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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis
  • Case-Control Studies
  • Disease-Free Survival
  • Female
  • Gene Expression Regulation, Leukemic
  • Genes, p53
  • Genotype
  • Humans
  • Introns
  • Leukemia, Experimental / etiology
  • Leukemia, Experimental / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • RNA, Neoplasm / genetics*
  • Tumor Cells, Cultured


  • MIRN34 microRNA, human
  • MicroRNAs
  • RNA, Neoplasm
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2