Involvement of the JAK ‐ STAT pathway in the molecular landscape of tyrosine kinase fusion‐negative hypereosinophilic syndromes: A nationwide CEREO study

作者：Matthieu Groh, Laurène Fenwarth, Mathilde Labro, Augustin Boudry, Élise Fournier, Mathieu Wémeau, Alice Marceau‐Renaut, Rafael Daltro De Oliveira, Julie T. Abraham, Marly Barry, Philippe Blanche, Quentin Bodard, Thorsten Braun, Safia Chebrek, Matthieu Décamp, Cécile‐Audrey Durel, Édouard Forcade, Mathieu Gerfaud‐Valentin, Camille Golfier, Clement Gourguechon, Nathalie Grardel, Olivier Kosmider, Nihal Martis, Sarah Melboucy Belkhir, Fatiha Merabet, Adrien Michon, Stéphane Moreau, Cécile Morice, Antoine Néel, Franck E. Nicolini, Laurent Benjamin Pascal, Florence Pasquier, Andréa Pieragostini, Catherine Roche‐Lestienne, Philippe Rousselot, Louis Terriou, Anne Thiebaut‐Bertrand, Jean‐François Viallard, Claude Preudhomme, Jean‐Emmanuel Kahn, Guillaume Lefèvre, Nicolas Duployez, CEREO Collaborators · 发表于：American Journal of Hematology · 年份：2024 · DOI：10.1002/ajh.27306 · 被引用次数：16 · 研究领域：Eosinophilic Disorders and Syndromes、Myeloproliferative Neoplasms: Diagnosis and Treatment、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Abstract We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion‐negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HE US used as controls; p < .001). Thirty‐five patients (54%) had at least one mutation involving the JAK‐STAT pathway, including STAT5B ( n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2 , JAK1 , STAT5B , and STAT5A , including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK‐STAT mutations were preceded by (or associated with) myelodysplasia‐related gene mutations, especially in RNA‐splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87–13.13]; p = .001), anemia (HR 5.50 [2.24–13.49]; p < .001), and the presence of a high‐risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39–19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK‐STAT‐mutated patients, ruxolitinib showed positive hem...