Germline bi-allelic <i>SH2B3/LNK</i> alteration predisposes to a neonatal juvenile myelomonocytic leukemia-like disorder
Chloé Arfeuille,
Yoann Vial,
Margaux Cadenet,
Aurélie Caye-Eude,
Odile Fenneteau,
Quentin Neven,
Adeline A Bonnard,
Simone Pizzi,
Giovanna Carpentieri,
Yline Capri,
Katia Girardi,
Lucia Pedace,
Marina Macchiaiolo,
Kamel Boudhar,
Monia ben Khaled,
Wadih Abou Chahla,
Anne Lutun,
Mony Fahd,
Séverine Drunat,
Elisabetta Flex,
Jean-Hugues Dalle,
Marion Strullu,
Franco Locatelli,
Marco Tartaglia,
Hélène Cavé
Affiliations
Chloé Arfeuille
Département de Génétique, Unité de Génétique Moléculaire, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France; INSERM UMR_S1131, Institut de Recherche Saint-Louis, Université Paris-Cité, Paris
Yoann Vial
Département de Génétique, Unité de Génétique Moléculaire, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France; INSERM UMR_S1131, Institut de Recherche Saint-Louis, Université Paris-Cité, Paris
Margaux Cadenet
Département de Génétique, Unité de Génétique Moléculaire, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France; INSERM UMR_S1131, Institut de Recherche Saint-Louis, Université Paris-Cité, Paris
Aurélie Caye-Eude
Département de Génétique, Unité de Génétique Moléculaire, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France; INSERM UMR_S1131, Institut de Recherche Saint-Louis, Université Paris-Cité, Paris
Odile Fenneteau
Service d’Hématologie Biologique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris
Quentin Neven
Service d’Onco-Hématologie pédiatrique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris
Adeline A Bonnard
Département de Génétique, Unité de Génétique Moléculaire, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France; INSERM UMR_S1131, Institut de Recherche Saint-Louis, Université Paris-Cité, Paris
Département de Génétique, Unité de Génétique clinique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris
Katia Girardi
Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children's Hospital IRCCS, 00146 Rome
Lucia Pedace
Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children's Hospital IRCCS, 00146 Rome
Marina Macchiaiolo
Rare Diseases and Medical Genetics, Bambino Gesù Children's Hospital IRCCS, 00146 Rome
Kamel Boudhar
Service de réanimation néonatale, Hôpital Central de l’Armée, Alger, Algérie
Monia ben Khaled
University of Tunis El Manar, Faculty of Medicine of Tunis, 1007, Tunisia. Pediatric Immuno- Hematology Unit, Bone Marrow Transplantation Center Tunis, Tunis, Tunisia
Wadih Abou Chahla
Service d’Hématologie Pédiatrique, Centre Hospitalier Universitaire de Lille, Lille
Anne Lutun
Service d’Hématologie Pédiatrique, Centre Hospitalier Universitaire d’Amiens, Amiens
Mony Fahd
Service d’Onco-Hématologie pédiatrique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris
Séverine Drunat
Département de Génétique, Unité de Génétique Moléculaire, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris
Elisabetta Flex
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome
Jean-Hugues Dalle
Service d’Onco-Hématologie pédiatrique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris
Marion Strullu
INSERM UMR_S1131, Institut de Recherche Saint-Louis, Université Paris-Cité, Paris, France; Service d’Onco-Hématologie pédiatrique, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris
Franco Locatelli
Department of Hematology/Oncology and Cell and Gene Therapy, Bambino Gesù Children's Hospital IRCCS, 00146 Rome, Italy; Department of Pediatrics, Catholic University of the Sacred Hearth, 00168 Rome
Département de Génétique, Unité de Génétique Moléculaire, Hôpital Robert Debré, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France; INSERM UMR_S1131, Institut de Recherche Saint-Louis, Université Paris-Cité, Paris
Juvenile myelomonocytic leukemia (JMML) is a rare, generally aggressive myeloproliferative neoplasm affecting young children. It is characterized by granulomonocytic expansion, with monocytosis infiltrating peripheral tissues. JMML is initiated by mutations upregulating RAS signaling. Approximately 10% of cases remain without an identified driver event. Exome sequencing of 2 unrelated cases of familial JMML of unknown genetics and analysis of the French JMML cohort identified 11 patients with variants in SH2B3, encoding LNK, a negative regulator of the JAK-STAT pathway. All variants were absent from healthy population databases, and mutation spectrum was consistent with a loss of function of the LNK protein. A stoploss variant was shown to affect both protein synthesis and stability. The other variants were either truncating or missense, the latter affecting the SH2 domain that interacts with activated JAK. Of the 11 patients, 8 from 5 families inherited pathogenic bi-allelic SH2B3 germline variants from their unaffected heterozygous parents. These children represent half of the cases with no identified causal mutation in the French cohort. They displayed typical clinical and hematological JMML features with neonatal onset and marked thrombocytopenia. They were characterized by absence of additional genetic alterations and a hypomethylated DNA profile with fetal characteristics. All patients showed partial or complete spontaneous clinical resolution. However, progression to thrombocythemia and immunity-related pathologies may be of concern later in life. Bi-allelic SH2B3 germline mutations thus define a new condition predisposing to a JMML-like disorder, suggesting that the JAK pathway deregulation is capable of initiating JMML, and opening new therapeutic options.
