Over the course of the last decade, genomic studies in the context of normal human hematopoiesis have provided new insights into the early pathogenesis of myeloproliferative neoplasms (MPN). A preclinical phase of MPN, termed clonal hematopoiesis (CH) was identified and subsequent lineage tracing studies revealed a multi-decade long time interval from acquisition of an MPN phenotypic driver mutation in a hematopoietic stem cell (HSC) to the development of overt MPN. Multiple germline variants associated with MPN risk have been identified through genome-wide association studies (GWAS) and in some cases functional interrogation of the impact of the variant has uncovered new insights into HSC biology and MPN development. Increasingly sophisticated methods to study clonal contributions to human hematopoiesis and measure HSC fitness have helped discern the biology underlying the tremendous clinical heterogeneity observed in MPN. Despite these advances, significant knowledge gaps remain particularly with respect to germline genetic contributors to both MPN pathogenesis and phenotypic diversity, as well as limitations in the ability to prospectively quantify rates of clonal expansion in individual MPN patients. Ultimately, we envisage a personalized approach to MPN care in the future, where an individualized genetic assessment can predict MPN trajectory and this information will be used to inform and guide therapy. MPN is particularly amenable to precision medicine strategies and our increased understanding of the evolution of MPN from normal blood stem cells provides a unique opportunity for early therapeutic intervention approaches and potentially MPN prevention strategies.

中文翻译：

---

骨髓增生性肿瘤从正常造血干细胞的进化。


在过去十年中，在正常人类造血背景下的基因组研究为骨髓增生性肿瘤 （MPN） 的早期发病机制提供了新的见解。确定了 MPN 的临床前阶段，称为克隆造血 （CH），随后的谱系追踪研究显示，从造血干细胞 （HSC） 中获得 MPN 表型驱动突变到显性 MPN 的发展存在数十年的漫长时间间隔。通过全基因组关联研究 （GWAS） 已经确定了与 MPN 风险相关的多个种系变异，在某些情况下，对变异影响的功能询问揭示了对 HSC 生物学和 MPN 发展的新见解。研究克隆对人类造血作用的贡献和测量 HSC 适应性的日益复杂的方法有助于辨别在 MPN 中观察到的巨大临床异质性背后的生物学。尽管取得了这些进展，但仍然存在重大知识差距，特别是在 MPN 发病机制和表型多样性的种系遗传因素方面，以及前瞻性量化个体 MPN 患者克隆扩增速率的能力方面的局限性。最终，我们设想了未来一种个性化的 MPN 护理方法，其中个体化遗传评估可以预测 MPN 轨迹，这些信息将用于信息和指导治疗。MPN 特别适合精准医学策略，我们对 MPN 从正常造血干细胞进化的了解不断加深，这为早期治疗干预方法和潜在的 MPN 预防策略提供了独特的机会。