MicroRNAs: Potential prognostic and theranostic biomarkers in chronic lymphocytic leukemia

Abstract

Small noncoding ribonucleic acids called microRNAs coordinate numerous critical physiological and biological processes such as cell division, proliferation, and death. These regulatory molecules interfere with the function of many genes by binding the 3'-UTR region of target mRNAs to inhibit their translation or even degrade them. Given that a large proportion of miRNAs behave as either tumor suppressors or oncogenes, any genetic or epigenetic aberration changeing their structure and/or function could initiate tumor formation and development. An example of such cancers is chronic lymphocytic leukemia (CLL), the most prevalent adult leukemia in Western nations, which is caused by unregulated growth and buildup of defective cells in the peripheral blood and lymphoid organs. Genetic alterations at cellular and molecular levels play an important role in the occurrence and development of CLL. In this vein, it was noted that the development of this disease is noticeably affected by changes in the expression and function of miRNAs. Many studies on miRNAs have shown that these molecules are pivotal in the prognosis of different cancers, including CLL, and their epigenetic alterations (e.g., methylation) can predict disease progression and response to treatment. Furthermore, miRNAs are involved in the development of drug resistance in CLL, and targeting these molecules can be considered a new therapeutic approach for the treatment of this disease. MiRNA screening can offer important information on the etiology and development of CLL. Considering the importance of miRNAs in gene expression regulation, their application in the diagnosis, prognosis, and treatment of CLL is reviewed in this paper.

Keywords: chronic lymphocytic leukemia; epigenetics; hematopoiesis; microRNA; prognosis; therapeutic biomarker.

FIGURE 1

Biogenesis of microRNAs (miRNAs). First, the miRNA gene is transcribed by RNA polymerase II enzyme to form a primary transcript called pri‐miRNA. After processing this initial transcript by DGCR8 and RNase III (Drosha), pri‐miRNA is transformed into a hairpin loop structure with 85 nucleotides (pre‐miRNA). The pre‐miRNA is transported from the nucleus to the cytoplasm via the Ran/GTP/Exportin 5 membrane complex and converted to the miRNA/miRNA duplex structure by the Dicer enzyme and finally, mature miRNA is formed. Mature miRNA can regulate the expression of the target gene by being located in the RISC protein complex.

FIGURE 2

Signaling pathways of B cell receptor (BCR). BCR contains a membrane‐bound immunoglobulin molecule (that attaches the antigen) and a heterodimer subunit consisted of Ig‐α and Ig‐β (signal transduction moiety) that has tyrosine kinase properties due to its ITAM motifs. After the activation of BCR, ITAM motifs are phosphorylated by tyrosine‐protein kinase Lyn, proto‐oncogene tyrosine‐protein kinase Fyn and tyrosine‐protein kinase SYK. Phosphorylation of CD79A and CD79B activates a set of kinases and adaptor proteins that ultimately triggers signaling pathways related to cell proliferation and differentiation, including NF‐κB. The miR‐150 and miR‐34a disrupt signal transduction from BCR and inhibit cell proliferation in CLL by negative regulation of FOXP1.

FIGURE 3

Epigenetic changes in miRNAs and their role in CLL prognosis. MiR‐129‐2, miR‐34b/c, miR‐3151, and miR‐9‐3 are tumor suppressors and hypermethylation of their promoter regions decreases their expression. Low expression of miR‐34b/c inhibits the activation of the Tp53 signaling pathway and reduces apoptosis. On the other hand, decreased expression of miR‐3151 and miR‐9‐3 initiate the MEK/ERK, PI3K/AKT, and NF‐κB pathways, leading to reduced apoptosis, increased cell proliferation, and unfavorable prognosis of CLL.