Mir-34a As Part Of The Chemotherapy Resistance Network In Chronic Lymphocytic Leukemia.

Abstract The central role of 17p (TP53) deletion and 11q (ATM) deletion in identifying patients with CLL who respond sub-optimally to chemotherapy suggests a prominent role of the DNA damage pathway in CLL. MiR34s have been shown to be direct p53 targets and mediate some of the p53 dependent effects. To assess the role of miR-34s in a large cohort of CLL patients (n=60), we studied miR34a and miR34b/c levels together with a detailed assessment of the DNA damage response. While no expression of miR-34b/c could be detected, we found diverse expression levels of miR34a. MiR34a levels in CLL are up-regulated after DNA damage in the presence of functional p53. In contrast, cases with 17p deletion showed low levels of miR-34a and failure to up-regulate miR-34a after irradiation (median basal expression 2.5 (1.0–15.78) vs. 32.8 (0.89–337.8) in cases without 17p deletion (p<0.0001); after irradiation (median 5.8 (1.38–12.9) vs. 121.8 (1.79–608.9) (p<0.0001)). Since we also observed heterogeneous expression in cases without 17p deletion we investigated causes for impaired miR-34a expression in the absence of 17p- and found a strong correlation of impaired miR-34a levels with impaired DNA damage response, TP53 mutations (without 17p deletion) and F-refractory disease (in the absence of 17p deletion). Importantly, decreased miR-34a expression was associated with resistance to apoptosis and the expression levels differentiated subgroups of CLL with different rates of apoptosis after irradiation better than induction of p21/p53 or cytogenetics. In order to assess the relation of miR-34a to other known targets of p53 we compared the miR-34a expression to mRNA levels of p21, Bax and Puma. Up-regulation of miR-34a after irradiation was associated with induction of Bax and p21 but not with PUMA. Low expression of miR-34a is associated with p53 inactivation but also chemotherapy-refractory disease, impaired DNA damage response and apoptosis, irrespective of 17p deletion/TP53 mutation. The demonstration of decreased miR-34a basal levels in cases with TP53 mutation could be interpreted as an oncogenic function of mutated TP53, where the mutated protein acts to decrease miR-34a levels and thus leads to reduced apoptosis. The mechanism underlying miR-34a regulation and function warrants further study.