Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation sequencing in clinical laboratories, have revolutionized the diagnosis, classification, and clinical decision making of myelofibrosis. Driver mutations involvingJAK2,CALR, andMPLinduce hyperactivity in the JAK-STAT signaling pathway, which plays a central role in cell survival and proliferation. Approximately 80% of myelofibrosis cases harbor additional mutations, frequently in the genes responsible for epigenetic regulation and RNA splicing. Detecting these mutations is crucial for diagnosing myeloproliferative neoplasms (MPNs), especially in cases where no mutations are present in the three driver genes (triple-negative MPNs). While fibrosis in the bone marrow results from the disturbance of inflammatory cytokines, it is fundamentally associated with mutation-driven hematopoiesis. The mutation profile and order of acquiring diverse mutations influence the MPN phenotype. Mutation profiling reveals clonal diversity in MF, offering insights into the clonal evolution of neoplastic progression. Prognostic prediction plays a pivotal role in guiding the treatment of myelofibrosis. Mutation profiles and cytogenetic abnormalities have been integrated into advanced prognostic scoring systems and personalized risk stratification for MF. Presently, JAK inhibitors are part of the standard of care for MF, with newer generations developed for enhanced efficacy and reduced adverse effects. However, only a minority of patients have achieved a significant molecular-level response. Clinical trials exploring innovative approaches, such as combining hypomethylation agents that target epigenetic regulators, drugs proven effective in myelodysplastic syndrome, or immune and inflammatory modulators with JAK inhibitors, have demonstrated promising results. These combinations may be more effective in patients with high-risk mutations and complex mutation profiles. Expanding mutation profiling studies with more sensitive and specific molecular methods, as well as sequencing a broader spectrum of genes in clinical patients, may reveal molecular mechanisms in cases currently lacking detectable driver mutations, provide a better understanding of the association between genetic alterations and clinical phenotypes, and offer valuable information to advance personalized treatment protocols to improve long-term survival and eradicate mutant clones with the hope of curing MF.
骨髓纤维化是原发性骨髓纤维化的核心特征，而继发性骨髓纤维化可在其他髓系肿瘤（特别是真性红细胞增多症和原发性血小板增多症）的晚期阶段发生。近二十年来，分子诊断技术的进步，尤其是新一代测序技术在临床实验室的整合应用，彻底改变了骨髓纤维化的诊断、分类及临床决策模式。涉及JAK2、CALR和MPL的驱动基因突变可导致JAK-STAT信号通路过度激活，该通路在细胞存活与增殖中发挥核心调控作用。约80%的骨髓纤维化病例存在附加突变，这些突变常发生于表观遗传调控和RNA剪接相关基因。在三个驱动基因均未发生突变（三阴性骨髓增殖性肿瘤）的情况下，检测这些附加突变对骨髓增殖性肿瘤的诊断至关重要。虽然骨髓纤维化由炎性细胞因子紊乱引发，但其根本机制与突变驱动的造血过程密切相关。突变谱特征及获得不同突变的顺序会影响骨髓增殖性肿瘤的表型。突变谱分析揭示了骨髓纤维化中克隆的多样性，为肿瘤进展的克隆演化提供了重要线索。预后预测在指导骨髓纤维化治疗中具有关键作用。突变谱特征和细胞遗传学异常已被整合进先进的预后评分系统，用于实现个体化风险分层。目前JAK抑制剂已成为骨髓纤维化的标准治疗方案，新一代药物在提升疗效和降低不良反应方面持续改进。然而仅少数患者能达到显著的分子学缓解。针对表观遗传调节剂的去甲基化药物、骨髓增生异常综合征有效药物或免疫炎症调节剂与JAK抑制剂的联合治疗方案等创新疗法的临床试验已展现出良好前景。这些联合方案可能对具有高风险突变和复杂突变谱的患者更为有效。通过更灵敏特异的分子检测方法扩展突变谱研究，并对临床患者进行更广谱的基因测序，有望揭示当前未检出驱动基因突变病例的分子机制，深化对基因改变与临床表型关联的理解，为推进个体化治疗方案提供关键信息，从而改善长期生存率、清除突变克隆，最终实现治愈骨髓纤维化的目标。
肿瘤(癌症)患者之家