Program in Cancer Biology, Cancer Institute, Institute for Stem Cell Biology and Regenerative Medicine, and Ludwig Center, Stanford University School of Medicine, Palo Alto, CA 94305, USA.
Sci Transl Med. 2012 Aug 29;4(149):149ra118. doi: 10.1126/scitranslmed.3004315.
Given that most bone marrow cells are short-lived, the accumulation of multiple leukemogenic mutations in a single clonal lineage has been difficult to explain. We propose that serial acquisition of mutations occurs in self-renewing hematopoietic stem cells (HSCs). We investigated this model through genomic analysis of HSCs from six patients with de novo acute myeloid leukemia (AML). Using exome sequencing, we identified mutations present in individual AML patients harboring the FLT3-ITD (internal tandem duplication) mutation. We then screened the residual HSCs and detected some of these mutations including mutations in the NPM1, TET2, and SMC1A genes. Finally, through single-cell analysis, we determined that a clonal progression of multiple mutations occurred in the HSCs of some AML patients. These preleukemic HSCs suggest the clonal evolution of AML genomes from founder mutations, revealing a potential mechanism contributing to relapse. Such preleukemic HSCs may constitute a cellular reservoir that should be targeted therapeutically for more durable remissions.
鉴于大多数骨髓细胞的寿命都比较短，因此单个克隆谱系中积累多个白血病相关突变的情况很难解释。我们提出，突变是在自我更新的造血干细胞（HSCs）中连续获得的。我们通过对 6 名新发急性髓系白血病（AML）患者的 HSCs 进行基因组分析来研究该模型。利用外显子组测序，我们鉴定了携带 FLT3-ITD（内部串联重复）突变的单个 AML 患者中存在的突变。然后，我们筛选了剩余的 HSCs，并检测到了其中一些突变，包括 NPM1、TET2 和 SMC1A 基因的突变。最后，通过单细胞分析，我们确定了一些 AML 患者的 HSCs 中存在多个突变的克隆进展。这些白血病前的 HSCs 提示 AML 基因组从创始突变开始的克隆进化，揭示了导致复发的潜在机制。这种白血病前的 HSCs 可能构成一个细胞储库，应该作为治疗靶点，以实现更持久的缓解。
