Stewart Brittany L, Carraway Hetty E, Alvarez Adriana L, Lesmana Harry, Molina John, Tu Zheng Jin, Bosler David S, Gerds Aaron, Jha Babal, Calvaresi Emilia, Nakitandwe Joy, Singh Abhay
Leukemia and Myeloid Disorders Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.
Department of Medical Genetics, Medical Specialties Institute, Cleveland Clinic, Cleveland, OH.
Blood Adv. 2025 Apr 8;9(7):1534-1543. doi: 10.1182/bloodadvances.2024013661.
The Janus kinase 2 (JAK2) V617F mutation activates the transcription pathway and has been well characterized as a driver of myeloproliferative neoplasms (MPNs). Recently, there has been a heightened interest in understanding germ line predisposition to hematologic malignancies such as MPN, including several reports of familial MPN. Here, we retrospectively analyzed medical records and data from genetic testing to describe 12 patients with germ line variants at amino acid position 564 of JAK2. This includes 3 supportive cases adding to prior literature regarding the germ line JAK2 R564Q association with hereditary thrombocythemia, as well as confirmation of JAK2 R564L as a germ line variant associated with MPN. Importantly, the symptomatic burden for many of the individuals in this series is comparable with that of individuals with the canonical V617F mutation profile. In the JAK2 R564Q cases, we noted a pattern of familial aggregation, presence of congenital thrombocythemia, and co-occurrence with hematologic neoplasms. Identification of germ line predisposition is essential for understanding the pathogenesis of disease, impact on families, and opportunities for preventive care. Continued research is essential to further characterize the penetrance of these conditions and how best to monitor, treat, and optimize management for these families.
Janus激酶2（JAK2）V617F突变激活转录途径，并且已被充分确认为骨髓增殖性肿瘤（MPN）的驱动因素。最近，人们对了解血液系统恶性肿瘤（如MPN）的种系易感性的兴趣日益浓厚，包括几篇关于家族性MPN的报道。在此，我们回顾性分析了病历和基因检测数据，以描述12例JAK2氨基酸位置564存在种系变异的患者。这包括3例支持性病例，补充了先前关于种系JAK2 R564Q与遗传性血小板增多症关联的文献，同时证实JAK2 R564L是与MPN相关的种系变异。重要的是，该系列中许多个体的症状负担与具有典型V617F突变谱的个体相当。在JAK2 R564Q病例中，我们注意到家族聚集模式、先天性血小板增多症的存在以及与血液系统肿瘤的共存。确定种系易感性对于理解疾病的发病机制、对家庭的影响以及预防保健机会至关重要。持续的研究对于进一步明确这些病症的外显率以及如何最好地监测、治疗和优化这些家庭的管理至关重要。
