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.
Authors
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, Luis Seabra, Marine Michelet, Federica Barzaghi, Davide Leardini, Francesco Saettini, Francesca Vendemini, Francesco Baccelli, Albert Catala, Eleonora Gambineri, Marinella Veltroni, Yurena Aguilar de la Red, Gillian I. Rice, Filippo Consonni, Laureline Berteloot, Laetitia Largeaud, Francesca Conti, Cécile Roullion, Cécile Masson, Boris Bessot, Yoann Seeleuthner, Tom Le Voyer, Darawan Rinchai, Jérémie Rosain, Anna-Lena Neehus, Lucia Erazo-Borrás, Hailun Li, Zarah Janda, En-Jui Cho, Edoardo Muratore, Camille Soudée, Candice Lainé, Eric Delabesse, Claire Goulvestre, Cindy S. Ma, Anne Puel, Stuart G. Tangye, Isabelle André, Christine Bole-Feysot, Laurent Abel, Miriam Erlacher, Shen-Ying Zhang, Vivien Béziat, Chantal Lagresle-Peyrou, Emmanuelle Six, Marlène Pasquet, Laia Alsina, Alessandro Aiuti, Peng Zhang, Yanick J. Crow, Nils Landegren, Riccardo Masetti, Danny T. Huang, Jean-Laurent Casanova, Jacinta Bustamante
Figure 1
The patients’ CBL variants are UbLOF but retain substrate-binding activity.
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)