文章：

研究慢性髓系白血病的病因

Getting to the stem of chronic myeloid leukaemia

原文发布日期：2008-05-01

DOI: 10.1038/nrc2368

类型: Review Article

开放获取: 否

要点：

1. The use of tyrosine-kinase inhibitors (TKIs) in chronic myeloid leukaemia (CML) is one of the greatest single advances in the targeted treatment of cancer but, in most cases, TKI therapy suppresses but does not eliminate the leukaemia.
2. Primitive CML cells are refractory to TKI therapy because of their acquisition of the complete physiology of stemness, which leads to relative quiescence and a protected reservoir for the breakpoint cluster region (BCR)–ABL (Abelson kinase) fusion. By contrast, progeny cells that persevere in the face of TKI therapy are resistant cells that might still be suppressed by second-generation TKIs or changes in doses of TKIs.
3. At the onset, carcinogenesis in CML is driven by BCR–ABL and is completely dependent on this mutation — an example of oncogenic addiction. Over time, the effects of BCR–ABL on the behaviour of the cell disrupt cellular homeostasis and promote genomic instability, leading to a point at which CML may progress irrespective of BCR–ABL. Beyond this anaplastic threshold, TKI therapy becomes less reliable, indicating transition to advanced-stage CML.
4. In advanced disease, it is genomic instability within the progeny cells that creates the disease phenotype, whereas the BCR–ABL fusion seems to simply persevere as a potential within the CML stem cell, implying that the fusion requires an increased rate of proliferation to exert its destabilizing effect. In fact, the relative quiescence might protect CML stem cells from TKI therapy, in so far as a minimum replicative index is required to actualize the pro-apoptotic effects of TKIs on the cell.
5. There may be two distinct cell types capable of self renewal in different phases of CML: first, a long-term haematopoietic stem cell with the BCR–ABL mutation, or CML stem cell, which maintains the more indolent chronic-phase disease, providing proliferative and survival advantages and, second, a leukaemic granulocyte macrophage progenitor responsible for rapid cell expansion in advanced disease.

要点翻译：

1. 酪氨酸激酶抑制剂（TKI）在慢性髓系白血病（CML）中的应用是癌症靶向治疗最重大的单一进展，但在多数情况下，TKI治疗仅能抑制而非根除白血病。
2. 原始CML细胞因获得完整的干细胞特性而对TKI治疗不敏感，这种特性导致细胞处于相对静息状态，并形成受保护的BCR-ABL融合基因储存库。相比之下，在TKI治疗中持续存在的子代细胞属于耐药细胞，或仍可通过第二代TKI或调整TKI剂量加以抑制。
3. 在疾病初期，CML的癌变由BCR-ABL驱动并完全依赖该突变——这是癌基因成瘾的典型例证。随着时间的推移，BCR-ABL对细胞行为的影响会破坏细胞稳态并促进基因组不稳定性，最终导致CML进展不再依赖BCR-ABL。超越这一去分化阈值后，TKI治疗的可靠性降低，标志着疾病向晚期CML转变。
4. 在晚期疾病中，子代细胞内的基因组不稳定性塑造了疾病表型，而BCR-ABL融合基因似乎仅作为潜在因素存在于CML干细胞中，这意味着该融合基因需要更高的增殖速率才能发挥其去稳定效应。实际上，相对静息状态可能保护CML干细胞免受TKI治疗影响，因为实现TKI促凋亡效应需要达到最低复制指数。
5. CML不同阶段可能存在两种具有自我更新能力的细胞类型：首先是携带BCR-ABL突变的长周期造血干细胞（即CML干细胞），它维持着惰性更强的慢性期疾病，提供增殖和生存优势；其次是负责晚期疾病中快速细胞扩增的白血病性粒细胞-巨噬细胞祖细胞。

英文摘要：

Tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukaemia (CML) is the consummate success story for targeted therapy, yet relapse is a nearly inevitable consequence of cessation or interruption of therapy. Primitive TKI-refractory CML stem cells are the likely source of these relapses, as they provide sanctuary for the Philadelphia chromosome. In advanced disease, their progressively anaplastic progeny ultimately maintain CML independently of the CML haematopoietic stem cell (HSC). Interestingly, there are at least two distinct cell types capable of self-renewal in different phases of CML: first, a primitive HSC with BCR–ABL mutation, which maintains the more indolent chronic-phase disease and, second, a coexisting mutated progenitor cell which acquires stem cell characteristics responsible for rapid cell expansion in advanced disease.

摘要翻译： 

酪氨酸激酶抑制剂（TKI）治疗慢性髓性白血病（CML）是靶向治疗的典范成功案例，但停药或中断治疗后复发几乎不可避免。原始的TKI耐药CML干细胞很可能是这些复发的根源，因为它们为费城染色体提供了“庇护所”。在疾病晚期，这些干细胞逐渐退化的子代最终可在不依赖CML造血干细胞（HSC）的情况下维持CML。有趣的是，在CML的不同阶段，至少存在两种具备自我更新能力的细胞类型：第一种是携带BCR-ABL突变的原始HSC，维持相对惰性的慢性期疾病；第二种是共存的突变祖细胞，其获得干细胞特性，负责晚期疾病中细胞的快速扩增。

原文链接：

Getting to the stem of chronic myeloid leukaemia