2010 OSU Molecular Life Sciences
Interdisciplinary Graduate Programs Symposium

 

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Talk on Thursday 04:30-04:45pm submitted by Urmila Santanam

Chronic lymphocytic leukemia modeled in mouse by targeted miR-29 expression

Urmila Santanam (MCDB, Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University), Nicola Zanesi, Alexey Efanov, Stefan Costinean, Alexey Palamarchuk (MVIMG, The Ohio State University), John Hagan, Stefano Volinia, Hansjuerg Alder (MVIMG, The Ohio State University), Laura Rassenti, Thomas Kipps, (Department of Medicine, University of California at San Diego), Carlo M Croce, Yuri Pekarsky (MVIMG, The Ohio State University)

Abstract:
B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the western world. Human B-CLL occurs in two forms: aggressive (showing high ZAP-70 expression and unmutated IgH VH) and indolent (showing low ZAP-70 expression and mutated IgH VH). We found that miR-29a is upregulated in indolent human B-CLL compared to aggressive B-CLL and normal CD19+ B-cells. To study the role of miR-29 in B-CLL, we generated Eµ-miR-29 transgenic mice overexpressing miR-29 in mouse B-cells. Flow cytometric analysis revealed a markedly expanded CD5+ population in the spleen of these mice starting at 2 months of age. 85% (34/40) of miR-29 transgenic mice exhibited an expanded population of CD5+ B-cells, a characteristic of the B-CLL phenotype. An average of 50% of the B-cell population in these transgenics were CD5 positive. At the age of 2 years these mice showed significantly enlarged spleens and an increase in CD5+ B-cell population of up to 100% of B-cells. Of 20 Eµ-miR-29 transgenic mice followed up to the age of 24-26 months, 4 (20%) developed frank leukemia and prematurely died from the disease. The expanded CD5+ B-cell population was found to be proliferative, with an increased number of cells in the S-phase of the cell cycle, compared to wild type CD19+ B-cells. These results suggest that deregulation of miR-29 can cause, or at least significantly contribute to the pathogenesis of indolent B-CLL.

Keywords: CLL, miR-29, transgenic mice