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DOI 10.1172/jci181604

Медицинская библиотека · The Journal of clinical investigation · 2024

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

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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод в очереди

Аннотация

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.

Для цитирования: Bohlen Jonathan, Bagarić Ivan, Vatovec Taja, Ogishi Masato, Ahmed Syed F, Cederholm Axel, Buetow Lori, Sobrino Steicy, Le Floc'h Corentin, Arango-Franco Carlos A, Seabra Luis, Michelet Marine, Barzaghi Federica, Leardini Davide, Saettini Francesco, Vendemini Francesca, Baccelli Francesco, Catala Albert, Gambineri Eleonora, Veltroni Marinella, Aguilar de la Red Yurena, Rice Gillian I, Consonni Filippo, Berteloot Laureline, Largeaud Laetitia, Conti Francesca, Roullion Cécile, Masson Cécile, Bessot Boris, Seeleuthner Yoann, Le Voyer Tom, Rinchai Darawan, Rosain Jérémie, Neehus Anna-Lena, Erazo-Borrás Lucia, Li Hailun, Janda Zarah, Cho En-Jui, Muratore Edoardo, Soudée Camille, Lainé Candice, Delabesse Eric, Goulvestre Claire, Ma Cindy S, Puel Anne, Tangye Stuart G, André Isabelle, Bole-Feysot Christine, Abel Laurent, Erlacher Miriam, Zhang Shen-Ying, Béziat Vivien, Lagresle-Peyrou Chantal, Six Emmanuelle, Pasquet Marlène, Alsina Laia, Aiuti Alessandro, Zhang Peng, Crow Yanick J, Landegren Nils, Masetti Riccardo, Huang Danny T, Casanova Jean-Laurent, Bustamante Jacinta. Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.. The Journal of clinical investigation. 2024. DOI: 10.1172/jci181604.

Предметные рубрики MeSH

HumansLoss of HeterozygosityProto-Oncogene Proteins c-cblMonocytesMAP Kinase Signaling SystemMaleFemaleInflammationHeterozygoteCytokinesAdult
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