文章：

高危多发性骨髓瘤的进化生物学

Evolutionary biology of high-risk multiple myeloma

原文发布日期：2017-08-24

DOI: 10.1038/nrc.2017.63

类型: Review Article

开放获取: 否

要点：

1. Treatment of myeloma has developed rapidly over the past two decades with the advent of proteasome inhibitors and immunomodulatory agents. Despite their dramatic impact on overall patient outcomes, there remains a high-risk group of patients, constituting 20–30% of all cases, who have not benefited to the same extent and continue to have poor outcomes.
2. There is no single pathogenic mechanism that can currently be used to unify and define high-risk disease; instead, the common features are clinically aggressive behaviours, including therapy resistance, proliferation and evasion of apoptosis, which are the consequences of following several evolutionary trajectories driven by distinct gene–gene interactions.
3. The key molecular hallmarks of high-risk disease biology include increased proliferation and the development of a high-risk ecosystem that facilitates both cancer cell survival and failure of the immune response.
4. Genetic lesions underlie the key hallmarks of high-risk disease states and may occur as tumour initiating or progression events. No one of these lesions explains all high-risk disease, and in order to effectively target high-risk disease, we need to understand how these drivers arise, interact with each other and mediate their downstream effects.
5. Pathologically, the high-risk biological states of multiple myeloma are the end stage of a multi-step clinical progression system typical of multiple myeloma comprising benign monoclonal gammopathy; an intermediate stage lacking clinical damage; multiple myeloma itself, which has a range of clinical behaviours; and an easily recognizable leukaemic phase wherein disease is no longer confined to the bone marrow. This progression system is driven by subclonal competition and selective pressures within the bone marrow microenvironment.
6. To improve the outcomes of patients with high-risk disease, it is important to recognize them at disease presentation and to enter them into specific risk-stratified clinical trials. The heterogeneous nature of the molecular mechanisms underlying high-risk disease makes this challenging and is discussed in detail.

要点翻译：

1. 多发性骨髓瘤的治疗在过去二十年中随着蛋白酶体抑制剂和免疫调节剂的出现而迅速发展。尽管这些药物对患者总体预后产生了显著影响，但仍有20%-30%的高危患者群体未能同等获益，其预后持续较差。
2. 目前尚无单一的致病机制能够统一定义高危疾病；其共同特征是具有临床侵袭性行为，包括治疗抵抗、增殖增强和凋亡逃逸，这些现象是由不同基因间相互作用驱动多种进化轨迹所导致的结果。
3. 高危疾病生物学的主要分子标志包括增殖加剧，以及形成既促进癌细胞存活又导致免疫应答失效的高危生态系统。
4. 遗传损伤是高危疾病状态关键特征的基础，可能作为肿瘤起始或进展事件发生。没有任何单一损伤能解释所有高危疾病，为有效靶向高危疾病，我们需要理解这些驱动因素如何产生、相互作用的机制及其介导下游效应的途径。
5. 从病理学角度看，多发性骨髓瘤的高危生物状态是多步骤临床进展系统的终末阶段——该系统包含良性单克隆丙种球蛋白病、缺乏临床损伤的中间阶段、具有多种临床行为的多发性骨髓瘤本体阶段，以及疾病不再局限于骨髓的易识别白血病期。这一进展系统由骨髓微环境中的亚克隆竞争和选择压力驱动。
6. 为改善高危疾病患者的预后，关键是在疾病呈现时及时识别并将其纳入特定的风险分层临床试验。然而，高危疾病分子机制的异质性特征使得这一目标充满挑战，相关细节将在下文详细探讨。

英文摘要：

The outcomes for the majority of patients with myeloma have improved over recent decades, driven by treatment advances. However, there is a subset of patients considered to have high-risk disease who have not benefited. Understanding how high-risk disease evolves from more therapeutically tractable stages is crucial if we are to improve outcomes. This can be accomplished by identifying the genetic mechanisms and mutations driving the transition of a normal plasma cell to one with the features of the following disease stages: monoclonal gammopathy of undetermined significance, smouldering myeloma, myeloma and plasma cell leukaemia. Although myeloma initiating events are clonal, subsequent driver lesions often occur in a subclone of cells, facilitating progression by Darwinian selection processes. Understanding the co-evolution of the clones within their microenvironment will be crucial for therapeutically manipulating the process. The end stage of progression is the generation of a state associated with treatment resistance, increased proliferation, evasion of apoptosis and an ability to grow independently of the bone marrow microenvironment. In this Review, we discuss these end-stage high-risk disease states and how new information is improving our understanding of their evolutionary trajectories, how they may be diagnosed and the biological behaviour that must be addressed if they are to be treated effectively.

摘要翻译： 

大多数骨髓瘤患者的结局在近几十年因治疗进展而有所改善，然而，有一部分被认为是高危疾病的患者并未从中获益。如果我们希望改善这些患者的结局，理解高危疾病是如何从治疗上更易控制的阶段演变而来至关重要。这可以通过识别驱动正常浆细胞向以下疾病阶段特征转变的遗传机制和突变来实现：意义未明的单克隆丙种球蛋白病、冒烟型骨髓瘤、骨髓瘤以及浆细胞白血病。尽管骨髓瘤的起始事件是克隆性的，但后续的驱动性病变往往发生在细胞的亚克隆中，通过达尔文选择过程促进疾病进展。理解这些克隆与其微环境之间的共同演化，对于在治疗上操控这一过程至关重要。疾病进展的终末阶段是形成一种与治疗耐药、增殖增加、逃避凋亡以及能够在不依赖骨髓微环境的情况下独立生长的状态。在本综述中，我们讨论了这些终末期高危疾病状态，以及新的信息如何增进我们对其演化轨迹的理解，如何诊断这些状态，以及如果我们要有效治疗它们，必须应对的生物学行为。

原文链接：

Evolutionary biology of high-risk multiple myeloma