Article

Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression

Department of Molecular Virology, Ohio State University School of Medicine, Ohio State University, Columbus, OH 43210, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 07/2010; 107(27):12210-5. DOI: 10.1073/pnas.1007186107
Source: PubMed

ABSTRACT B-cell chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world, occurs in two forms, aggressive (showing for the most part high ZAP-70 expression and unmutated IgH V(H)) and indolent (showing low ZAP-70 expression and mutated IgH V(H)). We found that miR-29a is up-regulated in indolent human B-CLL as compared with aggressive B-CLL and normal CD19(+) B cells. To study the role of miR-29 in B-CLL, we generated Emu-miR-29 transgenic mice overexpressing miR-29 in mouse B cells. Flow cytometric analysis revealed a markedly expanded CD5(+) population in the spleen of these mice starting at 2 mo of age, with 85% (34/40) of miR-29 transgenic mice exhibiting expanded CD5(+) B-cell populations, a characteristic of B-CLL. On average, 50% of B cells in these transgenic mice were CD5 positive. At 2 y of age the mice showed significantly enlarged spleens and an increase in the CD5(+) B-cell population to approximately 100%. Of 20 Emu-miR-29 transgenic mice followed to 24-26 mo of age, 4 (20%) developed frank leukemia and died of the disease. These results suggest that dysregulation of miR-29 can contribute to the pathogenesis of indolent B-CLL.

Download full-text

Full-text

Available from: Stefan Costinean, Feb 03, 2015
0 Followers
 · 
129 Views
  • Source
    • "Although aberrant expression of some miRNAs occurred in CRC metastasis, such as miR-17, miR-19a and miR-21 (Zhang et al, 2012), miR-31 (Wang et al, 2010), miR-103 and miR-107 (Chen et al, 2012), miR-143 and miR-145 (Arndt et al, 2009) and miR-200 family (Hur et al, 2012), novel candidates with a definite molecular mechanism in promoting CRC metastasis need to be further explored. It was reported that the dysregulation of miR-29a performed a diverse function in different types of cancer (Gebeshuber et al, 2009; Muniyappa et al, 2009; Eyholzer et al, 2010; Santanam et al, 2010; Cui et al, 2011; Kong et al, 2011; Teichler et al, 2011). It was previously believed that high serum expression of miR-29a in CRC patients was correlated with liver metastasis, and was proposed as a novel biomarker for early and noninvasive diagnosis of CRC (Wang and Gu, 2012). "
    W Tang · Y Zhu · J Gao · J Fu · C Liu · Y Liu · C Song · S Zhu · Y Leng · G Wang · W Chen · P Du · S Huang · X Zhou · J Kang · L Cui
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Growing evidence suggests that miR-29a has an important role in regulating tumourigenesis and development of various types of cancer. However, the role and the underlying mechanism of miR-29a in colorectal cancer (CRC) remain largely unknown. Methods: MiR-29a targeted gene was identified by the luciferase assay and western blot. MiR-29a function was analysed by invasion assays and the orthotopic transplantation mouse model. The miR-29a pathway was assayed by real-time PCR, western blot and chip analysis. Results: KLF4 was identified as a direct target gene of miR-29a. MiR-29a promoted CRC cell invasion, which was blocked by re-expression of KLF4. In addition, MMP2 was identified as a novel direct target of KLF4. Both miR-29a overexpression and KLF4 knockdown promoted MMP2 expression but inhibited E-cadherin expression. Furthermore, clinical data indicated that both miR-29a high expression and KLF4 mRNA low expression were associated with metastasis and poor prognosis in CRC patients, and KLF4 protein expression was inversely correlated with MMP2 but positively correlated with E-cad protein expression. Conclusion: Increased expression of miR-29a promoted CRC metastasis by regulating MMP2/E-cad through direct targeting KLF4, which highlights the potential of the miR-29a inhibitor as a novel agent against CRC metastasis.
    British Journal of Cancer 11/2013; 110(2). DOI:10.1038/bjc.2013.724 · 4.82 Impact Factor
  • Source
    • "), a miRNA associated with indolent B cell chronic lymphocytic leukemia . The transgenic expression of miR-29 in B cells and HSCs leads to CLL and acute myeloid leukemia (AML), respectively (Han et al. 2010; Santanam et al. 2010), which suggests that miR-B4 could be important for BLV-induced B cell tumorigenesis. Interestingly, the EBV miRNA miR-BART1-3p shares its minimal seed sequence (nts 2–7) with miR-29, suggesting that at least some targets are likely to be common for miR-BART1-3p and miR-29 (Skalsky et al. 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) are a class of small noncoding RNAs expressed by plants, animals, and some viruses. miRNAs generally function as part of miRNA-induced silencing complexes to modestly repress mRNAs with imperfect sequence complementarity. Over the last years, many different roles of miRNA mediated regulation in the life cycles of mammalian viruses have been uncovered. In this chapter, I will mainly explore four different examples of how cellular miRNAs interact with viruses: the role of miR-155 in viral oncogenesis, viral strategies to eliminate cellular miR-27, the contribution of miR-122 to the replication of hepatitis C virus, and miRNAs as an experimental tool to control virus replication and vector transgene expression. In the final part of this chapter, I will give a brief overview of virally encoded microRNAs.
    Current topics in microbiology and immunology 01/2013; 371:201-227. DOI:10.1007/978-3-642-37765-5_8 · 3.47 Impact Factor
  • Source
    • "Members of this family have been shown to be silenced or down - regulated in many different types of cancer and have subsequently been attributed tumor - suppressing properties , although exceptions have been described where miR - 29s have tumor - promoting functions ( Pekarsky and Croce 2010 ; Santanam et al . 2010 ) . Experimental evidence suggest that putative targets of miR - 29 family includes , the anti - apoptotic factor BCL - 2 ( Mott et al . 2007 ) , T - cell leukemia / lymphoma protein 1A ( TCL1A ) oncogene , found to be disrupted in many T - cell leukemias ( Pekarsky et al . 2006 ) and DNA methyltransferasesDNMT3A and DNMT3B , which are "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) are a recently discovered class of small RNA molecules that regulate gene expression at the post-transcriptional level.MiRNAs maintain the appropriate balance important process in tumor development including proliferation, differentiation,apoptosis, senescence, angiogenesis and metastasis. MiRNA deregulationmayhave profoundconsequences in the cell functionality, especially because individual miRNAs can modify the expression of multiples proteins. MiRNAs exhibit differential expression levels in cancer and have demonstrated capability to affect cellular transformation, acting either as oncogenes or tumour suppressors.In this chapter we discuss the role as oncogenes or tumor suppressor of miRNA in cancer from a traditional point of view considering them astumor suppressors when they impair tumor progression or as oncogenes when they promote it. However, since the effects of the miRNAs are intrinsically pleiotropic, this classification should be considered flexible. Interestingly, miRNA expression profiles may become useful biomarkers for cancer diagnostics and prediction. In addition, miRNA therapy could be a powerful tool for cancer prevention and therapeutics.Although the microRNA era started only a few years ago, it has brought great promise for clinical applications of many human pathologies, including cancer.
    MicroRNAs in Medicine, Edited by Charlie Lawrie, 01/2013: chapter 14, Section III: pages 215-222; John Wiley &Sons, Inc.., ISBN: 978-1-1183-0039-8
Show more