In chronic lymphocytic leukemia (B-CLL), aberrations along the p53 axis lead to decreased overall survival and therapy resistance. Recent studies identified microRNA34a (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 upregulated 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. Introduction microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by near-perfect base pairing with target mRNAs resulting in either degradation or silencing. 1,2 They play important roles in leukemias 3-5 and solid malignancies 6,7 and offer elegant possibilities for future therapeutic intervention. [8][9][10][11] Recently, the miR-34 family, consisting of miR-34a, b, and c, has been described as a downstream target of the tumor suppressor p53. [12][13][14][15][16][17] Overexpression of miR-34 can evoke p53-like effects, including senescence, apoptosis, or cell cycle arrest depending on the cell type analyzed. [12][13][14][15][16][17] In normal unstressed cells, p53 functions are tightly controlled mainly by the ubiquitin ligase murine double minute zprotein (MDM2). It has been demonstrated that single nucleotide polymorphism 309 (SNP309) resulting in a T to G alteration within the first intron of the intronic MDM2 gene promoter, henceforth termed SNP309, can enhance MDM2 expression and therefore lead to a reduced tumor suppressor function of p53. 18 SNP309 has been shown to affect onset of disease or tumor progression in various cancer types including gastric carcinoma, 19 colorectal cancer, 20 and also chronic lymphocytic leukemia (B-CLL). 21 B-CLL is the most prevalent lymphoma in the western world, and p53 deletion has dramatic effects such as therapy resistance and reduced median overall survival from 111 to 32 months. 22 Two independent recent studies suggest that p53 mutations, which go undetected in routine sample workup, are equivalent to p53 deletions in their frequency and prognostic impact. 23,24 In B-CLL miR-34b and c are not expressed, and several studies have confirmed the dependence of miR-34a expression on p53 status in this disease. [25][26][27] However, the reasons for low miR-34a expression in many B-CLL cases without p53 deletions or mutations and its role ...

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