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    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; IRRADIATION ; CELL ; Germany ; NETWORK ; SUPPORT ; COHORT ; cohort studies ; DISEASE ; PATIENT ; DNA ; MECHANISM ; FAMILY ; INDUCTION ; mechanisms ; MEMBERS ; TARGET ; DELETION ; HUMANS ; resistance ; UP-REGULATION ; MUTATION ; chemotherapy ; leukemia ; inactivation ; p53 ; DAMAGE ; MUTATIONS ; DNA-DAMAGE ; BAX ; TARGETS ; TP53 ; ADULT ; FAMILIES ; CLL ; regulation ; LEVEL ; DNA damage ; female ; Male ; Aged ; Middle Aged ; Aged,80 and over ; TP53 mutation ; 17p deletion ; *Gene Expression Regulation,Leukemic ; Apoptosis Regulatory Proteins/genetics/metabolism ; Apoptosis/radiation effects ; bcl-2-Associated X Protein/genetics/metabolism ; Chromosome Deletion ; Chromosomes,Human,Pair 17/genetics/metabolism ; DNA Damage/radiation effects ; Leukemia,Lymphocytic,Chronic,B-Cell/genetics/*metabolism ; MicroRNAs/*biosynthesis/genetics ; Proto-Oncogene Proteins/genetics/metabolism ; RNA,Neoplasm/*biosynthesis/genetics ; Tumor Cells,Cultured ; Tumor Suppressor Protein p53/genetics/metabolism ; Up-Regulation/radiation effects
    Abstract: 17p (TP53) deletion identifies patients with chronic lymphocytic leukemia (CLL) who are resistant to chemotherapy. The members of the miR-34 family have been discovered to be direct p53 targets and mediate some of the p53-dependent effects. We studied miR-34a and miR-34b/c expression in a large cohort to define their potential role in refractory CLL. While no expression of miR-34b/c could be detected, we found variable expression levels of miR-34a. miR-34a levels were up-regulated after DNA damage in the presence of functional p53, but not in cases with 17p deletion (P 〈 .001). We found a strong correlation of low miR-34a levels with impaired DNA damage response, TP53 mutations (without 17p deletion), and fludarabine-refractory disease (also in the absence of 17p deletion). Up-regulation of miR-34a after irradiation was associated with induction of Bax and p21, but not Puma. CLL cells with reduced miR-34a expression showed increased viability after DNA damage independently of 17p status. Therefore, low expression of miR-34a in CLL is associated with p53 inactivation but also chemotherapy-refractory disease, impaired DNA damage response, and apoptosis resistance irrespective of 17p deletion/TP53 mutation. The elucidation of mechanisms underlying miR-34a regulation and overcoming its role in chemotherapy resistance warrant further study.
    Type of Publication: Journal article published
    PubMed ID: 18941118
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