Abstract 4045: Restoring miR-15a/16 in the NZB mouse model of chronic lymphocytic leukemia reduces disease and enhances drug sensitivity

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8_Supplement), p.4045-4045
• Main Authors: Salerno, Erica, Yuan, Yao, Coffman, Frederick D., Scaglione, Brian J., Brown, Brian D., Bonci, Desiree, Raveche, Elizabeth S.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM10-4045

Alterations in the human 13q14 genomic region containing the microRNAS, mir-15a and mir-16-1 are present in a majority of human chronic lymphocytic leukemia (CLL). We have previously found the development of CLL in the New Zealand Black (NZB) murine model to be associated with a point mutation in the primary mir-15a/16-1 region, as well as a decrease in both mature miR-16 and miR-15a levels. Addition of exogenous miR-15a and miR-16 led to an accumulation of cells in G1 in both normal B cell and NZB-derived malignant B-1 cell lines. However, the NZB line had a significantly greater G1 accumulation, suggesting a restoration of cell cycle control upon exogenous miR-15a/16 addition. Our experiments demonstrated a reduction in protein levels of cyclin D1, a miR-15a/16 target and cell cycle regulator of G1/S transition, in the NZB cell line following miR-15a/16 addition. These miRNAs were shown to directly target the cyclin D1 3′UTR using a GFP lentiviral sensor. In vivo restoration of NZB with a miR-16-producing lentiviral vector resulted in the depletion of endogenous-transduced malignant aneuploid B-1 cells. In addition, experimentally increasing miR-16 in either a drug-resistant malignant NZB B-1 cell line or ex vivo splenic NZB B-1 cells augmented apoptosis induction by the following agents: genistein, a soy isoflavone tyrosine kinase inhibitor; nutlin, an MDM2 antagonist; and 2-fluoroadenine-9-B-D-arabinofuranoside, a purine nucleotide analog. Our data support a role for miR-16 in apoptosis induction, either alone, or in synergy with chemotherapeutic agents to increase their efficacy in murine CLL cells. This research was funded in part by the NJCCR pre-doctoral fellowship awarded to E.S. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4045.