Stivala Simona, Meyer Sara C
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
Division of Hematology, University Hospital Basel, 4031 Basel, Switzerland.
Cancers (Basel). 2021 Oct 9;13(20):5035. doi: 10.3390/cancers13205035.
Somatic mutations in JAK2, calreticulin, and MPL genes drive myeloproliferative neoplasms (MPN), and recent technological advances have revealed a heterogeneous genomic landscape with additional mutations in MPN. These mainly affect genes involved in epigenetic regulation and splicing and are of diagnostic and prognostic value, predicting the risk of progression and informing decisions on therapeutic management. Thus, genetic testing has become an integral part of the current state-of-the-art laboratory work-up for MPN patients and has been implemented in current guidelines for disease classification, tools for prognostic risk assessment, and recommendations for therapy. The finding that JAK2, CALR, and MPL driver mutations activate JAK2 signaling has provided a rational basis for the development of targeted JAK2 inhibitor therapies and has fueled their translation into clinical practice. However, the disease-modifying potential of JAK2 inhibitors remains limited and is further impeded by loss of therapeutic responses in a substantial proportion of patients over time. Therefore, the investigation of additional molecular vulnerabilities involved in MPN pathogenesis is imperative to advance the development of new therapeutic options. Combination of novel compounds with JAK2 inhibitors are of specific interest to enhance therapeutic efficacy of molecularly targeted treatment approaches. Here, we summarize the current insights into the genetic basis of MPN, its use as a diagnostic and prognostic tool in clinical settings, and the most recent advances in targeted therapies for MPN.
JAK2、钙网蛋白和MPL基因的体细胞突变驱动骨髓增殖性肿瘤（MPN），最近的技术进展揭示了MPN中存在具有额外突变的异质性基因组格局。这些突变主要影响参与表观遗传调控和剪接的基因，具有诊断和预后价值，可预测疾病进展风险并为治疗管理决策提供依据。因此，基因检测已成为当前MPN患者先进实验室检查的一个组成部分，并已纳入当前疾病分类指南、预后风险评估工具和治疗建议中。JAK2、CALR和MPL驱动突变激活JAK2信号这一发现为开发靶向JAK2抑制剂疗法提供了合理依据，并推动了其向临床实践的转化。然而，JAK2抑制剂的疾病修饰潜力仍然有限，并且随着时间的推移，相当一部分患者治疗反应的丧失进一步阻碍了其应用。因此，研究MPN发病机制中涉及的其他分子易损性对于推进新治疗方案的开发至关重要。将新型化合物与JAK2抑制剂联合使用对于提高分子靶向治疗方法的疗效具有特殊意义。在此，我们总结了目前对MPN遗传基础的认识、其在临床环境中作为诊断和预后工具的应用，以及MPN靶向治疗的最新进展。
