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Blood. 2010 May 27;115(21):4191-7. doi: 10.1182/blood-2009-07-234823. Epub 2010 Jan 20.

microRNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia.

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1
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department of Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectiology, Paracelsus Medical University Salzburg, Salzburg, Austria.

Abstract

In chronic lymphocytic leukemia (B-CLL), aberrations along the p53 axis lead to decreased overall survival and therapy resistance. Recent studies identified microRNA-34a (miR-34a) as a major downstream target of p53. We monitored the expression of miR-34a during disease development in a murine B-CLL model. miR-34a was up-regulated more than 20-fold during the leukemic but not during the preleukemic phase. In the human system, B-CLL cells also had 4.6-fold higher miR-34a expression compared with B cells of healthy controls. In B-CLL cells of patients with p53 aberrations, miR-34a expression was consistently low. The broad distribution of miR-34a levels in p53 wild-type patients prompted us to study the correlation between single nucleotide polymorphism 309 (SNP309) in the intronic promoter of MDM2 and miR-34a expression. B-CLL cells of patients with the SNP309 GG genotype had significantly lower miR-34a expression levels compared with patients with the TT genotype (P = .002). Low miR-34a levels were able to predict shorter time to treatment (P = .003) and were associated with an abbreviated lymphocyte doubling time. Further, overexpression of miR-34a in primary B-CLL cells induced apoptosis. These findings suggest miR-34a as a possible therapeutic avenue and a sensitive indicator of the activity of the p53 axis in B-CLL.

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PMID:
20089965
DOI:
10.1182/blood-2009-07-234823
[Indexed for MEDLINE]
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