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; 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

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, Luis Seabra, Marine Michelet, Federica Barzaghi, Davide Leardini, Francesco Saettini, Francesca Vendemini, Francesco Baccelli , Albert Catala, Eleonora Gambineri , Marinella VeltroniYurena 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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 (UPD). 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 secrete 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 (HSPC) 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 i

Original language	English
Journal	Journal of Clinical Investigation
Publication status	Published - 15 Oct 2024

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CBL-myeloid_v31_cleanAccepted author manuscript, 13.7 MBLicence: Creative Commons: Attribution (CC-BY)
Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activationFinal published version, 3.9 MBLicence: Creative Commons: Attribution (CC-BY)

Genetic disorders of human neurological and immune function
Crow, Y.
1/04/23 → 31/03/28
Project: Research

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Bohlen, J., Bagarić , I., Vatovec, T., Ogishi, M., Ahmed, S. F., Cederholm, A., Buetow, L., Sobrino, S., Le Floc'h, C., Arango-Franco, C. A., Seabra, L., Michelet, M., Barzaghi, F., Leardini, D., Saettini, F., Vendemini, F., Baccelli , F., Catala, A., Gambineri , E., ... Bustamante, J. (2024). Autoinflammation in patients with leukocytic CBL loss-of-heterozygosity is caused by constitutive ERK-mediated monocyte activation. Journal of Clinical Investigation.

@article{2f01e30d881e41af880b6de7cb66c86a,

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

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 (UPD). 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 secrete 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 (HSPC) 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 i",

author = "Jonathan Bohlen and Ivan Bagari{\'c} and Taja Vatovec and Masato Ogishi and Ahmed, {Syed F.} and Axel Cederholm and Lori Buetow and Steicy Sobrino and {Le Floc'h}, Corentin and Arango-Franco, {Carlos A} and Luis Seabra and Marine Michelet and Federica Barzaghi and Davide Leardini and Francesco Saettini and Francesca Vendemini and Francesco Baccelli and Albert Catala and Eleonora Gambineri and Marinella Veltroni and {Aguilar de la Red}, Yurena and Rice, {Gillian I} and Filippo Consonni and Laureline Berteloot and Laetitia Largeaud and Francesca Conti and C{\'e}cile Roullion and C{\'e}cile Masson and Boris Bessot and Yoann Seeleuthner and {Le Voyer}, Tom and Darawan Rinchai and J{\'e}r{\'e}mie Rosain and Anna-Lena Neehus and Lucia Erazo-Borr{\'a}s and Hailun Li and Zarah Janda and En-Jui Cho and Edoardo Muratore and Camille Soud{\'e}e and Candice Lain{\'e} and Eric Delabesse and Claire Goulvestre and Ma, {Cindy S} and Anne Puel and Tangye, {Stuart G.} and Isabelle Andr{\'e} and Christine Bole-Feysot and Laurent Abel and Miriam Erlacher and Shen-ying Zhang and Vivien B{\'e}ziat and Chantal Lagresle-Peyrou and Emmanuelle Six and Marl{\`e}ne Pasquet and Laia Alsina and Alessandro Aiuti and Peng Zhang and Crow, {Yanick J} and Nils Landegren and Riccardo Masetti and Huang, {Danny T} and Jean-Laurent Casanova and Jacinta Bustamante",

year = "2024",

month = oct,

day = "15",

language = "English",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

}

Bohlen, J, Bagarić , I, Vatovec, T, Ogishi, M, Ahmed, SF, Cederholm, A, Buetow, L, Sobrino, S, Le Floc'h, C, Arango-Franco, CA, Seabra, L, Michelet, M, Barzaghi, F, Leardini, D, Saettini, F, Vendemini, F, Baccelli , F, Catala, A, Gambineri , E, Veltroni, M, Aguilar de la Red, Y, Rice, GI, Consonni , F, Berteloot, L, Largeaud, L, Conti, F, Roullion, C, Masson, C, Bessot, B, Seeleuthner, Y, Le Voyer, T, Rinchai, D, Rosain, J, Neehus, A-L, Erazo-Borrás, L, Li, H, Janda, Z, Cho, E-J, Muratore, E, Soudée, C, Lainé, C, Delabesse, E, Goulvestre, C, Ma, CS, Puel, A, Tangye, SG, André, I, Bole-Feysot, C, Abel, L, Erlacher , M, Zhang, S, Béziat, V, Lagresle-Peyrou , C, Six, E, Pasquet, M, Alsina, L, Aiuti, A, Zhang, P, Crow, YJ, Landegren, N, Masetti, R, Huang, DT, Casanova, J-L & Bustamante, J 2024, 'Autoinflammation in patients with leukocytic CBL loss-of-heterozygosity is caused by constitutive ERK-mediated monocyte activation', Journal of Clinical Investigation.

TY - JOUR

T1 - Autoinflammation in patients with leukocytic CBL loss-of-heterozygosity is caused by constitutive ERK-mediated monocyte activation

AU - Bohlen, Jonathan

AU - Bagarić , Ivan

AU - Vatovec, Taja

AU - Ogishi, Masato

AU - Ahmed, Syed F.

AU - Cederholm, Axel

AU - Buetow, Lori

AU - Sobrino, Steicy

AU - Le Floc'h, Corentin

AU - Arango-Franco, Carlos A

AU - Seabra, Luis

AU - Michelet, Marine

AU - Barzaghi, Federica

AU - Leardini, Davide

AU - Saettini, Francesco

AU - Vendemini, Francesca

AU - Baccelli , Francesco

AU - Catala, Albert

AU - Gambineri , Eleonora

AU - Veltroni, Marinella

AU - Aguilar de la Red, Yurena

AU - Rice, Gillian I

AU - Consonni , Filippo

AU - Berteloot, Laureline

AU - Largeaud, Laetitia

AU - Conti, Francesca

AU - Roullion, Cécile

AU - Masson, Cécile

AU - Bessot, Boris

AU - Seeleuthner, Yoann

AU - Le Voyer, Tom

AU - Rinchai, Darawan

AU - Rosain, Jérémie

AU - Neehus, Anna-Lena

AU - Erazo-Borrás, Lucia

AU - Li, Hailun

AU - Janda, Zarah

AU - Cho, En-Jui

AU - Muratore, Edoardo

AU - Soudée, Camille

AU - Lainé, Candice

AU - Delabesse, Eric

AU - Goulvestre, Claire

AU - Ma, Cindy S

AU - Puel, Anne

AU - Tangye, Stuart G.

AU - André, Isabelle

AU - Bole-Feysot, Christine

AU - Abel, Laurent

AU - Erlacher , Miriam

AU - Zhang, Shen-ying

AU - Béziat, Vivien

AU - Lagresle-Peyrou , Chantal

AU - Six, Emmanuelle

AU - Pasquet, Marlène

AU - Alsina, Laia

AU - Aiuti, Alessandro

AU - Zhang, Peng

AU - Crow, Yanick J

AU - Landegren, Nils

AU - Masetti, Riccardo

AU - Huang, Danny T

AU - Casanova, Jean-Laurent

AU - Bustamante, Jacinta

PY - 2024/10/15

Y1 - 2024/10/15

N2 - 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 (UPD). 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 secrete 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 (HSPC) 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 i

AB - 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 (UPD). 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 secrete 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 (HSPC) 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 i

M3 - Article

SN - 0021-9738

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

ER -

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

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Genetic disorders of human neurological and immune function

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