Hormoz Sahand, Sankaran Vijay G, Mullally Ann
Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA.
Haematologica. 2025 Apr 1;110(4):840-849. doi: 10.3324/haematol.2023.283951. Epub 2024 Dec 5.
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 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 to the development of overt MPN. Multiple germline variants associated with MPN risk have been identified through genome-wide association studies and in some cases functional interrogation of the impact of the variant has uncovered new insights into hematopoietic stem cell biology and MPN development. Increasingly sophisticated methods to study clonal contributions to human hematopoiesis and measure hematopoietic stem cell fitness have helped to 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, in which 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.
在过去十年中，针对正常人类造血过程的基因组研究为骨髓增殖性肿瘤（MPN）的早期发病机制提供了新的见解。MPN的一个临床前阶段，即克隆性造血被识别出来，随后的谱系追踪研究揭示了从造血干细胞中获得MPN表型驱动突变到明显的MPN发生之间长达数十年的时间间隔。通过全基因组关联研究已经确定了多个与MPN风险相关的种系变异，在某些情况下，对这些变异影响的功能研究揭示了造血干细胞生物学和MPN发展的新见解。用于研究克隆对人类造血的贡献以及测量造血干细胞适应性的方法越来越复杂，这有助于洞察MPN中观察到的巨大临床异质性背后的生物学机制。尽管取得了这些进展，但仍存在重大的知识空白，特别是在MPN发病机制和表型多样性的种系遗传因素方面，以及在个体MPN患者中前瞻性量化克隆扩增率的能力方面存在局限性。最终，我们设想未来采用个性化的MPN治疗方法，其中个性化的基因评估可以预测MPN的发展轨迹，并且这些信息将用于指导治疗。MPN特别适合精准医学策略，我们对MPN从正常血液干细胞演变过程的深入理解为早期治疗干预方法以及潜在的MPN预防策略提供了独特的机会。
