The miR-17-92 cluster expands multipotent hematopoietic progenitors whereas imbalanced expression of its individual oncogenic miRNAs promotes leukemia in mice
The miR-17-92 cluster expands multipotent hematopoietic progenitors whereas imbalanced expression of its individual oncogenic miRNAs promotes leukemia in mice
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DOI：
10.1182/blood-2011-09-378687
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发表时间：
2012-05-10
期刊：
影响因子：
20.3
通讯作者：
Ben-David, Yaacov
中科院分区：
文献类型：
--
作者：
Li, Yanmei;Vecchiarelli-Federico, Laura M.;Ben-David, Yaacov
MiR-17-92簇及其编码的6个miRNAs在多种恶性肿瘤中频繁扩增和异常表达。这项研究表明，逆转录病毒介导的miR-17-92过表达促进了小鼠多潜能造血祖细胞的扩增。这些miR-17-92高表达小鼠的细胞系能够分化为髓系和淋巴系，并在移植到非肥胖型糖尿病/严重联合免疫缺陷小鼠后重现正常的淋巴系表型。然而，来自该座位的单个miRNAs的过度表达，即miR-19a或miR-92a，分别导致B细胞增生和红白血病。该簇的另一个成员miR-17与miR-92a共表达，可消除miR-92a诱导的红白血病发生。因此，我们确定了几个调控红系存活和增殖的新的miR-92a和miR-17靶基因，包括p53。该关键靶点的表达可显著抑制miR-92a红白血病细胞的生长。在小鼠和人类白血病中，p53失活导致致癌基因miR-92a和miR-19a选择性过表达，以及肿瘤抑制基因miR-17下调。这种miR-17-92的表达特征在表现出侵袭性临床表型的p53(-)B细胞慢性淋巴细胞白血病患者中也被检测到。这些结果表明，miR-17-92的不平衡表达，也是由p53介导的，直接改变了造血室。因此，对这种miRNA表达特征的检测应该有助于对表现出miR-17-92基因扩增的癌症的诊断和治疗。(血。2012年；119(19)：4486-4498)
The miR-17-92 cluster and its 6 encoded miRNAs are frequently amplified and aberrantly expressed in various malignancies. This study demonstrates that retroviral-mediated miR-17-92 overexpression promotes expansion of multipotent hematopoietic progenitors in mice. Cell lines derived from these miR-17-92-overexpressing mice are capable of myeloid and lymphoid lineage differentiation, and recapitulate the normal lymphoid phenotype when transplanted to nonobese diabetic/severe combined immunodeficiency mice. However, overexpression of individual miRNAs from this locus, miR-19a or miR-92a, results in B-cell hyperplasia and erythroleukemia, respectively. Co-expression of another member of this cluster miR-17, with miR-92a, abrogates miR-92a-induced erythroleukemogenesis. Accordingly, we identified several novel miR-92a and miR-17 target genes regulating erythroid survival and proliferation, including p53. Expression of this critical target results in marked growth inhibition of miR-92a erythroleukemic cells. In both murine and human leukemias, p53 inactivation contributed to the selective overexpression of oncogenic miR-92a and miR-19a, and down-regulation of tumor-suppressive miR-17. This miR-17-92 expression signature was also detected in p53(-) B-cell chronic lymphocytic leukemia patients displaying an aggressive clinical phenotype. These results revealed that imbalanced miR-17-92 expression, also mediated by p53, directly transforms the hematopoietic compartment. Thus examination of such miRNA expression signatures should aid in the diagnosis and treatment of cancers displaying miR-17-92 gene amplification. (Blood. 2012;119(19):4486-4498)