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<p>The case report presents the first documented instance of <i>ARAF</i>-mutated Langerhans cell histiocytosis (LCH) arising in a patient with <i>ARAF</i>/<i>JAK2</i>-mutated polycythaemia vera (PV), providing compelling evidence for a clonal relationship and branching evolution from a common progenitor precursor. The patient, a 63-year-old male, initially presented with classic PV symptoms and was diagnosed with <i>JAK2</i> p.V617F mutated PV. Over the disease course, persistent monocytosis and progressive splenomegaly were noted, with subsequent development of a diffuse, non-itching maculopapular skin eruption in the setting of LCH. Histopathological and molecular analyses of bone marrow and skin lesions revealed the presence of <i>ARAF</i>, <i>IDH2</i> and <i>ASXL1</i> mutations in both tissues. This molecular profile supports the hypothesis of divergent evolution from a shared <i>ARAF/IDH2/ASXL1</i>-mutated clone, with subsequent acquisition of <i>JAK2</i>. Therapeutic management included phlebotomies, aspirin, hydroxyurea, peginterferon alfa-2a, and ruxolitinib, with variable responses and eventual disease progression. The patient ultimately succumbed to infectious complications. We further reviewed the literature on clonally related myeloproliferative neoplasms and LCH, highlighting the rarity of such cases and the potential role of chronic inflammation, monocytosis, and targeted therapies (e.g., JAK inhibitors) in disease evolution. The findings underscore the importance of comprehensive molecular profiling in patients with overlapping haematologic and histiocytic disorders and propose a model of branching evolution that may inform future research and therapeutic strategies. This first reported case expands the understanding of LCH ontogeny and its association with myeloid neoplasms, emphasizing the need for further studies on clonal haematopoiesis and lineage plasticity in these rare disease intersections.</p>

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ARAF mutated langerhans cell histiocytosis developed on the background of ARAF/JAK2 mutated polycythaemia vera: evidence of branching evolution from the same progenitor cell. A case report and literature review

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  • 发表日期：

    2026年7月15日

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  • Gorana Gašljević,
  • Panna Dora,
  • Biljana Grčar-Kuzmanov,
  • Tereza Urdih,
  • Sandra Šućurović,
  • Helena Podgornik,
  • Vida Stegel,
  • Matjaž Sever

摘要

The case report presents the first documented instance of ARAF-mutated Langerhans cell histiocytosis (LCH) arising in a patient with ARAF/JAK2-mutated polycythaemia vera (PV), providing compelling evidence for a clonal relationship and branching evolution from a common progenitor precursor. The patient, a 63-year-old male, initially presented with classic PV symptoms and was diagnosed with JAK2 p.V617F mutated PV. Over the disease course, persistent monocytosis and progressive splenomegaly were noted, with subsequent development of a diffuse, non-itching maculopapular skin eruption in the setting of LCH. Histopathological and molecular analyses of bone marrow and skin lesions revealed the presence of ARAF, IDH2 and ASXL1 mutations in both tissues. This molecular profile supports the hypothesis of divergent evolution from a shared ARAF/IDH2/ASXL1-mutated clone, with subsequent acquisition of JAK2. Therapeutic management included phlebotomies, aspirin, hydroxyurea, peginterferon alfa-2a, and ruxolitinib, with variable responses and eventual disease progression. The patient ultimately succumbed to infectious complications. We further reviewed the literature on clonally related myeloproliferative neoplasms and LCH, highlighting the rarity of such cases and the potential role of chronic inflammation, monocytosis, and targeted therapies (e.g., JAK inhibitors) in disease evolution. The findings underscore the importance of comprehensive molecular profiling in patients with overlapping haematologic and histiocytic disorders and propose a model of branching evolution that may inform future research and therapeutic strategies. This first reported case expands the understanding of LCH ontogeny and its association with myeloid neoplasms, emphasizing the need for further studies on clonal haematopoiesis and lineage plasticity in these rare disease intersections.