Department of Medicine and Committee on Genetics, University of Chicago, Chicago, IL 60637, USA.
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3710-5. doi: 10.1073/pnas.0914900107. Epub 2010 Feb 2.
MicroRNA (miRNA)-17-92 cluster (miR-17-92), containing seven individual miRNAs, is frequently amplified and overexpressed in lymphomas and various solid tumors. We have found that it is also frequently amplified and the miRNAs are aberrantly overexpressed in mixed lineage leukemia (MLL)-rearranged acute leukemias. Furthermore, we show that MLL fusions exhibit a much stronger direct binding to the locus of this miRNA cluster than does wild-type MLL; these changes are associated with elevated levels of histone H3 acetylation and H3K4 trimethylation and an up-regulation of these miRNAs. We further observe that forced expression of this miRNA cluster increases proliferation and inhibits apoptosis of human cells. More importantly, we show that this miRNA cluster can significantly increase colony-forming capacity of normal mouse bone marrow progenitor cells alone and, particularly, in cooperation with MLL fusions. Finally, through combinatorial analysis of miRNA and mRNA arrays of mouse bone marrow progenitor cells transfected with this miRNA cluster and/or MLL fusion gene, we identified 363 potential miR-17-92 target genes that exhibited a significant inverse correlation of expression with the miRNAs. Remarkably, these potential target genes are significantly enriched (P < 0.01; >2-fold) in cell differentiation, hematopoiesis, cell cycle, and apoptosis. Taken together, our studies suggest that overexpression of miR-17-92 cluster in MLL-rearranged leukemias is likely attributed to both DNA copy number amplification and direct up-regulation by MLL fusions, and that the miRNAs in this cluster may play an essential role in the development of MLL-associated leukemias through inhibiting cell differentiation and apoptosis, while promoting cell proliferation, by regulating relevant target genes.
miRNA(miRNA)-17-92 簇(miR-17-92)，包含七个个体 miRNA，在淋巴瘤和各种实体瘤中频繁扩增和过表达。我们发现，它也在混合谱系白血病（MLL）重排的急性白血病中频繁扩增，miRNAs 异常过表达。此外，我们表明，MLL 融合比野生型 MLL 更强烈地直接结合到该 miRNA 簇的基因座；这些变化与组蛋白 H3 乙酰化和 H3K4 三甲基化水平升高以及这些 miRNA 的上调有关。我们进一步观察到，该 miRNA 簇的强制表达增加了人细胞的增殖并抑制了凋亡。更重要的是，我们表明，该 miRNA 簇可以单独显著增加正常小鼠骨髓祖细胞的集落形成能力，特别是与 MLL 融合协同作用。最后，通过转染该 miRNA 簇和/或 MLL 融合基因的小鼠骨髓祖细胞的 miRNA 和 mRNA 阵列的组合分析，我们鉴定了 363 个潜在的 miR-17-92 靶基因，这些靶基因的表达与 miRNA 呈显著负相关。值得注意的是，这些潜在的靶基因在细胞分化、造血、细胞周期和凋亡中显著富集（P<0.01；>2 倍）。总之，我们的研究表明，MLL 重排白血病中 miR-17-92 簇的过表达可能归因于 DNA 拷贝数扩增和 MLL 融合的直接上调，并且该簇中的 miRNA 通过调节相关靶基因，在抑制细胞分化和凋亡、促进细胞增殖方面可能在 MLL 相关白血病的发生中发挥重要作用。
