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The Role of Microrna in Human Leukemia: a Review

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The Role of Microrna in Human Leukemia: a Review Leukemia (2009) 23, 1257–1263 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu SPOTLIGHT REVIEW The role of microRNA in human leukemia: a review S Yendamuri1 and GA Calin2 1Department of Thoracic Surgery, Roswell Park Cancer Institute, Buffalo, NY, USA and 2Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA MicroRNAs (miRNAs or miRs) are 18–22-nucleotide non-coding target. If the sequence is a perfect match, the final result seems RNAs that have emerged as a new paradigm of epigenetic to be target mRNA degradation in a manner similar to siRNA- regulation in both normal development and cellular function, and in the pathogenesis of human disease including cancer. induced gene expression silencing. This seems to be the This review summarizes the current literature of mechanism of predominant mechanism in plants. A less than perfect match gene regulation by miRNA and their role in hematopoiesis and may result in inefficient translation leading to effective down- leukemogenesis. An understanding of these processes sug- regulation of the gene, a mechanism more common in gests further avenues for research to understand gene regula- animals.7–9 Isolated examples of miRNA leading to upregulation tion and miRNA-based therapeutic approaches. of genes have been reported.10 Leukemia (2009) 23, 1257–1263; doi:10.1038/leu.2008.382; The mechanism of translational repression is known only published online 15 January 2009 11 Keywords: microRNA; non-coding RNA; microarray; partially. The mRNA segments that miRNAs bind seem to be mostly in the 30UTRs of genes. In these regions, typically, several miRNA-binding sequences seem to act in concert. The combined effect of this binding seems to depend on the distance between the binding sequences and the number of binding 12 0 MicroRNAs regulate gene expression sequences. However, if these sequences are placed in the 5 end or even in the exons, repression still takes place, suggesting 1 that sequence rather than location may be the over-riding factor. Discovered in Caenorhabditis elegans in 1993, microRNAs 30UTR binding may affect translation both at the initiation step (miRNAs) have emerged as a major mechanism of epigenetic and at the post-initiation translation. It has been shown that regulation in forms of life as diverse as algae and human beings. reporter genes with the m7G-capped mRNA are repressed by Although the number of miRNAs in lower life forms is about miRNAs but not those with internal ribosome entry site 100–200, B1000 miRNAs are predicted to be present in sequences, suggesting some effect of miRNAs on initiation.13 humans. Bioinformatics predicts that about one-third of all However, some miRNAs cause repression of mRNA with protein-coding genes are regulated by miRNAs. Therefore, it is internal ribosome entry site sequences.14 Also, polysomes co- no surprise that miRNAs are being shown to regulate all facets of sediment with miRNAs and their target mRNAs, suggesting an normal and abnormal cellular activity. influence on the elongation process of translation.15,16 Some MicroRNA precursors (pre-miRNA) are transcripts that often evidence also exists that miRNA may regulate repression by contain several miRNAs. These are processed by Drosha (a preventing 60S subunit joining.17 Ribonuclease III) to form pre-miRNAs, B70 nucleotide hairpin Early in the investigation of miRNA-mediated gene regulation, structures. Drosha partners include DiGeorge syndrome critical 2 the over-riding theme invoked was that miRNAs alter gene region 8 (DGCR8). After being transported to the cytoplasm by expression in animals purely by translational repression. Exportin-5, these pre-miRNAs are processed by Dicer (another 3 However, an increasing body of evidence suggests that Ribonuclease III) into dsRNA with two nucleotide overhangs. 4 miRNA–mRNA interaction leads to a de-stabilization of mRNA Dicer partners include TAR RNA binding protein. Single-strand leading to alteration in mRNA levels, albeit modest. Although RNAs from these dsRNA associate with several proteins to form enough evidence of alteration of transcript levels exists in SPOTLIGHT the RNA induced silencing complex (RISC), which is thought to 18 5 microarray experiments, the exact mechanism has only been be responsible for regulation of translation of the target genes. partially elucidated in Drosophila melanogaster and zebra- Prominent components of the RISC include the argonaute family 19,20 6 fish. Experiments have shown that the P body protein GW of proteins. The final effect of the miRNA on a specific target is 182 marks the mRNA for decay. This is based on an interaction both sequence specific and context specific. Although a with Argonaute 1, a key player in miRNA activity. Also, miR- minimum of six nucleotides need to be a perfect match 430 induces deadenylation and decay of several mRNA during (nucleotide 2–8), the preceding and succeeding nucleotides zebrafish embryogenesis. Therefore, the mechanism of regula- need not be so. In fact, in some instances, a mismatch ‘bulge’ tion of gene expression by miRNAs is multi-faceted and still region seems to be required. Following the bulge, complemen- being elucidated. tarity at nucleotide 13–16 seems to enhance repression of the Correspondence: Dr GA Calin, Department of Experimental Therapeutics Unit 36, The University of Texas MD Anderson Cancer Technologies to investigate the miRNA expression in normal Center, 1515 Holcombe Blvd, Houston, TX 77030, USA. and malignant tissues E-mail: [email protected] or Dr S Yendamuri, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. E-mail: [email protected] The most commonly used high-throughput technique for the Received 20 October 2008; revised 28 November 2008; accepted 8 genome-wide assessment of miRNA expression levels in a large December 2008; published online 15 January 2009 number of samples is represented by miRNA microarrays.21–23 The role of microRNA in human leukemia S Yendamuri and GA Calin 1258 Several technical variants of miRNA arrays have been indepen- uses on the slide application of the Klenow fragment of the DNA dently developed in the past few years, and the main differences polymerase I to extend miRNAs hybridized to DNA probes.29 between them are the oligo-probe design, the probe immo- Generation of small RNA libraries and deep sequencing using a bilization chemistry, the sample labeling and the microarray high-throughput approach is another way of identification and chip signal detection method. miRNA expression analysis can relative quantification of miRNAs.30 Each of these techniques also be assessed by alternative methodologies. For example, the has its strengths and weaknesses (Table 1), and the confirmatory bead-based flow cytometric technique,24 characterized by use of a second independent technique is mandatory at the highly specific solution-phase probe/target hybridization present time to identify false-positive/negative data for all the kinetics, is able to profile only limited subsets of miRNAs different assays undertaken. (o100 miRNAs/profile) due to the limitations of the color- decoding system per sample; quantitative RT-PCR specific either miRNAs regulate hematopoiesis for precursor miRNA25 or for active miRNA26 is a highly sensitive methodology, requiring small amounts of starting The hematopoietic system is a good model because of the material for the rapid and quantitative analysis of a subset of principle that a common progenitor cell can give rise to cells of miRNAs, and is excellent for microarray data validation or for different lineages. This process of commitment is governed by the study of a limited number of miRNAs. The miRNA serial the alteration in expression of several genes together. Given the analysis of gene expression (miRAGE) approach, the genome- ability of a single miRNA to control the expression of several wide miRNA analysis with serial analysis of gene expression,27 genes, it is conceptually attractive to propose that miRNAs is used for both the analysis of known miRNAs and discovery of SPOTLIGHT regulate this process (Figure 1). unknown miRNAs with large amounts of computational and bioinformatics efforts for the analysis of the obtained tagged sequences. The invader assay directly detects specific RNA Lymphoid development molecules using an isothermal signal amplification process with a fluorescence resonance energy transfer-based fluorescence The first evidence that miRNAs may be involved in regulation readout.28 The RNA primed, array-based Klenow enzyme assay of hematopoiesis came from Chen et al.31 In a series of Table 1 Comparison of the methods used for the identification and detection of microRNAs Technique Sensitivity Specificity Throughput Reproducibility Steps in method miRna microarrays Medium Low Very high Very high Medium Real-time PCR High High Medium High Medium Bead-based flow cytometry Low High High Medium Many Northern blotting Low Very low Low Medium Many In situ hybridization Low High Low Medium Few Deep sequencing Medium High High High Many RAKEa Low Low High Very high Few Invader assay Medium Medium Low Low Few aRNA primed array-based Klenow enzyme assay. Hematopoeitic stem cell Common lymphoid progenitor Common myeloid progenitor miR-223 miR-142 miR150 Double negative pro-B Erythrocyte megakaryocyte Granulocyte monocyte progenitor progenitor miR221 miR223 miR222 miR223 miR424 miR17~92 miR150 miR150 miR155 miR146 Double positive pre-B Erythroid Megakaryocyte Granulocyte Monocyte progenitor progenitor progenitor progenitor miR-181 CD8 CD4 Mature B RBC Platelets Granulocytes Monocyte/ Macrophage Figure 1 Known microRNA (miRNA) that regulate hematopoeisis. miRNA in bold italics promote differentiation along the pathway. Conversely, miRNA in regular font inhibit differentiation along the pathway. Leukemia The role of microRNA in human leukemia S Yendamuri and GA Calin 1259 experiments they showed that different hematopoietic tissues miR-424, which is located on chromosome X.37 The expression had different levels of expression of three miRNAs: miR-181, of miR-424 is also controlled by PU.1.
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