| Correcting miR-15a/16 genetic defect in New Zealand Black mouse model of CLL enhances drug sensitivity. | |
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MedLine Citation:
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PMID: 19723889 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Alterations in the human 13q14 genomic region containing microRNAs mir-15a and mir-16-1 are present in most human chronic lymphocytic leukemia (CLL). We have previously found the development of CLL in the New Zealand Black murine model to be associated with a point mutation in the primary mir-15a/16-1 region, which correlated with a decrease in mature miR-16 and miR-15a levels. In this study, addition of exogenous miR-15a and miR-16 led to an accumulation of cells in G(1) in non-New Zealand Black B cell and New Zealand Black-derived malignant B-1 cell lines. However, the New Zealand Black line had significantly greater G(1) accumulation, suggesting a restoration of cell cycle control upon exogenous miR-15a/16 addition. Our experiments showed a reduction in protein levels of cyclin D1, a miR-15a/16 target and cell cycle regulator of G(1)/S transition, in the New Zealand Black cell line following miR-15a/16 addition. These microRNAs were shown to directly target the cyclin D1 3' untranslated region using a green fluorescent protein lentiviral expression system. miR-16 was also shown to augment apoptosis induction by nutlin, a mouse double minute 2 (MDM2) antagonist, and genistein, a tyrosine kinase inhibitor, when added to a B-1 cell line derived from multiple in vivo passages of malignant B-1 cells from New Zealand Black mice with CLL. miR-16 synergized with nutlin and genistein to induce apoptosis. Our data support a role for the mir-15a/16-1 cluster in cell cycle regulation and suggest that these mature microRNAs in both the New Zealand Black model and human CLL may be targets for therapeutic efficacy in this disease. |
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Authors:
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Erica Salerno; Brian J Scaglione; Frederick D Coffman; Brian D Brown; Alessia Baccarini; Helen Fernandes; Gerald Marti; Elizabeth S Raveche |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-09-01 |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 8 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2009 Sep |
Date Detail:
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Created Date: 2009-09-21 Completed Date: 2010-01-05 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 2684-92 Citation Subset: IM |
Affiliation:
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Pathology and Laboratory Medicine, New Jersey Medical School, MSB C512, Newark, NJ 07103, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antineoplastic Agents / pharmacology Apoptosis Base Sequence Cyclin D1 / genetics DNA Primers Disease Models, Animal* Drug Screening Assays, Antitumor Genistein / therapeutic use Imidazoles / therapeutic use Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy, genetics*, pathology Mice Mice, Inbred C57BL MicroRNAs / genetics* Piperazines / therapeutic use RNA, Messenger / genetics |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/DNA Primers; 0/Imidazoles; 0/MicroRNAs; 0/Piperazines; 0/RNA, Messenger; 0/nutlin 3; 136601-57-5/Cyclin D1; 446-72-0/Genistein |
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