Contribution of molecular characterization to the diagnosis of MPN in patients with low JAK2 variant allelic fraction in a real-world cohort.

Since 2008, the JAK2 mutation has been key for diagnosing myeloproliferative neoplasms (MPN) according to the World Health Organization criteria. However, the clinical and biological significance of low JAK2 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 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 JAK2 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 JAK2 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 JAK2 MPN to ensure accurate diagnosis and appropriate management.