MicroRNAs in chronic lymphocytic leukemia: miRacle or miRage for prognosis and targeted therapies?

Abstract

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease and has a highly variable clinical course with survival ranging from a couple of months to several decades. MicroRNAs (miRNAs), small non-coding RNAs that regulate transcription and translation of genes, have been found to be involved in CLL initiation, progression, and resistance to therapy. In addition, they can be used as prognostic biomarkers and as targets for novel therapies. In this review, we describe the association between miRNAs and the cytogenetic aberrations commonly found in CLL, as well as with other prognostic factors. We describe the presence of miRNAs as extracellular entities in the plasma and serum of CLL patients and discuss their role in resistance to therapy. Finally, we will explore the potential of targeted miRNA therapy for the treatment of CLL, with a special emphasis on MRX34, the first miRNA mimic that is currently being evaluated for clinical use.

Keywords: Biomarker; Chronic lymphocytic leukemia; MicroRNA; Targeted therapy; miR-34 mimic.

Figure 1. MicroRNAs associated with common cytogenetic aberrations in CLL

CLL patients an be categorized in different cytogenetic subgroups based on prognosis: del13 is a good prognostic factor, tri12 and NL cyto/FISH are intermediate prognostic factors and del11q and del17p are associated with poor prognosis. The protein-coding and non-coding genes between brackets in the blue boxes represent targets of the cytogenetic aberration; the miRNAs highlighted in the yellow boxes represent miRNAs that have been associated with the specific cytogenetic aberration.

Figure 2. Therapeutic strategies to target oncogenic microRNAs (or oncomiRs) and tumor suppressor microRNAs

(A) Under normal conditions, miRNAs repress their mRNA targets resulting in reduced expression of proteins. (B) When an oncomiR is overexpressed, its tumor suppressor target is blocked, resulting in inhibition of protein expression. An oncomiR can be targeted by the introduction of miRNA inhibitors, which prohibit miRNA-based targeting and results in re-expression of the tumor suppressor target (marked in red). (C) When a tumor suppressor miRNA is downregulated, its oncogenic target loses its repression, resulting in overexpression of the oncoprotein. Re-expression of a miRNA mimic will block the translation of the oncogene, resulting in normal levels of protein expression (marked in red). Verliezen