and the Göran Gustafsson Foundation. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technolgy, the Honjo International Scholarship Foundation, and the New York Hideyo Noguchi Memorial Society. YJC acknowledges funding from the European Research Council (786142 E-T1IFNs), a UK Medical Research Council Human Genetics Unit core grant (MC_UU_00035/11), and a state subsidy from the ANR (France) under Investissements d’Avenir program reference ANR-10-IAHU-01. AC was supported by a La Marató de TV3 grant (202001-32). DTH was supported by a Cancer Research UK core grant (A29256). FB and AA thank the ERN-RITA association for their help and support. CSM and SGT are supported by Investigator Grants by the National Health and Medical Research Council of Australia (grant ID 2017463, 1176665). TLV was supported by the Poste CCA-INSERM-Bettencourt (with the support of the Fondation Bettencourt-Schueller).
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Date Deposited 11 Jun 2025 16:35
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