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ResearchIn-Press PreviewGeneticsHematology Open Access | 10.1172/JCI180981

Human Oncostatin M deficiency underlies an inherited severe bone marrow failure syndrome

Alexandrine Garrigue,1 Laëtitia Kermasson,2 Sandrine Susini,1 Ingrid Fert,1 Christopher B. Mahony,3 Hanem Sadek,1 Sonia Luce,1 Myriam Chouteau,1 Marina Cavazzana,1 Emmanuelle Six,1 Marie-Caroline Le Bousse-Kerdilès,4 Adrienne Anginot,4 Jean-Baptiste Souraud,5 Valérie Cormier-Daire,6 Marjolaine Willems,7 Anne Sirvent,7 Jennifer Russello,8 Isabelle Callebaut,9 Isabelle André,1 Julien Y. Bertrand,3 Chantal Lagresle-Peyrou,1 and Patrick Revy2

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Garrigue, A. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Kermasson, L. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Susini, S. in: JCI | PubMed | Google Scholar |

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Fert, I. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Mahony, C. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Sadek, H. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Luce, S. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Chouteau, M. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Cavazzana, M. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Six, E. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Le Bousse-Kerdilès, M. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Anginot, A. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Souraud, J. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Cormier-Daire, V. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Willems, M. in: JCI | PubMed | Google Scholar |

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Sirvent, A. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Russello, J. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Callebaut, I. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by André, I. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Bertrand, J. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Lagresle-Peyrou, C. in: JCI | PubMed | Google Scholar

1Laboratory of Human Lymphohematopoiesis, Institut Imagine, Université Paris Cité, INSERM UMR1163, Paris, France

2Laboratory of Genome Dynamics in the Immune, INSERM UMR 116, Équipe Labellisée LIGUE 2023, Paris, France

3Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland

4INSERM UMRS-MD 1197, Université de Paris-Saclay, Hôpital Paul Brousse, Villejuif, France

5Service anatomo-pathologie, Hôpital d'Instruction des Armées Begin, Saint-Mandé, France

6Imagine Institute, Paris Cité University, Paris, France

7Medical Genetics Department, CHU de Montpellier, Montpellier, France

8Service d’Hématologie Biologique, CHU de Montpellier, Montpellier, France

9Muséum National d’Histoire Naturelle, UMR CNRS 7590, Sorbonne Université, Paris, France

Find articles by Revy, P. in: JCI | PubMed | Google Scholar |

Published January 23, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI180981.
Copyright © 2025, Garrigue et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 23, 2025 - Version history
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Abstract

Oncostatin M (OSM) is a cytokine with the unique ability to interact with both the OSM receptor (OSMR) and the leukemia inhibitory factor receptor (LIFR). On the other hand, OSMR interacts with IL31RA to form the interleukin-31 receptor. This intricate network of cytokines and receptors makes it difficult to understand the specific function of OSM. While monoallelic loss-of-function (LoF) mutations in OSMR underlie autosomal dominant familial primary localized cutaneous amyloidosis, the in vivo consequences of human OSM deficiency have never been reported so far. Here, we identified three young individuals from a consanguineous family presenting with inherited severe bone marrow failure syndromes (IBMFS) characterized by profound anemia, thrombocytopenia, and neutropenia. Genetic analysis revealed a homozygous one base-pair insertion in the sequence of OSM associated with the disease. Structural and functional analyses showed that this variant causes a frameshift that replaces the C-terminal portion of OSM, which contains the FxxK motif that interacts with both OSMR and LIFR, with a neopeptide. The lack of detection and signaling of the mutant OSM suggests a LoF mutation. Analysis of zebrafish models further supported the role of the OSM/OSMR signaling in erythroid progenitor proliferation and neutrophil differentiation. Our study provides the previously uncharacterized and unexpectedly limited in vivo consequence of OSM deficiency in humans.

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