The Philadelphia negative myeloproliferative neoplasms (MPN) compromise a heterogeneous group of clonal myeloid stem cell disorders comprising polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Despite distinct clinical entities, these disorders are linked by morphological similarities and propensity to thrombotic complications and leukaemic transformation. Current therapeutic options are limited in disease-modifying activity with a focus on the prevention of thrombus formation. Constitutive activation of the JAK/STAT signalling pathway is a hallmark of pathogenesis across the disease spectrum with driving mutations in JAK2, CALR and MPL identified in the majority of patients. Co-occurring somatic mutations in genes associated with epigenetic regulation, transcriptional control and splicing of RNA are variably but recurrently identified across the MPN disease spectrum, whilst epigenetic contributors to disease are increasingly recognised. The prognostic implications of one MPN diagnosis may significantly limit life expectancy, whilst another may have limited impact depending on the disease phenotype, genotype and other external factors. The genetic and clinical similarities and differences in these disorders have provided a unique opportunity to understand the relative contributions to MPN, myeloid and cancer biology generally from specific genetic and epigenetic changes. This review provides a comprehensive overview of the molecular pathophysiology of MPN exploring the role of driver mutations, co-occurring mutations, dysregulation of intrinsic cell signalling, epigenetic regulation and genetic predisposing factors highlighting important areas for future consideration.

中文翻译：

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骨髓增殖性肿瘤的分子发病机制

费城阴性骨髓增殖性肿瘤 (MPN) 涉及一组异质性克隆性骨髓干细胞疾病，包括真性红细胞增多症、原发性血小板增多症和原发性骨髓纤维化。尽管有不同的临床实体，但这些疾病通过形态相似性和血栓并发症和白血病转化的倾向联系在一起。目前的治疗选择仅限于预防血栓形成的疾病缓解活动。JAK/STAT 信号通路的组成性激活是整个疾病谱中发病机制的标志，在大多数患者中发现了 JAK2、CALR 和 MPL 的驱动突变。与表观遗传调控相关的基因中同时发生的体细胞突变，RNA 的转录控制和剪接在 MPN 疾病谱中不同但经常被发现，而导致疾病的表观遗传因素越来越多地得到认可。一种 MPN 诊断的预后意义可能会显着限制预期寿命，而另一种可能具有有限的影响，具体取决于疾病表型、基因型和其他外部因素。这些疾病的遗传和临床相似性和差异提供了一个独特的机会来了解一般从特定遗传和表观遗传变化对 MPN、骨髓和癌症生物学的相对贡献。本综述全面概述了 MPN 的分子病理生理学，探讨了驱动突变、共发生突变、内在细胞信号传导失调、