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

doi:10.1172/JCI181604

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

J Clin Invest. 2024 Oct 15;134(20):e181604. doi: 10.1172/JCI181604.

Authors

Jonathan Bohlen^{1

2}, Ivan Bagarić^{1

2

3}, Taja Vatovec^{1

2

3}, Masato Ogishi⁴, Syed F Ahmed⁵, Axel Cederholm⁶, Lori Buetow⁵, Steicy Sobrino^{2

7

8}, Corentin Le Floc'h^{1

2}, Carlos A Arango-Franco^{1

2

9}, Luis Seabra², Marine Michelet¹⁰, Federica Barzaghi¹¹, Davide Leardini¹², Francesco Saettini¹³, Francesca Vendemini¹⁴, Francesco Baccelli¹², Albert Catala¹⁵, Eleonora Gambineri^{16

17}, Marinella Veltroni¹⁷, Yurena Aguilar de la Red¹⁸, Gillian I Rice¹⁹, Filippo Consonni^{17

20}, Laureline Berteloot^{21

22}, Laetitia Largeaud²³, Francesca Conti^{24

25}, Cécile Roullion^{2

26}, Cécile Masson^{2

27}, Boris Bessot², Yoann Seeleuthner^{1

2}, Tom Le Voyer^{1

2

4

28}, Darawan Rinchai⁴, Jérémie Rosain^{1

2

4

29}, Anna-Lena Neehus^{1

2}, Lucia Erazo-Borrás^{1

2

9}, Hailun Li^{1

2}, Zarah Janda^{1

3}, En-Jui Cho^{1

3}, Edoardo Muratore¹², Camille Soudée^{1

2}, Candice Lainé^{1

2}, Eric Delabesse³⁰, Claire Goulvestre³¹, Cindy S Ma^{32

33}, Anne Puel^{1

2

4}, Stuart G Tangye^{32

33}, Isabelle André², Christine Bole-Feysot^{2

26}, Laurent Abel^{1

2

4}, Miriam Erlacher^{34

35}, Shen-Ying Zhang^{1

2

4}, Vivien Béziat^{1

2

4}, Chantal Lagresle-Peyrou^{2

36}, Emmanuelle Six^{2

8}, Marlène Pasquet³⁷, Laia Alsina³⁸, Alessandro Aiuti^{11

39}, Peng Zhang⁴, Yanick J Crow^{2

40}, Nils Landegren^{6

41}, Riccardo Masetti¹⁰, Danny T Huang^{5

42}, Jean-Laurent Casanova^{1

2

4

43

44}, Jacinta Bustamante^{1

2

4

29}

Affiliations

¹ Laboratory of Human Genetics of Infectious Diseases, Necker Hospital for Sick Children, Paris, France.
² Paris Cité University, Imagine Institute, INSERM U1163, Paris, France.
³ Heidelberg University, Heidelberg, Germany.
⁴ St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, New York, USA.
⁵ Cancer Research UK Scotland Institute, Glasgow, United Kingdom.
⁶ Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
⁷ Laboratory of Chromatin and Gene Regulation during Development, Paris Cité University, INSERM U1163, Imagine Institute, Paris, France.
⁸ Laboratory of Human Lymphohematopoiesis, INSERM U1163, Imagine Institute, Paris, France.
⁹ Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia.
¹⁰ Unit of Allergy and Pneumology, Children's Hospital, Toulouse, France.
¹¹ San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
¹² Pediatric Hematology and Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
¹³ Centro Tettamanti, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.
¹⁴ Department of Pediatrics, Fondazione IRCCS San Gerardo, Monza, Italy.
¹⁵ Pediatric Hematology and Oncology Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
¹⁶ Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy.
¹⁷ Centre of Excellence, Division of Pediatric Oncology/Hematology, Meyer Children's Hospital IRCCS, Florence, Italy.
¹⁸ Pediatric Oncology and Hematology Department, Miguel Servet Hospital, Zaragoza, Spain.
¹⁹ Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.
²⁰ "Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
²¹ Department of Pediatric Imaging, Necker Hospital for Sick Children, Paris, France.
²² INSERM U1163, Paris, France.
²³ Laboratory of Hematology, Hospital Center of the University of Toulouse, Toulouse, France.
²⁴ Pediatric Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
²⁵ Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.
²⁶ Genomics Core Facility and.
²⁷ Bioinformatic Plateform, INSERM U1163 and INSERM US24/CNRS UAR3633, Paris Cité University, Paris, France.
²⁸ Clinical Immunology Department, Assistance Publique Hôpitaux de Paris (AP-HP), Saint-Louis Hospital, Paris, France.
²⁹ Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children-AP-HP, Paris, France.
³⁰ Department of Hematology, CHU and Centre de Recherche de Cancérologie de Toulouse, Paul-Sabatier University, Toulouse, France.
³¹ Laboratory of Immunology, Cochin Hospital, Paris, France.
³² Garvan Institute of Medical Research, New South Wales, Australia.
³³ School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney, Sydney, Australia.
³⁴ Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
³⁵ Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
³⁶ Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, AP-HP, INSERM, Paris, France.
³⁷ Department of Pediatric Hematology and Oncology, Centre Hospitalo-Universitaire de Toulouse, Toulouse, France.
³⁸ Clinical Immunology and Primary Immunodeficiencies Unit, Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Barcelona, Spain.
³⁹ Università Vita-Salute San Raffaele, Milan, Italy.
⁴⁰ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.
⁴¹ Centre for Molecular Medicine, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.
⁴² School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
⁴³ Department of Pediatrics, Necker Hospital for Sick Children-AP-HP, Paris, France.
⁴⁴ Howard Hughes Medical Institute, New York, New York, USA.

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.

Keywords: Autoimmunity; Immunology; Innate immunity; Monocytes.

MeSH terms

Adult
Cytokines / genetics
Cytokines / metabolism
Female
Heterozygote
Humans
Inflammation / genetics
Inflammation / pathology
Loss of Heterozygosity*
MAP Kinase Signaling System* / genetics
Male
Monocytes* / metabolism
Monocytes* / pathology
Proto-Oncogene Proteins c-cbl* / genetics
Proto-Oncogene Proteins c-cbl* / metabolism

Substances

Proto-Oncogene Proteins c-cbl
CBL protein, human
Cytokines

Abstract

MeSH terms

Substances

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