Document Detail

Correcting miR-15a/16 genetic defect in New Zealand Black mouse model of CLL enhances drug sensitivity.
MedLine Citation:
PMID:  19723889     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-09-01
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  8     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-21     Completed Date:  2010-01-05     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2684-92     Citation Subset:  IM    
Pathology and Laboratory Medicine, New Jersey Medical School, MSB C512, Newark, NJ 07103, USA.
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MeSH Terms
Antineoplastic Agents / pharmacology
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, Inbred C57BL
MicroRNAs / genetics*
Piperazines / therapeutic use
RNA, Messenger / genetics
Reg. No./Substance:
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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