Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations
Gene expression profiling of leukemic cell lines reveals conserved molecular signatures among subtypes with specific genetic aberrations
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DOI：
10.1038/sj.leu.2403749
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发表时间：
2005-06-01
期刊：
影响因子：
11.4
通讯作者：
Fioretos, T
中科院分区：
文献类型：
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作者：
Andersson, A;Edén, P;Fioretos, T
血液恶性肿瘤的特征在于具有生物学/临床重要性的融合基因。具有这种畸变的永生化细胞系如今被广泛用于白血病发生的不同方面的建模。应用cDNA微阵列技术，我们测定了40个细胞系以及携带11 q23/MLL重排的原发性白血病的基因表达谱：t（1;19）[TCF 3/PBX 1]，t（12;21）[ETV 6/RUNX 1]，t（8;21）[RUNX 1/CBFA 2 T 1]，t（8; 14）[IGH@/MYC]，t（8; 14）[TRA@/MYC]，t（9;22）[BCR/ABL 1]，t（10; 11）[PICALM/MLLT 10]、t（15;17）[PML/RARA]或inv（16）[CBFB/MYH 11]。无监督分类显示，不同来源的造血细胞系，但具有相同的主要遗传变化，分离在一起，这表明，尽管有许多通道，致病重要的调控网络仍然保守。此外，原发性白血病与携带相同遗传重排的细胞系共分离，进一步支持造血细胞系中关键调控途径保持完整。基于其生物学/分子特性和染色体定位，鉴定并注释与临床亚型/原发性遗传变化相关的转录特征。此外，酪氨酸激酶编码基因的表达谱进行了研究，确定了几个差异表达的成员，分离与主要的遗传变化，这可能是有针对性的酪氨酸激酶抑制剂。所确定的保守签名可能反映了对主要遗传变化的转化能力具有重要意义的调控网络，并为未来合理的药物设计提供了重要的发病机理见解以及许多靶点。
Hematologic malignancies are characterized by fusion genes of biological/clinical importance. Immortalized cell lines with such aberrations are today widely used to model different aspects of leukemogenesis. Using cDNA microarrays, we determined the gene expression profiles of 40 cell lines as well as of primary leukemias harboring 11q23/MLL rearrangements, t(1;19)[TCF3/PBX1], t(12;21)[ETV6/RUNX1], t(8;21)[RUNX1/CBFA2T1], t(8;14) [IGH@/MYC], t(8;14)[TRA@/MYC], t(9;22)[BCR/ABL1], t(10;11) [PICALM/MLLT10], t(15;17)[PML/RARA], or inv(16)[CBFB/MYH11]. Unsupervised classification revealed that hematopoietic cell lines of diverse origin, but with the same primary genetic changes, segregated together, suggesting that pathogenetically important regulatory networks remain conserved despite numerous passages. Moreover, primary leukemias cosegregated with cell lines carrying identical genetic rearrangements, further supporting that critical regulatory pathways remain intact in hematopoietic cell lines. Transcriptional signatures correlating with clinical subtypes/primary genetic changes were identified and annotated based on their biological/molecular properties and chromosomal localization. Furthermore, the expression profile of tyrosine kinase-encoding genes was investigated, identifying several differentially expressed members, segregating with primary genetic changes, which may be targeted with tyrosine kinase inhibitors. The identified conserved signatures are likely to reflect regulatory networks of importance for the transforming abilities of the primary genetic changes and offer important pathogenetic insights as well as a number of targets for future rational drug design.