miR-34a as part of the resistance network in chronic lymphocytic leukemia

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 upregulated 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. IntroductionChronic lymphocytic leukemia (CLL) is the most frequent type of leukemia in the Western world and is characterized by a highly variable clinical course. 1-3 Traditionally, therapy has been used for advanced stage or symptomatic disease and consists of chemotherapy with alkylating agents, purine analogs, and more recently antibody-chemotherapy combinations. Different molecular prognostic factors have been used to predict time to treatment, likelihood of responding to chemotherapy and survival time. [4][5][6] A central role of the DNA damage-response pathway and particularly p53 has been suggested by the prognostic role of 17p and 11q deletions in CLL. In the critical regions, 2 prominent genes are located that are involved in the cells' response to DNA damage (eg, induced by chemotherapy). ATM and TP53 have been shown to be deleted in virtually all cases with deletion 11q and 17p, respectively. In contrast, TP53 and ATM are mutated in different proportions. [7][8][9][10][11] There is growing evidence that mutations of TP53 or ATM also in the absence of deletion of 17p or 11q are associated with poor prognosis as a result of impaired response to chemotherapy. 12 Particularly loss of 17p has been associated with failure to respond to chemotherapy and short event-free and overall survival. 8,13,14 However, in chemotherapy-refractory CLL, only 30% to 40% percent of cases will have a deletion or mutation of TP53, whereas approximately one-third of the remaining cases have a deletion of 11q. 15 This suggests that almost half of the refractory cases cannot be explained by a direct defect of p53 or loss of 11q. A hypothesis explaining resistance in these cases might be defects ...

The miR-34 family in cancer and apoptosis

“…This was associated with p53 mutations, chemotherapy (fludarabine)-refractory disease, impaired DNA damage response and decreased apoptosis. 64 Mraz et al 65 also found that miR-34a is consistently downregulated in CLL with p53 mutations. This implies that the detection of miR-34a expression may potentially be used as a predictor of therapy response.…”

“…For example Lu et al 63 could show that the expression analysis of 217 miRNAs is superior to genome-wide analysis of mRNAs for the purpose of classifying tumors. Zenz et al 64 found that the expression of miR-34a is decreased in CLL. This was associated with p53 mutations, chemotherapy (fludarabine)-refractory disease, impaired DNA damage response and decreased apoptosis.…”

MicroRNAs: Biogenesis, Roles for Carcinogenesis and as Potential Biomarkers for Cancer Diagnosis and Prognosis

“…However, in some tumourigenesis it still harbours either acquired or inherent mechanisms for resistance due to miRNAs regulation of multiple biological functions and it seems plausible that miRNA expression may guide the drug response. These statements have been reviewed by Zenz et al (2009) who found that the low expression of miR-34a in CLL is associated with p53 inactivation due to chemotherapy-refractory disease, which impaired the DNA damage response and apoptosis resistance irrespective of TP53 mutation or 17p deletion. Hence, miR-34a is shown to have a role in chemotherapy resistance and thus may serve as a marker for poor prognosis for CLL.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…In addition, some of p53's downstream targets, such as CDKN1A (coding for p21), have a very low mutation frequency in cancers, making assessment of their impact on therapy response challenging. 75,76 However, Zenz et al 77 found expression of miR-34a, a p53-inducible micro-RNA, to predict resistance to fludarabine in chronic lymphatic leukemias independent of TP53 and 17p deletion status.…”