Mian Syed A, Rouault-Pierre Kevin, Smith Alexander E, Seidl Thomas, Pizzitola Irene, Kizilors Aytug, Kulasekararaj Austin G, Bonnet Dominique, Mufti Ghulam J
Department of Haematological Medicine, King's College London School of Medicine, London SE5 9NU, UK.
Human Normal and Malignant Haematopoiesis Stem Cells and Their Microenvironment Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratories, London WC2A 3LY, UK.
Nat Commun. 2015 Dec 8;6:10004. doi: 10.1038/ncomms10004.
Despite the recent evidence of the existence of myelodysplastic syndrome (MDS) stem cells in 5q-MDS patients, it is unclear whether haematopoietic stem cells (HSCs) could also be the initiating cells in other MDS subgroups. Here we demonstrate that SF3B1 mutation(s) in our cohort of MDS patients with ring sideroblasts can arise from CD34(+)CD38(-)CD45RA(-)CD90(+)CD49f(+) HSCs and is an initiating event in disease pathogenesis. Xenotransplantation of SF3B1 mutant HSCs leads to persistent long-term engraftment restricted to myeloid lineage. Moreover, genetically diverse evolving subclones of mutant SF3B1 exist in mice, indicating a branching multi-clonal as well as ancestral evolutionary paradigm. Subclonal evolution in mice is also seen in the clinical evolution in patients. Sequential sample analysis shows clonal evolution and selection of the malignant driving clone leading to AML transformation. In conclusion, our data show SF3B1 mutations can propagate from HSCs to myeloid progeny, therefore providing a therapeutic target.
尽管最近有证据表明5q-骨髓增生异常综合征（MDS）患者中存在MDS干细胞，但尚不清楚造血干细胞（HSC）是否也可能是其他MDS亚组的起始细胞。在此我们证明，在我们患有环形铁粒幼细胞的MDS患者队列中，SF3B1突变可源自CD34(+)CD38(-)CD45RA(-)CD90(+)CD49f(+)造血干细胞，并且是疾病发病机制中的起始事件。SF3B1突变型造血干细胞的异种移植导致仅限于髓系谱系的持续长期植入。此外，在小鼠中存在基因多样的SF3B1突变进化亚克隆，表明存在分支多克隆以及祖先进化模式。小鼠中的亚克隆进化在患者的临床演变中也可见。连续样本分析显示克隆进化以及导致急性髓系白血病（AML）转化的恶性驱动克隆的选择。总之，我们的数据表明SF3B1突变可从造血干细胞传播至髓系后代，因此提供了一个治疗靶点。
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