Corces-Zimmerman M R, Majeti R
Program in Cancer Biology, Stanford Cancer Institute, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center, Stanford, CA, USA.
1] Program in Cancer Biology, Stanford Cancer Institute, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center, Stanford, CA, USA [2] Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Leukemia. 2014 Dec;28(12):2276-82. doi: 10.1038/leu.2014.211. Epub 2014 Jul 9.
Cancer has been shown to result from the sequential acquisition of genetic alterations in a single lineage of cells. In leukemia, increasing evidence has supported the idea that this accumulation of mutations occurs in self-renewing hematopoietic stem cells (HSCs). These HSCs containing some, but not all, leukemia-specific mutations have been termed as pre-leukemic. Multiple recent studies have sought to understand these pre-leukemic HSCs and determine to what extent they contribute to leukemogenesis. These studies have elucidated patterns in mutation acquisition in leukemia, demonstrated resistance of pre-leukemic cells to standard induction chemotherapy and identified these pre-leukemic cells as a putative reservoir for the generation of relapsed disease. When combined with decades of research on clonal evolution in leukemia, mouse models of leukemogenesis, and recent massively parallel sequencing-based studies of primary patient leukemia, studies of pre-leukemic HSCs begin to piece together the evolutionary puzzle of leukemogenesis. These results have broad implications for leukemia treatment, targeted therapies, minimal residual disease monitoring and early detection screening.
癌症已被证明是由单个细胞谱系中基因改变的顺序获得所导致的。在白血病中，越来越多的证据支持这样一种观点，即这种突变的积累发生在自我更新的造血干细胞（HSC）中。这些含有一些但并非全部白血病特异性突变的造血干细胞被称为白血病前期细胞。最近的多项研究试图了解这些白血病前期造血干细胞，并确定它们在多大程度上促成白血病的发生。这些研究阐明了白血病中突变获得的模式，证明了白血病前期细胞对标准诱导化疗的抗性，并将这些白血病前期细胞确定为复发疾病产生的假定来源。当与数十年来关于白血病克隆进化、白血病发生的小鼠模型以及近期基于大规模平行测序的原发性患者白血病研究相结合时，对白血病前期造血干细胞的研究开始拼凑出白血病发生的进化难题。这些结果对白血病治疗、靶向治疗、微小残留病监测和早期检测筛查具有广泛的意义。
