Whole-exon sequencing of human myeloma cell lines shows mutations related to myeloma patients at relapse with major hits in the DNA regulation and repair pathways
Whole-exon sequencing of human myeloma cell lines shows mutations related to myeloma patients at relapse with major hits in the DNA regulation and repair pathways
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DOI：
10.1186/s13045-018-0679-0
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发表时间：
2018-12-13
影响因子：
28.5
通讯作者：
Pellat-Deceunynck, Catherine
中科院分区：
文献类型：
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作者：
Tessoulin, Benoit;Moreau-Aubry, Agnes;Pellat-Deceunynck, Catherine
背景人类骨髓瘤细胞系（human myeloma cell lines，HMCL）广泛用于代表原发性骨髓瘤细胞，因为它们涵盖了患者的多样性，尽管并不完全。他们的遗传背景大多是未被发现的，并没有进行全面的研究，以揭示这些details.MethodsWe进行全外显子测序的33 HMCLs，这是建立在过去的50年中，在12个实验室。基因表达谱和药物检测的33 HMCLs也提供相关的外显子测序findings.ResultsMissense突变是最常见的命中基因（92%）。HMCL每个样本含有307至916个突变，TP 53是突变最多的基因（67%）。在参与细胞周期调控（RB 1，CDKN 2C），NFB途径（TRAF 3，BIRC 2）和p53途径（TP 53，CDKN 2A）的基因中发现了复发性双等位基因丢失。HMCL中突变/缺失的频率与患者相似（例如，DIS 3、PRDM 1、KRAS）或高度增加（例如，TP53、CDKN2C、NRAS、PRKD 2）。MAPK是改变最多的途径（82%的HMCL），主要由RAS突变体引起。令人惊讶的是，HMCL在表观遗传（73%）和范可尼贫血（54%）中显示出改变，而在凋亡机制中几乎没有改变。我们进一步确定了在MAPK和p53通路中涉及的基因以及染色质调节/修饰基因中相互排斥和相关的突变/缺失。最后，通过结合基因表达谱，基因突变，基因缺失，和药物反应，我们证明了几种靶向药物克服或绕过一些mutation.ConclusionsWith这项工作，我们检索的HMCLs的基因组改变，突出显示，他们展示了许多前所未有的异常，特别是在DNA调控和修复途径。此外，我们证明了HMCL是一种可靠的模型，用于难治性患者在诊断或复发时的药物筛选。
BackgroundHuman myeloma cell lines (HMCLs) are widely used for their representation of primary myeloma cells because they cover patient diversity, although not fully. Their genetic background is mostly undiscovered, and no comprehensive study has ever been conducted in order to reveal those details.MethodsWe performed whole-exon sequencing of 33 HMCLs, which were established over the last 50years in 12 laboratories. Gene expression profiling and drug testing for the 33 HMCLs are also provided and correlated to exon-sequencing findings.ResultsMissense mutations were the most frequent hits in genes (92%). HMCLs harbored between 307 and 916 mutations per sample, with TP53 being the most mutated gene (67%). Recurrent bi-allelic losses were found in genes involved in cell cycle regulation (RB1, CDKN2C), the NFB pathway (TRAF3, BIRC2), and the p53 pathway (TP53, CDKN2A). Frequency of mutations/deletions in HMCLs were either similar to that of patients (e.g., DIS3, PRDM1, KRAS) or highly increased (e.g., TP53, CDKN2C, NRAS, PRKD2). MAPK was the most altered pathway (82% of HMCLs), mainly by RAS mutants. Surprisingly, HMCLs displayed alterations in epigenetic (73%) and Fanconi anemia (54%) and few alterations in apoptotic machinery. We further identified mutually exclusive and associated mutations/deletions in genes involved in the MAPK and p53 pathways as well as in chromatin regulator/modifier genes. Finally, by combining the gene expression profile, gene mutation, gene deletion, and drug response, we demonstrated that several targeted drugs overcome or bypass some mutations.ConclusionsWith this work, we retrieved genomic alterations of HMCLs, highlighting that they display numerous and unprecedented abnormalities, especially in DNA regulation and repair pathways. Furthermore, we demonstrate that HMCLs are a reliable model for drug screening for refractory patients at diagnosis or at relapse.