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miR-34a as part of the resistance network in chronic lymphocytic leukemia
Thorsten Zenz1, Julia Mohr, Eric Eldering
1Department of Internal Medicine III, University of Ulm, Ulm, Germany.
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.
Insights
Low miR-34a expression in chronic lymphocytic leukemia (CLL) correlates with chemotherapy resistance and impaired DNA damage response, regardless of TP53 deletion or mutation status. Further research is needed to understand miR-34a regulation and overcome its role in treatment failure.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- 17p (TP53) deletion is a marker for chemotherapy-resistant chronic lymphocytic leukemia (CLL).
- The miR-34 family are direct p53 targets involved in p53-dependent cellular effects.
- Understanding miR-34a's role in refractory CLL is crucial for treatment development.
Purpose of the Study:
- To investigate the expression and role of miR-34a in chronic lymphocytic leukemia (CLL).
- To determine the association between miR-34a levels and chemotherapy resistance, TP53 status, and DNA damage response in CLL patients.
Main Methods:
- Studied miR-34a and miR-34b/c expression in a large cohort of CLL patients.
- Analyzed miR-34a expression levels after DNA damage in relation to TP53 status (17p deletion or mutation).
- Correlated miR-34a levels with DNA damage response, apoptosis, and fludarabine resistance.
Main Results:
- miR-34b/c expression was undetectable; miR-34a expression varied among patients.
- miR-34a was upregulated by DNA damage only in the presence of functional p53, not with 17p deletion.
- Low miR-34a levels strongly correlated with impaired DNA damage response, TP53 mutations, and fludarabine resistance, independent of 17p deletion status.
Conclusions:
- Low miR-34a expression in CLL is linked to p53 inactivation and chemotherapy resistance.
- Reduced miR-34a contributes to apoptosis resistance and impaired DNA damage response in CLL cells.
- Mechanisms of miR-34a regulation and strategies to overcome its role in chemoresistance require further investigation.
