MicroRNAs in B-cells: from normal differentiation to treatment of malignancies

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that play important post-transcriptional regulatory roles in a wide range of biological processes. They are fundamental to the normal development of cells, and evidence suggests that the deregulation of specific miRNAs is involved in malignant transformation due to their function as oncogenes or tumor suppressors. We know that miRNAs are involved in the development of normal B-cells and that different B-cell subsets express specific miRNA profiles according to their degree of differentiation. B-cell-derived malignancies contain transcription signatures reminiscent of their cell of origin. Therefore, we believe that normal and malignant B-cells share features of regulatory networks controlling differentiation and the ability to respond to treatment. The involvement of miRNAs in these processes makes them good biomarker candidates. B-cell malignancies are highly prevalent, and the poor overall survival of patients with these malignancies demands an improvement in stratification according to prognosis and therapy response, wherein we believe miRNAs may be of great importance. We have critically reviewed the literature, and here we sum up the findings of miRNA studies in hematological cancers, from the development and progression of the disease to the response to treatment, with a particular emphasis on B-cell malignancies.

Figure 1. Biogenesis of miRNAs

The synthesis of miRNAs via the canonical pathway starts with transcription of miRNA genes by RNA polymerase II, which results in primary-miRNAs. These are processed by Drosha and DiGeorge syndrome critical region gene 8 (DGCR8), generating precursor-miRNAs which are transported to the cytoplasm by Exportin 5 and cleaved by Dicer and TAR RNA-binding protein (TRBP). The resulting duplex is separated, generating mature miRNAs. MiRNAs can also arise from splicing through the non-canonical pathway. The designation of miRNAs includes the term “miR” preceding a number attributed sequentially. Similar sequences can have the same number but a different suffix (number or letter). Letters defining the species are added as prefixes, such as hsa for Homo sapiens. Additionally, they can be designated miR-#-3p or miR-#-5p depending on which arm of the precursor structure the leading strand is located [168].

Figure 2. Involvement of miRNAs on normal and malignant human B-cell differentiation

The downregulation (↓) or upregulation (↑) of the miRNAs depicted here has been shown to be involved in the reaction to which they are adjacent. ALL: Acute Lymphoblastic Leukemia; CLL: Chronic Lymphocytic Leukemia; HL: Hodgkin Lymphoma; NHL: Non-Hodgkin Lymphoma; MM: Multiple Myeloma