Synergistic effect of concurrent high molecular risk mutations and lower JAK2 mutant variant allele frequencies on prognosis in patients with myelofibrosis-insights from a multicenter study.

Autor: Wang YH; Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. yuhungwang922@gmail.com.; Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, The University of Manchester, Manchester, UK. yuhungwang922@gmail.com., Wei CH; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.; Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan., Lin CC; Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan., Gurnari C; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.; Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy., Awada H; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., Benajiba L; Centre d'Investigations Cliniques, Hospital Saint Louis and University Paris Cité, Paris, France., Daltro de Oliveira R; Centre d'Investigations Cliniques, Hospital Saint Louis and University Paris Cité, Paris, France., Soret-Dulphy J; Centre d'Investigations Cliniques, Hospital Saint Louis and University Paris Cité, Paris, France., Cassinat B; Laboratoire de Biologie Cellulaire, Hospital Saint Louis and University Paris Cité, Paris, France., Zucenka A; Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.; Hematology and Oncology Department, Faculty of Medicine, Vilnius University, Vilnius, Lithuania., Mosquera Orgueira A; Hematology Department, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain.; Group of Computational Hematology and Genomics, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Santiago de Compostela, Spain., Yuan CT; Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan., Lee SH; Division of Cellular Therapy, Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan., Yao CY; Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan., Gurashi K; Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, The University of Manchester, Manchester, UK., Hou HA; Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan., Batta K; Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, The University of Manchester, Manchester, UK., Pérez Encinas MM; Hematology Department, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain., Chou WC; Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.; Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan., Maciejewski JP; Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA., Wiseman DH; Epigenetics of Haematopoiesis Laboratory, Division of Cancer Sciences, The University of Manchester, Manchester, UK., Kiladjian JJ; Centre d'Investigations Cliniques, Hospital Saint Louis and University Paris Cité, Paris, France., Tien HF; Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. hftien@ntu.edu.tw.; Department of Internal Medicine, Far-Eastern Memorial Hospital, New Taipei City, Taiwan. hftien@ntu.edu.tw.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2024 Oct 04. Date of Electronic Publication: 2024 Oct 04.
DOI: 10.1038/s41375-024-02422-4
Abstrakt: In addition to high-molecular risk (HMR) mutations (ASXL1, EZH2, SRSF2, IDH, and U2AF1 Q157 ), lower JAK2V617F variant allele frequencies (VAF) have been demonstrated to be associated with poor prognosis of myelofibrosis (MF) patients. Nevertheless, the relationship between JAK2V617F VAF and HMR mutations remains inconclusive. To address this, we analyzed the mutation status of 54 myeloid neoplasm-relevant genes using targeted next-generation sequencing in 124 MF patients. Three cohorts from multiple international centers were analyzed for external validation. Among JAK2-mutated patients, the presence of HMR mutations drove poor prognosis in patients with lower JAK2V617F VAF but not in those with higher JAK2V617F VAF. Survival analyses showed consistent results across validation cohorts. In multivariable analysis, concurrent HMR and a lower JAK2V617F VAF was identified as an independent adverse prognostic factor for survival, irrespective of age, MIPSS70, MIPSS70 + v2, and GIPSS risk groups. Mutation co-occurrence tests revealed no shared mutational pattern over different cohorts, excluding potential confounding effect from other concurrent mutations. Importantly, the integration of HMR/JAK2V617F VAF (≤50%) status significantly enhanced existing prognostic models, as evidenced by higher c-indexes and time-dependent ROC analyses. Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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