Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias.
Consistent deregulation of gene expression between human and murine MLL rearrangement leukemias.
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DOI：
10.1158/0008-5472.can-08-3381
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Thirman MJ
中科院分区：
文献类型：
--
作者：
Li Z;Luo RT;Mi S;Sun M;Chen P;Bao J;Neilly MB;Jayathilaka N;Johnson DS;Wang L;Lavau C;Zhang Y;Tseng C;Zhang X;Wang J;Yu J;Yang H;Wang SM;Rowley JD;Chen J;Thirman MJ
重要的生物学和病理学特性通常在物种之间保持不变。虽然已经建立了几种小鼠白血病模型，但在人类和小鼠白血病细胞中失调的基因尚未得到系统的研究。我们对人类和小鼠MLL-ELL或MLL-ENL白血病细胞的基因表达进行了一系列基因表达分析（SAGE）分析，并确定了88个基因，这些基因在两种类型的白血病细胞中似乎显著失调，其中包括57个先前未报道的在MLL相关白血病中失调的基因。通过定量PCR验证这些变化。上调最多的基因包括几个HOX基因（例如，HOXA 5、HOXA 9和HOXA 10）和MEIS 1，它们是MLL重排白血病的典型标志。下调最多的基因包括LTF、LCN 2、MMP 9、S100 A8、S100 A9、PADI 4、TGFBI和CYBB。值得注意的是，上调的基因在基因本体学术语如“基因表达”和“转录”中富集，而下调的基因在“信号转导”和“细胞凋亡”中富集。我们发现下调基因的CpG岛是高甲基化的。我们还发现，来自mir-17-92簇的7个单独的microRNA，已知在人类MLL重排白血病中过表达，也在小鼠MLL重排白血病细胞中持续过表达。鉴定了这些microRNA的19种可能的靶点，其中两种（即，APP和RASSF 2）通过荧光素酶报告基因和诱变测定进一步证实。人类和小鼠MLL重排白血病中基因表达的一致变化的鉴定和验证为MLL相关白血病发生的遗传基础提供了重要的见解。
Important biological and pathological properties are often conserved across species. Although several mouse leukemia models have been well established, the genes deregulated in both human and murine leukemia cells have not been studied systematically. We performed a serial analysis of gene expression (SAGE) analysis on gene expression in both human and murine MLL-ELL or MLL-ENL leukemia cells, and identified 88 genes that appeared to be significantly deregulated in both types of leukemia cells, including 57 genes not reported previously as being deregulated in MLL-associated leukemias. These changes were validated by quantitative PCR. The most up-regulated genes include several HOX genes (e.g., HOX A5, HOXA9 and HOXA10) and MEIS1 that are the typical hallmark of MLL-rearrangement leukemia. The most down-regulated genes include LTF, LCN2, MMP9, S100A8, S100A9, PADI4, TGFBI and CYBB. Notably, the up-regulated genes are enriched in Gene Ontology terms such as “gene expression” and “transcription”, whereas the down-regulated genes are enriched in “signal transduction” and “apoptosis”. We showed that the CpG islands of the down-regulated genes are hypermethylated. We also showed that seven individual microRNAs from the mir-17-92 cluster, which are known to be overexpressed in human MLL-rearrangement leukemias, are also consistently overexpressed in mouse MLL-rearrangement leukemia cells. Nineteen possible targets of these microRNAs were identified and two of them (i.e., APP and RASSF2) were confirmed further by luciferase reporter and mutagenesis assays. The identification and validation of consistent changes of gene expression in human and murine MLL-rearrangement leukemias provides important insights into the genetic base for MLL-associated leukemogenesis.