Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia.
Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia.
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DOI：
10.1101/gr.152132.112
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发表时间：
2014-02
期刊：
影响因子：
7
通讯作者：
Guigó R
中科院分区：
文献类型：
--
作者：
Ferreira PG;Jares P;Rico D;Gómez-López G;Martínez-Trillos A;Villamor N;Ecker S;González-Pérez A;Knowles DG;Monlong J;Johnson R;Quesada V;Djebali S;Papasaikas P;López-Guerra M;Colomer D;Royo C;Cazorla M;Pinyol M;Clot G;Aymerich M;Rozman M;Kulis M;Tamborero D;Gouin A;Blanc J;Gut M;Gut I;Puente XS;Pisano DG;Martin-Subero JI;López-Bigas N;López-Guillermo A;Valencia A;López-Otín C;Campo E;Guigó R
慢性淋巴细胞白血病（CLL）具有异质性的临床和生物学行为。全基因组和外显子组测序有助于表征该疾病的突变谱，但潜在的转录谱仍然知之甚少。我们对 98 名患者的正常 B 淋巴细胞和 CLL 细胞的不同亚群进行了深度 RNA 测序，并以前所未有的分辨率表征了 CLL 转录景观。我们检测到 CLL 和正常 B 细胞之间差异表达的数千个转录元件，包括蛋白质编码基因、非编码 RNA 和假基因。转座因子在 CLL 细胞中全面去抑制。此外，2000 个基因（其中大部分没有差异表达）表现出 CLL 特异性剪接模式。参与代谢途径的基因在 CLL 中表达较高，而与剪接体、蛋白酶体和核糖体相关的基因在 CLL 中表达下调最严重。根据 RNA-seq 衍生的基因表达水平对 CLL 样本进行聚类，揭示了两个强大的分子亚组：C1 和 C2。在具有主要临床生物学特征的多变量分析中，C1/C2 亚组和免疫球蛋白重可变区 (IGHV) 的突变状态是预测治疗时间的唯一自变量。这一细分在通过 DNA 微阵列监测的独立患者队列中得到了验证。进一步分析表明，淋巴结微环境中 B 细胞受体 (BCR) 的激活可能是 C1/C2 差异的根源。
Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein-coding genes, noncoding RNAs, and pseudogenes. Transposable elements are globally derepressed in CLL cells. In addition, two thousand genes—most of which are not differentially expressed—exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome, and ribosome were among the most down-regulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences.