BCL-XL mediates the strong selective advantage of a 20q11.21 amplification commonly found in human embryonic stem cell cultures.
BCL-XL mediates the strong selective advantage of a 20q11.21 amplification commonly found in human embryonic stem cell cultures.
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DOI：
10.1016/j.stemcr.2013.10.005
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发表时间：
2013
影响因子：
5.9
通讯作者：
Knowles, Barbara B.
中科院分区：
文献类型：
--
作者：
Avery, Stuart;Hirst, Adam J.;Baker, Duncan;Lim, Chin Yan;Alagaratnam, Sharmini;Skotheim, Rolf I.;Lothe, Ragnhild A.;Pera, Martin F.;Colman, Alan;Robson, Paul;Andrews, Peter W.;Knowles, Barbara B.
人类胚胎干细胞（hESC）在培养过程中经常获得非随机的基因组畸变，引起了人们对其安全治疗应用的关注。国际干细胞倡议组织在25%的显示正常核型的hESC系中鉴定出染色体20q11.21的拷贝数变异（CNV）扩增。通过比较四个细胞系配对的存在或不存在这种CNV，我们表明，那些含有这种扩增子具有较高的人口倍增率，归因于通过抗凋亡增强细胞存活。在最小扩增子内编码并在hESC中表达的三个基因中，仅BCL 2L 1（BCL-XL同种型）的过表达提供了具有与含CNV细胞的生长特征相似的生长特征的对照细胞，而BCL-XL的抑制抑制CNV细胞的生长优势，确立BCL 2L 1为驱动突变。20q11.21区域的扩增也可在人胚胎癌细胞系和一些畸胎瘤中检测到，将该突变与恶性转化联系起来。20q11.21 CNV的存在保护hESC免于凋亡20q11.21 CNV细胞具有增加的抗凋亡BCL-XL水平，驱动选择hECCs和原发性胚胎癌样本也显示20q11.21 CNV 20q11.21 CNV可能是肿瘤进展的一个特征Avery及其同事报道BCL 2L 1（基因产物BCL-XL）是染色体20q11.21的拷贝数变异（CNV）扩增的驱动突变（存在于25%的正常核型hESC系中）。CNV细胞通过BCL-XL相关的凋亡抗性表现出增强的细胞存活，并迅速胜过非突变细胞。对于用于治疗的hESC，应考虑对该突变进行常规筛查。
Human embryonic stem cells (hESCs) regularly acquire nonrandom genomic aberrations during culture, raising concerns about their safe therapeutic application. The International Stem Cell Initiative identified a copy number variant (CNV) amplification of chromosome 20q11.21 in 25% of hESC lines displaying a normal karyotype. By comparing four cell lines paired for the presence or absence of this CNV, we show that those containing this amplicon have higher population doubling rates, attributable to enhanced cell survival through resistance to apoptosis. Of the three genes encoded within the minimal amplicon and expressed in hESCs, only overexpression of BCL2L1 (BCL-XL isoform) provides control cells with growth characteristics similar to those of CNV-containing cells, whereas inhibition of BCL-XL suppresses the growth advantage of CNV cells, establishing BCL2L1 as a driver mutation. Amplification of the 20q11.21 region is also detectable in human embryonal carcinoma cell lines and some teratocarcinomas, linking this mutation with malignant transformation. The presence of the 20q11.21 CNV protects hESCs against apoptosis 20q11.21 CNV cells have increased levels of antiapoptotic BCL-XL, driving selection hECCs and primary embryonal carcinoma samples also display the 20q11.21 CNV 20q11.21 CNV could be a feature of neoplastic progression Avery and colleagues report that BCL2L1 (gene product BCL-XL) is the driver mutation for the copy number variant (CNV) amplification of chromosome 20q11.21 (present in 25% of normal-karyotype hESC lines). CNV cells exhibit enhanced cell survival through BCL-XL-associated resistance to apoptosis and rapidly outcompete nonmutant cells. Routine screening for this mutation should be considered for hESCs to be used in therapy.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.1019047108
发表时间：
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影响因子：
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