The miR-17-92 cluster expands multipotent hematopoietic progenitors whereas imbalanced expression of its individual oncogenic miRNAs promotes leukemia in mice

Abstract

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. Coexpression of another member of this cluster miR-17, with miR-92a, abrogates miR92a-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 miR19a, and down-regulation of tumorsuppressive 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) IntroductionHematopoiesis is regulated by genes governing cellular proliferation, differentiation, and apoptosis. Recent studies demonstrated that microRNAs (miRNAs), an important class of small nonprotein-coding RNA molecules, play a critical role during hematopoiesis by post-transcriptionally regulating the expression of critical genes involved in these processes. 1,2 Many miRNAs are specifically expressed in hematopoietic cells and their expression is dynamically regulated during hematopoiesis and lineage commitment. 1,3 Therefore it is not surprising that aberrant miRNA expression has frequently been observed in a wide variety of human cancers [4][5][6] and has been implicated in the initiation and progression of both solid and hematopoietic tumors. 7,8 Although the oncogenic and tumor-suppressor functions of miRNAs are not completely understood, it is known that miRNAs regulate the expression of key genes governing malignant transformation. 9,10 Recent studies revealed that aberrant miRNA expression may directly contribute to tumorigenesis. Our group identified the miR-17-92 locus as a retroviral insertion site in a subset of erythroleukemias induced in p53 knockout mice. 11 The miR-17-92 cluster produces a single polycistronic primary transcript processed to yield 6 individual mature miRNAs; miR-17, miR-18, miR-19a, miR-19b, miR-20, and miR-92a. This cluster is located on huma...

Variations of MicroRNAs in Human Placentas and Plasma From Preeclamptic Pregnancy

“…It has been proposed that members in the same miRNA cluster might have similar functions. 27 In the present study, we chose miR-17-92 cluster to perform the functional study in human trophoblast cells. The miR-17-92 cluster has been reported to be frequently amplified in malignancies and solid tumors, 28 and its oncogenic activity has been well demonstrated.…”

Novel regulation and functional interaction of polycistronic miRNAs

“…For example, the oncogenic mir-17 92 cluster encodes miRNAs that target both positive and negative cell cycle regulators and pro-and anti-apoptotic proteins (O'Donnell et al 2005;Hossain et al 2006;Zhang et al 2006;Shan et al 2009;Li et al 2012). Moreover, miR-92a and miR-17 have antagonistic effects: Although overexpression of miR92a in mice caused erythroleukemia, coexpression of miR-17 abrogated this effect (Li et al 2012). Similarly to the context-dependent differences in function of miRNAs from the mir-17 92 cluster, we show here that miR-11 and miR-998 carry different functions.…”

Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A

“…These miRs are members of the miR-17-92 cluster on chromosome 13. 29,30 Luciferase assays with NIH-3T3 cells transiently transfected with reporter genes containing these seed sequences, along with miR-17 ( Figure 5A, top 2 rows) or miR-19a ( Figure 5A, bottom 2 rows) expression vectors were PBMCs, given bi-weekly injections of splenic stromal cell conditioned media (ie, SS) (1 ml) or (B) daily injections of IL-6, treated with resiquimod (100 mg) with or without actemra (100 mg), and euthanized 1 week later. CLL cells in spleens were calculated from total cell counts in a hemocytometer and percentages of human CD5 consistent with regulation of TLR7 and TNFA by miR-17 and miR-19a.…”

“…29 IL-6 might then inhibit TLR7 signaling through miR. miRs are 22 nucleotide noncoding RNA molecules that bind to seed sequences in 39-UTRs of mRNAs, preventing their transcription in ribosomes.…”