Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria.
Curr Cancer Drug Targets. 2011 Jan;11(1):56-71. doi: 10.2174/156800911793743655.
The concept of leukemic stem cells (LSC) is increasingly employed to explain the biology of various myeloid neoplasms and to screen for essential targets, with the hope to improve drug therapy through elimination of disease-initiating cells. Although the stem cell hypothesis may apply to all neoplasms, leukemia-initiating cells have so far only been characterized in some detail in advanced acute (AML) and chronic myeloid leukemia (CML). An intriguing observation is that although expressing various targets, LSC often remain unresponsive against most drugs, presumably because of 'intrinsic' resistance. Moreover, LSC represent heterogeneous populations of cells, grow in separate subclones, and acquire numerous defects, which points to substantial genetic instability and stem cell plasticity. The situation is complicated by the fact that stem cell evolution is a step-wise process with variable latency periods, so that many LSC-derived subclones remain small (undetectable) at diagnosis, but later, during therapy, may expand to a dominant clone and clinically overt relapsing disease. Finally the interaction between LSC and the microenvironment may contribute to stem cell function and LSC resistance. Taking all these considerations into account, the application of broadly acting targeted drugs and of drug combinations has been proposed in order to better suppress or even eliminate LSC in AML and CML. The current article provides a summary of our knowledge on LSC in various myeloid neoplasms with special reference to novel arising treatment concepts.
白血病干细胞（LSC）的概念越来越多地被用于解释各种髓系肿瘤的生物学特性，并筛选出关键靶点，以期通过消除疾病起始细胞来改善药物治疗。虽然干细胞假说可能适用于所有肿瘤，但迄今为止，白血病起始细胞仅在一些晚期急性髓系白血病（AML）和慢性髓系白血病（CML）中得到了详细描述。一个有趣的观察结果是，尽管表达各种靶标，但 LSC 通常对大多数药物仍无反应，这可能是因为存在“内在”耐药性。此外，LSC 代表细胞的异质性群体，在不同的亚克隆中生长，并获得许多缺陷，这表明存在大量的遗传不稳定性和干细胞可塑性。由于干细胞进化是一个逐步的过程，具有不同的潜伏期，因此许多由 LSC 衍生的亚克隆在诊断时仍然很小（无法检测到），但在治疗过程中，它们可能会扩展为优势克隆，并出现临床显性复发疾病，这使得情况变得更加复杂。最后，LSC 与微环境之间的相互作用可能有助于干细胞功能和 LSC 耐药性。考虑到所有这些因素，人们提出了应用广泛作用的靶向药物和药物联合治疗，以更好地抑制甚至消除 AML 和 CML 中的 LSC。本文总结了我们对各种髓系肿瘤中 LSC 的认识，特别提到了新出现的治疗概念。
