miRNA
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Leukemia is a malignant disease of the blood or bone marrow (hematological neoplasm), resulting from somatic mutations in DNA, followed by activation of oncogenes or deactivation of tumor suppressor genes that disrupt regulation of cellular apoptosis, differentiation, or division. Early landmark research in 1960 identified an abnormally short chromosome 22 involved in a translocation with chromosome 9 (termed the “Philadelphia Chromosome”), proving to be the first consistent chromosome abnormality found in any kind of malignancy. In recent years, information has emerged on the role of regulatory factors and cytokines affecting cell proliferation, implicating genes that encode various transcription factors as candidate genes involved in molecular regulation. One emerging area of leukemia research involves the interaction of miRNAs with target messenger RNAs in order to induce cleavage or inhibit message translation, particularly in genes that are linked to the pathogenesis of leukemia. Traditionally, miRNA expression has been tested using low-throughput techniques such as Northern-blot analysis and real-time PCR, but new developments in microarray technology now enable global profiling of all miRNA genes and their precursors in any sample type.
Jia Yu and colleagues (2006) analyzed the clustering properties of all 326 human miRNA genes from the Sanger miRNA registry (edition 7.1) and found that 148 genes were organized into a total of 51 clusters and subsequently, nine paralogous groups (based on detailed homologous analysis). Based on modeling results, the researchers then performed Northern blot analysis in diverse hematopoietic cell lines to identify those clusters involved in hematopoiesis and leukemia. This groundbreaking research was the first systematic report of hematopoietic expression profiling of human miRNA clusters, providing new insights into the function and mechanism of these clusters in diverse biological processes.
Title: Human microRNA clusters: genomic organization and expression profile in leukemia cell lines.
Authors: Yu J, Wang F, Yang GH, Wang FL, Ma YN, Du ZW, Zhang JW
Journal: Biochem Biophys Res Commun, Vol 349, Issue 1: 59-68
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George Calin and an international collaborative research team (2004) used miRNA profiling to reveal distinct signatures in B cell chronic lymphocytic leukemia (CLL), employing an oligo-based microarray featuring probes that corresponded to 245 human and mouse miRNA genes. This approach enabled the research team to identify significant differences in miRNome expression between CLL samples and normal CD5+ B cells. Results obtained with the miRNA-specific microarray were confirmed with Northern blot analysis and real-time RT-PCR. The group found that by using the miRNA microarray to study human CLL, they were able to demonstrate that fewer than 200 miRNA genes revealed distinct miRNA signatures associated with specific bio-pathological features, including factors related to disease prognosis.
Title: MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias.
Authors: Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, Shimizu M, Cimmino A, Zupo S, Dono M, Dell'Aquila ML, Alder H, Rassenti L, Kipps TJ, Bullrich F, Negrini M, Croce CM
Journal: Proc Natl Acad Sci U S A, Vol 101, Issue 32: 11755-60
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Yuri Pekarsky and other researchers from Ohio State University (including George Calin) and the University of California at San Diego (2006) examined expression of the TCL1 (T-cell leukemia/lymphoma 1) oncogene in B-cell chronic lymphocytic leukemia (B-CLL) to identify miRNAs involved in gene regulation. The researchers used microRNA microchips containing features that corresponded to 326 human and 249 mouse microRNA genes to reveal that three groups of B-CLL exhibited significant characteristic differences in miRNA expression patterns. Microarray analysis was followed by Western blot analysis to determine Tcl1 protein expression supporting the idea that Tcl1 overexpression correlates with aggressive B-CLL phenotype and 11q deletions. Further analyses depended upon the use of RNAhybrid software to determine which miRNA(s) targeted TCL1, identifying miR-29b and miR-181b, as the primary candidates. Real-time RT-PCR and luciferase assays were then used to conclude that the expression of these two specific miRNAs target Tcl1 expression at mRNA and protein levels. These findings suggest that expression of the Tcl1 protein is, at least in part, regulated by miR-29b and miR-181b.
Title: Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181.
Authors: Pekarsky Y, Santanam U, Cimmino A, Palamarchuk A, Efanov A, Maximov V, Volinia S, Alder H, Liu CG, Rassenti L, Calin GA, Hagan JP, Kipps T, Croce CM
Journal: Cancer Res, Vol 66, Issue 24: 11590-3
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Title: Genomics of chronic lymphocytic leukemia microRNAs as new players with clinical significance.
Authors: Calin GA, Croce CM
Journal: Semin Oncol, Vol 33, Issue 2: 167-73
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Title: Chronic lymphocytic leukemia: molecular genetics and animal models.
Authors: Pekarsky Y, Calin GA, Aqeilan R
Journal: Curr Top Microbiol Immunol. 2005;294:51-70.
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Title: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.
Authors: Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM
Journal: Proc Natl Acad Sci U S A, Vol 101, Issue 9: 2999-3004
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Title: Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice.
Authors: Costinean S, Zanesi N, Pekarsky Y, Tili E, Volinia S, Heerema N, Croce CM
Journal: Proc Natl Acad Sci U S A, Vol 103, Issue 18: 7024-9
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