microRNA-34a expression correlates with MDM2 SNP309 polymorphism and treatment-free survival in chronic lymphocytic leukemia.
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.
Asslaber
Daniela
D
Laboratory for Immunological and Molecular Cancer Research, 3rd Medical Department of Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectiology, Paracelsus Medical University Salzburg, Salzburg, Austria.
Piñón
Josefina D
JD
Seyfried
Irina
I
Desch
Petra
P
Stöcher
Markus
M
Tinhofer
Inge
I
Egle
Alexander
A
Merkel
Olaf
O
Greil
Richard
R
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D016158:Genes, p53; D005838:Genotype; D006801:Humans; D007438:Introns; D007942:Leukemia, Experimental / Q000209:etiology / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012334:RNA, Neoplasm / Q000235:genetics*; D014407:Tumor Cells, Cultured
C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012334:RNA, Neoplasm; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2