Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis.
Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis.
复制标题
DOI：
10.1016/j.celrep.2015.02.005
复制
发表时间：
2015-03-03
期刊：
影响因子：
8.8
通讯作者：
Vassiliou GS
中科院分区：
文献类型：
--
作者：
McKerrell T;Park N;Moreno T;Grove CS;Ponstingl H;Stephens J;Understanding Society Scientific Group;Crawley C;Craig J;Scott MA;Hodkinson C;Baxter J;Rad R;Forsyth DR;Quail MA;Zeggini E;Ouwehand W;Varela I;Vassiliou GS
由白血病相关基因突变驱动的克隆造血可以在没有血液疾病证据的情况下发生。为了研究这一现象，我们使用超深度测序技术对4219人血液DNA中的15个突变热点进行了研究。仅使用研究热点，我们在60岁以下的个体中发现了0.8%的克隆造血，在≥90岁的个体中上升到19.5%，从而预测克隆造血比以前认识到的要普遍得多。DNMT3A-R882突变是最常见的，尽管其患病率随着年龄的增长而增加，但在25岁的个体中发现。相比之下，影响剪接体基因SF3B1和SRSF2的突变，与骨髓增生异常综合征密切相关，仅在年龄在bb0 - 70岁的人群中被发现，并且一些个体携带不止一个这样的突变。这表明剪接体基因突变在选择压力下驱动克隆扩增，特别是在衰老的造血系统中，并解释了与这些突变相关的克隆疾病在老年晚期的高发。克隆造血是人类衰老几乎不可避免的结果，剪接体基因突变仅在年龄≥70岁的人群中驱动克隆造血。NPM1突变是白血病发生的守门人。McKerrell等人利用超深度测序表明，与年龄相关的克隆造血比以前认识到的要普遍得多。他们发现，由剪接体SF3B1和SRSF2基因突变驱动的克隆造血仅在70岁或以上的个体中发现，而NPM1突变未见与这种现象相关，这表明它们与白血病发生密切相关。
Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged >70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age. Clonal hemopoiesis is an almost inevitable consequence of aging in humans Spliceosome gene mutations drove clonal hemopoiesis only in persons aged ≥70 years NPM1 mutations behave as gatekeepers for leukemogenesis McKerrell et al. employ ultra-deep sequencing to show that age-related clonal hemopoiesis is much more common than previously realized. They find that clonal hemopoiesis, driven by mutations in spliceosome genes SF3B1 and SRSF2, was noted exclusively in individuals aged 70 years or older and that NPM1 mutations are not seen in association with this phenomenon, endorsing their close association with leukemogenesis.