A novel somatic mutation in ACD induces telomere lengthening and apoptosis resistance in leukemia cells.
A novel somatic mutation in ACD induces telomere lengthening and apoptosis resistance in leukemia cells.
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DOI：
10.1186/s12885-015-1639-5
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发表时间：
2015-09-07
期刊：
影响因子：
3.8
通讯作者：
Sinnett D
中科院分区：
文献类型：
--
作者：
Spinella JF;Cassart P;Garnier N;Rousseau P;Drullion C;Richer C;Ouimet M;Saillour V;Healy J;Autexier C;Sinnett D
致癌驱动突变的鉴定在很大程度上依赖于这样的假设，即偶然表现出比预期更多突变的基因更可能在肿瘤发生中发挥积极作用。因此，主要的癌症测序计划都集中在更有可能成为驱动因素的复发性突变上。然而，在特定的遗传背景下，低频突变也可能参与致癌过程。为了阐明更个性化的癌症诊断和治疗方法，需要可靠的策略来识别这些罕见的甚至是患者特异性（私人）突变。在这里，我们进行了全外显子组测序的3例儿童前B急性淋巴细胞白血病（cALL），代表三个细胞遗传学定义的亚组（高超二倍体，t（12;21）易位，和细胞遗传学正常）。我们应用数据简化策略来识别具有高功能潜力的常见和罕见/私人躯体事件。排名靠前的候选突变随后在独立平台上以高测序深度进行验证，并进行体外表达测定以评价鉴定的突变对细胞生长和存活的影响。我们在3例cALL患者中发现了6个损伤性非同义体细胞突变。这些突变中有3个是充分表征的常见cALL突变，涉及丝裂原活化蛋白激酶途径的组成性激活（FLT 3 p.D835Y、NRAS p.G13D、BRAF p.G466A）。其余三个患者特异性突变（ACD p.G223V、DOT 1 L p.V114F、HCFC 1 p.Y103H）是以前在公共癌症数据库中未描述的新突变。细胞毒性试验证明ACD p.G223V突变对白血病细胞凋亡具有保护作用。ACD在保护端粒和募集端粒酶中起关键作用。使用端粒限制性片段分析，我们还表明，这种新的突变ACD导致白血病细胞端粒长度增加。这项研究确定ACD作为一个新的基因参与cALL和点ACD在提高白血病细胞存活的功能作用。这些结果强调了罕见/私有体细胞突变在理解cALL病因学中的重要性，即使是在充分表征的分子亚组中。本文的在线版本（doi：10.1186/s12885-015-1639-5）包含补充材料，可供授权用户使用。
The identification of oncogenic driver mutations has largely relied on the assumption that genes that exhibit more mutations than expected by chance are more likely to play an active role in tumorigenesis. Major cancer sequencing initiatives have therefore focused on recurrent mutations that are more likely to be drivers. However, in specific genetic contexts, low frequency mutations may also be capable of participating in oncogenic processes. Reliable strategies for identifying these rare or even patient-specific (private) mutations are needed in order to elucidate more personalized approaches to cancer diagnosis and treatment. Here we performed whole-exome sequencing on three cases of childhood pre-B acute lymphoblastic leukemia (cALL), representing three cytogenetically-defined subgroups (high hyperdiploid, t(12;21) translocation, and cytogenetically normal). We applied a data reduction strategy to identify both common and rare/private somatic events with high functional potential. Top-ranked candidate mutations were subsequently validated at high sequencing depth on an independent platform and in vitro expression assays were performed to evaluate the impact of identified mutations on cell growth and survival. We identified 6 putatively damaging non-synonymous somatic mutations among the three cALL patients. Three of these mutations were well-characterized common cALL mutations involved in constitutive activation of the mitogen-activated protein kinase pathway (FLT3 p.D835Y, NRAS p.G13D, BRAF p.G466A). The remaining three patient-specific mutations (ACD p.G223V, DOT1L p.V114F, HCFC1 p.Y103H) were novel mutations previously undescribed in public cancer databases. Cytotoxicity assays demonstrated a protective effect of the ACD p.G223V mutation against apoptosis in leukemia cells. ACD plays a key role in protecting telomeres and recruiting telomerase. Using a telomere restriction fragment assay, we also showed that this novel mutation in ACD leads to increased telomere length in leukemia cells. This study identified ACD as a novel gene involved in cALL and points to a functional role for ACD in enhancing leukemia cell survival. These results highlight the importance of rare/private somatic mutations in understanding cALL etiology, even within well-characterized molecular subgroups. The online version of this article (doi:10.1186/s12885-015-1639-5) contains supplementary material, which is available to authorized users.