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<p>Since 2008, the <i>JAK2</i><sup><i>V617F</i></sup> mutation has been key for diagnosing myeloproliferative neoplasms (MPN) according to the World Health Organization criteria. However, the clinical and biological significance of low <i>JAK2</i><sup><i>V617F</i></sup> variant allelic fraction (VAF) remains poorly understood. To address this, we performed a comprehensive molecular characterization of a monocentric real-world retrospective cohort of MPN patients with low JAK2<sup>V617F</sup> VAF, diagnosed between 2007 and 2019. Our analysis revealed that 46.3% of these cases had additional driver mutations into <i>JAK2</i>, <i>CALR</i>, and <i>MPL</i> genes associated with very low <i>JAK2</i><sup>V617F</sup> VAF (median: 0.09%). Furthermore, next-generation sequencing of cases without these driver mutations showed that 67.7% harbored other mutations, including low VAF <i>CALR</i> mutations, as well as <i>TP53</i> alterations or predisposition genes. These findings highlight the importance of comprehensive molecular analysis in conjunction with bone marrow biopsy (BMB). Notably, we found a negative BMB did not exclude an MPN diagnosis, and molecular results confirmed MPN in some patients even without BMB evidence. Integrating BMB findings, molecular data, and low <i>JAK2</i><sup>V617F</sup> VAF with clinical assessments highlights the potential for misdiagnoses, especially in cases that might overlap with age-related clonal hematopoiesis. Our study emphasizes the need for extensive molecular investigation in cases of low <i>JAK2</i><sup>V617F</sup> MPN to ensure accurate diagnosis and appropriate management.</p>

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Contribution of molecular characterization to the diagnosis of MPN in patients with low JAK2V617F variant allelic fraction in a real-world cohort

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月1日

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  • Benjamin Lebecque,
  • Carolyne Croizier,
  • Thomas Tassin,
  • Esteban Louis,
  • Nathalie Tribalat,
  • William Bombardier,
  • Anne-Pascale Grandjean,
  • Vanessa Pante,
  • Hélène Monjanel,
  • Jean-Baptiste Bouillon-Minois,
  • Rémi Martel,
  • Albane Ledoux-Pilon,
  • Nathalie Boiret-Dupré,
  • Benoit De Renzis,
  • Marc Gabriel Berger,
  • Céline Bourgne

摘要

Since 2008, the JAK2V617F mutation has been key for diagnosing myeloproliferative neoplasms (MPN) according to the World Health Organization criteria. However, the clinical and biological significance of low JAK2V617F variant allelic fraction (VAF) remains poorly understood. To address this, we performed a comprehensive molecular characterization of a monocentric real-world retrospective cohort of MPN patients with low JAK2V617F VAF, diagnosed between 2007 and 2019. Our analysis revealed that 46.3% of these cases had additional driver mutations into JAK2, CALR, and MPL genes associated with very low JAK2V617F VAF (median: 0.09%). Furthermore, next-generation sequencing of cases without these driver mutations showed that 67.7% harbored other mutations, including low VAF CALR mutations, as well as TP53 alterations or predisposition genes. These findings highlight the importance of comprehensive molecular analysis in conjunction with bone marrow biopsy (BMB). Notably, we found a negative BMB did not exclude an MPN diagnosis, and molecular results confirmed MPN in some patients even without BMB evidence. Integrating BMB findings, molecular data, and low JAK2V617F VAF with clinical assessments highlights the potential for misdiagnoses, especially in cases that might overlap with age-related clonal hematopoiesis. Our study emphasizes the need for extensive molecular investigation in cases of low JAK2V617F MPN to ensure accurate diagnosis and appropriate management.