| Title: |
Diagnostic relevance of SH2B3 mutations in suspected myeloid malignancies: Insights from a large-scale NGS-based screening study |
| Authors: |
Ben Dhia, Leïla; Wemeau, Mathieu; Fenwarth, Laurene; Marceau-Renaut, Alice; Fournier, Elise; Benoit, Ducourneau; Tricot, Sabine; Deschildt, Manon; Huchette, Pascal; Darre, Stéphane; Benhalima, Ilyes; Margat, Emilie; Bories, Claire; Dufosse, Maxime; Boyer, Thomas; Paubelle, Etienne; Charbonnier, Amandine; Lebon, Delphine; Hieulle, Julia; Dennetiere, Sophie; Malbranque, Zoé; Daniel, Adrien; Bruge, Judith; Pascal, Laurent; Brijs, Jan; Carpentier, Benjamin; Willaume, Alexandre; Coiteux, Valerie; Goursaud, Laure; Preudhomme, Claude; Nibourel, Olivier; Duployez, Nicolas |
| Contributors: |
Centre Hospitalier de Roubaix; Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER); Institut Pasteur de Lille; Pasteur Network (Réseau International des Instituts Pasteur)-Pasteur Network (Réseau International des Instituts Pasteur)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS); Centre Hospitalier Régional Universitaire CHU Lille (CHRU Lille); Institut pour la recherche sur le cancer de Lille Lille (IRCL); Centre Hospitalier de Valenciennes (CHV); Groupe Hospitalier Artois-Ternois Centre Hospitalier d’Arras; Centre Hospitalier de Lens; Hôpital Claude Huriez Lille; Université Paris Cité (UPCité); Département de Biologie - ENS-PSL (IBENS); École normale supérieure - Paris (ENS-PSL); Université Paris Sciences et Lettres (PSL)-Université Paris Sciences et Lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Laboratoire d'Hématologie CHU Amiens; CHU Amiens-Picardie; HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM); Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM); Service d'Hématologie Clinique et Thérapie Cellulaire CHU Amiens |
| Source: |
ISSN: 0006-4971. |
| Publisher Information: |
CCSD; American Society of Hematology |
| Publication Year: |
2025 |
| Subject Terms: |
[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology |
| Description: |
International audience ; INTRODUCTION The SH2B3 gene encodes the cytoplasmic adaptor protein LNK that acts as a negative regulator of hematopoietic progenitor cell expansion and self-renewal, particularly through its interaction with JAK2 and regulation of the JAK-STAT pathway. In humans, SH2B3 alterations have been identified across a spectrum of hematologic malignancies, especially myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), MDS/MPN overlap syndromes including chronic myelomonocytic leukemia (CMML), and acute lymphoblastic leukemias (ALLs). Despite increasing recognition, their precise clinical relevance and pathogenic role remain incompletely understood. Here, we retrospectively investigated a cohort of 17 833 patients referred for suspicion of a myeloid neoplasm or acute leukemia. Through systematic assessment of SH2B3 as part of routine next-generation sequencing (NGS)-based diagnostic workflows, we aimed to delineate the mutational spectrum and clinical implications of SH2B3 variants. METHODS DNA was extracted from bone marrow or peripheral blood samples and analyzed using a custom targeted NGS panel covering the entire coding region of SH2B3, along with 125 other genes recurrently mutated in hematological malignancies.Clinical and biological data were retrospectively collected from medical records and communication with the referring physicians who ordered the molecular analyses. RESULTS Among the 17 833 individuals tested, 13 423 (75.3%) carried at least one SH2B3 variant. The vast majority (n = 11 589, 86.3%) harbored only the common p.W262R polymorphism (rs3184504).The remaining 1 830 individuals carried 415 unique SH2B3 variants, which were classified hierarchically into four tiers of pathogenicity based on variant type, minor allele frequency in gnomAD v4.1.0 and variant allele frequency in patient samples. This led to the following distribution: 169 individuals with Tier I variants, 86 with Tier II variants, 167 with Tier III variants and 1 451 individuals with Tier IV ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1182/blood-2025-2016 |
| Availability: |
https://u-picardie.hal.science/hal-05413758; https://doi.org/10.1182/blood-2025-2016 |
| Accession Number: |
edsbas.918AF196 |
| Database: |
BASE |