Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) characterized by progressive bone marrow fibrosis, extramedullary hematopoiesis, and cytopenias. PMF often has a variable clinical course, but in some cases, it progresses to a blastic phase (PMF-BP), which resembles acute myeloid leukemia (AML). This transformation is associated with poor prognosis and presents significant therapeutic challenges. While several genetic mutations are known to drive MPN pathogenesis, the molecular mechanisms underlying the transition to blast crisis remain poorly understood. Next-generation sequencing technologies, such as whole-exome sequencing (WES), offer a powerful approach to unravel the complex genetic landscape of PMF-BP, providing insights into both known cancer biomarkers and novel genetic variants that may contribute to disease progression. In this study, WES was employed to identify key genetic mutations in a patient with PMF-BP, with a focus on the potential role of these variants in leukemogenesis. Methods: A ۵۹-year-old male with a long-standing diagnosis of PMF was admitted in blast crisis (PMF-BP). A peripheral blood sample was collected, and WES was performed to identify somatic mutations. The findings were interpreted based on AMP (Association for Molecular Pathology) and ACMG (American College of Medical Genetics) guidelines. Potentially important findings (PIFs) and potentially actionable findings (PAFs) were assessed, focusing on their roles in known leukemogenesis pathways and their potential impact on clinical outcomes. Results: WES identified seven PIFs in cancer-associated genes, representing various functional classes. These included signaling pathway components (JAK۲-V۶۱۷F, CSF۳R-S۶۲۴L), transcription factors (CTCF-R۳۳۹Q), epigenetic regulators (IDH۱-R۱۳۲C), tumor suppressor and DNA repair genes (CHEK۲-D۳۱۱N), and components of the spliceosome (SRSF۲-P۹۵H, SF۳B۱-A۱۴۹A). Among these, JAK۲-V۶۱۷F, IDH۱-R۱۳۲C, CTCF-R۳۳۹Q, and SRSF۲-P۹۵H were characterized as actionable findings. Notably, IDH۱-R۱۳۲C, a known driver of epigenetic dysregulation, may contribute to abnormal DNA methylation patterns, while the
CTCF-R۳۳۹Q variant could influence chromatin structure and histone modifications via interactions with the Polycomb repressive complex ۲ (PRC۲). Conclusion: This case highlights the utility of WES in identifying clinically relevant mutations in patients with PMF-BP. The identified mutations, particularly those affecting epigenetic reprogramming, such as IDH۱-R۱۳۲C and CTCF-R۳۳۹Q, suggest that epigenetic dysregulation may play a critical role in the progression of PMF to blast phase. The involvement of CTCF, a key regulator of chromatin architecture, in PMF-BP pathogenesis is a novel finding that warrants further investigation. These findings underscore the importance of comprehensive genomic profiling in identifying actionable targets for personalized therapeutic strategies in patients with advanced myeloid malignancies.