Majeti Ravindra
Department of Internal Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, USA.
Best Pract Res Clin Haematol. 2014 Sep-Dec;27(3-4):229-34. doi: 10.1016/j.beha.2014.10.003. Epub 2014 Oct 15.
Massively parallel DNA sequencing has uncovered recurrent mutations in many human cancers. In acute myeloid leukemia (AML), cancer genome/exome resequencing has identified numerous recurrently mutated genes with an average of 5 mutations in each case of de novo AML. In order for these multiple mutations to accumulate in a single lineage of cells, they are serially acquired in clones of self-renewing hematopoietic stem cells (HSC), termed pre-leukemic HSC. Isolation and characterization of pre-leukemic HSC have shown that their mutations are enriched in genes involved in regulating DNA methylation, chromatin modifications, and the cohesin complex. On the other hand, genes involved in regulating activated signaling are generally absent. Pre-leukemic HSC have been found to persist in clinical remission and may ultimately give rise to relapsed disease through the acquisition of novel mutations. Thus, pre-leukemic HSC may constitute a key cellular reservoir that must be eradicated for long-term cures.
大规模平行DNA测序揭示了许多人类癌症中的复发性突变。在急性髓系白血病（AML）中，癌症基因组/外显子组重测序已鉴定出众多复发性突变基因，在每例新发AML中平均有5个突变。为了使这些多个突变在单个细胞谱系中积累，它们是在自我更新的造血干细胞（HSC）克隆中依次获得的，这些克隆被称为白血病前期HSC。白血病前期HSC的分离和表征表明，它们的突变在参与调节DNA甲基化、染色质修饰和黏连蛋白复合体的基因中富集。另一方面，参与调节激活信号的基因通常不存在。已发现白血病前期HSC在临床缓解期持续存在，并可能最终通过获得新的突变导致疾病复发。因此，白血病前期HSC可能构成一个关键的细胞库，为实现长期治愈必须将其清除。
