University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA.
Leuk Lymphoma. 2011 Feb;52 Suppl 1:60-80. doi: 10.3109/10428194.2010.546921.
Chronic myeloid leukemia therapy has remarkably improved with the use of frontline BCR-ABL kinase inhibitors such that newly diagnosed patients have minimal disease manifestations or progression. Effective control of disease may also set the stage for eventual 'cure' of this leukemia. However, the existence of Philadelphia chromosome-positive leukemic cells that are unaffected by BCR-ABL inhibition represents a major barrier that may delay or prevent curative therapy with the current approaches. The most commonly reported mechanism of resistance to tyrosine kinase inhibitor-based therapies involves BCR-ABL gene mutations and amplification, but these changes may not be solely responsible for disease relapse when inhibitor-based therapies are curtailed. Therefore new targets may need to be defined before significant advancement in curative therapies is possible. Emerging evidence suggests that persistence of chronic myeloid leukemia stem cells or acquisition of stem cell-like characteristics prevents complete elimination of chronic myeloid leukemia by tyrosine kinase inhibition alone. This review focuses on several recently emerging concepts regarding the existence and characteristics of chronic myeloid leukemia stem cells. Definitions based on human primary cells and animal model studies are highlighted as are the potential signaling pathways associated with disease repopulating cells. Finally, several recently defined therapeutic targets and active compounds that have emerged from stem cell studies are described. Our goal is to provide an unbiased report on the current state of discovery within the chronic myeloid leukemia stem cell field and to orient the reader to emerging therapeutic targets and strategies that may lead to elimination of this leukemia.
慢性髓性白血病的治疗已经取得了显著的进展，一线使用 BCR-ABL 激酶抑制剂，使得新诊断的患者疾病表现或进展最小化。疾病的有效控制也可能为这种白血病的最终“治愈”奠定基础。然而，费城染色体阳性白血病细胞的存在不受 BCR-ABL 抑制的影响，这是一个主要障碍，可能会延迟或阻止目前方法的治愈性治疗。最常报道的对基于酪氨酸激酶抑制剂的治疗产生耐药性的机制涉及 BCR-ABL 基因突变和扩增，但当抑制基于抑制剂的治疗时，这些变化可能并非疾病复发的唯一原因。因此，在可能的治愈性治疗取得重大进展之前，可能需要定义新的靶点。新出现的证据表明，慢性髓性白血病干细胞的持续存在或获得干细胞样特征，可防止酪氨酸激酶抑制单独完全消除慢性髓性白血病。这篇综述重点介绍了最近出现的关于慢性髓性白血病干细胞的存在和特征的几个新概念。突出了基于人类原代细胞和动物模型研究的定义，以及与疾病再生细胞相关的潜在信号通路。最后，描述了几个最近从干细胞研究中出现的治疗靶点和活性化合物。我们的目标是公正地报告慢性髓性白血病干细胞领域的最新发现状况，并为读者提供新兴的治疗靶点和策略，以消除这种白血病。
