Distinct microRNA expression profiles in acute myeloid leukemia with common translocations
Distinct microRNA expression profiles in acute myeloid leukemia with common translocations
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DOI：
10.1073/pnas.0808266105
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发表时间：
2008-10-07
影响因子：
11.1
通讯作者：
Chen, Jianjun
中科院分区：
文献类型：
--
作者：
Li, Zejuan;Lu, Jun;Chen, Jianjun
MicroRNAs(MiRNAs)被认为是癌症的重要调节因子。在这里，我们报告了52例具有常见易位的急性髓系白血病(AML)样本的全基因组miRNA表达分析，包括t(8；21)/AML1(RUNX1)-ETO(Runx1t1)、inv(16)/Cbfb-MYH11、t(15；17)/PML-RARA和MLL重排。T(15；17)、MLL重排和核心结合因子(CBF)AML的miRNA表达模式不同，包括t(8；21)和inv(16)样本。至少两个(即miR-126/126*)、三个(即miR-224、miR-368和miR-382)和七个(miR-17-5p和miR-20a，加上上述五个)miRNAs的表达签名可以分别准确地区分CBF、t(15；17)和MLL重排AML。我们进一步表明，在CBF AML中miR-126/126*的高表达与启动子去甲基化有关，而与基因组位点的扩增或突变无关。我们的功能获得和丧失实验表明，miR-126/126*单独和AML1-ETO协同作用，可能通过靶向肿瘤抑制因子Polo-like kinase2(PLK2)，抑制了AML细胞的凋亡，提高了AML细胞的活力，并增强了正常小鼠骨髓祖细胞的集落形成能力。我们的结果表明，miRNA表达的特异性变化将AML与常见易位区分开来，并暗示特定ILL的解除调控可能在白血病的发生发展中发挥作用，并伴随着这些相关的基因重排。
MicroRNAs (miRNAs) are postulated to be important regulators in cancers. Here, we report a genome-wide miRNA expression analysis in 52 acute myeloid leukemia (AML) samples with common translocations, including t(8;21)/AML1(RUNX1)-ETO(RUNX1T1), inv(16)/CBFB-MYH11, t(15;17)/PML-RARA, and MLL rearrangements. Distinct miRNA expression patterns were observed for t(15;17), MLL rearrangements, and core-binding factor (CBF) AMLs including both t(8;21) and inv(16) samples. Expression signatures of a minimum of two (i.e., miR-126/126*), three (i.e., miR-224, miR-368, and miR-382), and seven (miR-17-5p and miR-20a, plus the aforementioned five) miRNAs could accurately discriminate CBF, t(15;17), and MLL-rearrangement AMLs, respectively, from each other. We further showed that the elevated expression of miR-126/126* in CBF AMLs was associated with promoter demethylation but not with amplification or mutation of the genomic locus. Our gain- and loss-of-function experiments showed that miR-126/ 126* inhibited apoptosis and increased the viability of AML cells and enhanced the colony-forming ability of mouse normal bone marrow progenitor cells alone and particularly, in cooperation with AML1-ETO, likely through targeting Polo-like kinase 2 (PLK2), a tumor suppressor. Our results demonstrate that specific alterations in miRNA expression distinguish AMLs with common translocations and imply that the deregulation of specific Ill may play a role in the development of leukemia with these associated genetic rearrangements.