Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.
Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland.
Leuk Lymphoma. 2021 Sep;62(9):2064-2078. doi: 10.1080/10428194.2021.1894652. Epub 2021 May 4.
The fusion gene, which causes aberrant kinase activity and uncontrolled cell proliferation, is the hallmark of chronic myeloid leukemia (CML). The development of tyrosine kinase inhibitors (TKI) that target the BCR-ABL oncoprotein has led to dramatic improvement in CML management. However, some challenges remain to be addressed in the TKI era, including patient stratification and the selection of frontline TKIs and CML progression. Additionally, with the emerging goal of treatment-free remission (TFR) in CML management, biomarkers that predict the outcomes of stopping TKI remain to be identified. Notably, recent reports have revealed the power of genome screening in understanding the role of genome aberrations other than in CML pathogenesis. These studies have discovered the presence of disease-phase specific mutations and linked certain mutations to inferior responses to TKI treatment and CML progression. A personalized approach that incorporates genetic data in tailoring treatment strategies has been successfully implemented in acute leukemia, and it represents a promising approach for the management of high-risk CML patients. In this article, we will review current knowledge about the mutational profile in different phases of CML as well as patterns of mutational dynamics in patients having different outcomes. We highlight the effects of somatic mutations involving certain genes (e.g. epigenetic modifiers) on the outcomes of TKI treatment. We also discuss the potential value of incorporating genetic data in treatment decisions and the routine care of CML patients as a future direction for optimizing CML management.
融合基因导致异常激酶活性和不受控制的细胞增殖，是慢性髓细胞白血病（CML）的标志。针对 BCR-ABL 癌蛋白的酪氨酸激酶抑制剂（TKI）的发展，使得 CML 的治疗取得了显著的改善。然而，在 TKI 时代，仍有一些挑战需要解决，包括患者分层以及一线 TKI 和 CML 进展的选择。此外，随着 CML 管理中无治疗缓解（TFR）目标的出现，预测停止 TKI 治疗结果的生物标志物仍有待确定。值得注意的是，最近的报告揭示了基因组筛选在理解除 以外的基因组异常在 CML 发病机制中的作用的强大功能。这些研究发现了疾病阶段特异性突变的存在，并将某些突变与对 TKI 治疗和 CML 进展的反应较差联系起来。一种将遗传数据纳入治疗策略定制的个性化方法已成功应用于急性白血病，它为高危 CML 患者的管理提供了一种很有前途的方法。在本文中，我们将回顾 CML 不同阶段的突变特征以及不同结局患者的突变动态模式的现有知识。我们强调了涉及某些基因（如表观遗传修饰因子）的体细胞突变对 TKI 治疗结果的影响。我们还讨论了在治疗决策中纳入遗传数据以及将其纳入 CML 患者常规护理的潜在价值，作为优化 CML 管理的未来方向。
