Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that control the expression of many target messenger RNAs (mRNAs) involved in normal cell functions (differentiation, proliferation and apoptosis). Consequently their aberrant expression and/or functions are related to pathogenesis of many human diseases including cancers. Haematopoiesis is a highly regulated process controlled by a complex network of molecular mechanisms that simultaneously regulate commitment, differentiation, proliferation, and apoptosis of hematopoietic stem cells (HSC). Alterations on this network could affect the normal haematopoiesis, leading to the development of haematological malignancies such as lymphomas. The incidence of lymphomas is rising and a significant proportion of patients are refractory to standard therapies. Accurate diagnosis, prognosis and therapy still require additional markers to be used for diagnostic and prognostic purpose and evaluation of clinical outcome. The dysregulated expression or function of miRNAs in various types of lymphomas has been associated with lymphoma pathogenesis. Indeed, many recent findings suggest that almost all lymphomas seem to have a distinct and specific miRNA profile and some miRNAs are related to therapy resistance or have a distinct kinetics during therapy. MiRNAs are easily detectable in fresh or paraffin-embedded diagnostic tissue and serum where they are highly stable and quantifiable within the diagnostic laboratory at each consultation. Accordingly they could be specific biomarkers for lymphoma diagnosis, as well as useful for evaluating prognosis or disease response to the therapy, especially for evaluation of early relapse detection and for greatly assisting clinical decisions making. Here we summarize the current knowledge on the role of miRNAs in normal and aberrant lymphopoiesis in order to highlight their clinical value as specific diagnosis and prognosis markers of lymphoid malignancies or for prediction of therapy response. Finally, we discuss their controversial therapeutic role and future applications in therapy by modulating miRNA.
Highlights
The term “lymphoma” encompasses at least 48 distinct types of malignancy that vary in clinical behavior, morphologic appearance, and immunologic and molecular phenotype
Most non–germinal centers (GC) type Diffuse Large B-Cell Lymphoma (DLBCL) cases (77%) lacked blimp1 protein expression, despite the presence of blimp1 messenger RNAs (mRNAs), suggesting that the same gene was inactivated by epigenetic mechanisms in an additional large number of cases. These findings indicate a role as a tumor suppressor gene for PRDM1/blimp1, whose inactivation may contribute to lymphomagenesis by blocking post-GC differentiation of B cells toward plasma cells
Despite the encouraging results obtained in preclinical models and the availability of the Phase I clinical trial with miR-34a mimic, there are still many issues that need to be addressed for an effective translation into clinical practice
Summary
The term “lymphoma” encompasses at least 48 distinct types of malignancy that vary in clinical behavior, morphologic appearance, and immunologic and molecular phenotype. MiRNAs are small, non-coding RNA molecules that control the expression of many target messenger RNAs (mRNAs) involved in normal cell functions (differentiation, proliferation and apoptosis). Their aberrant expression and/or function are related to the pathogenesis of many human diseases such as cancers. Studies on the whole genome miRNA (miRome) have demonstrated that it changes dynamically during lymphoid maturation, as it is tissue- and stage-specific as well as temporally regulated [12] Because of their important role in the differentiation and proliferation of different hematopoietic lineages, it is not surprising that miRNAs have been implicated in immune cell functions as well as the secretion of cytokines in microenvironments. Recent studies have documented that miRNAs have unique expression profiles in the cells of both innate and adaptive immune systems, and play significant roles in the regulation of cell development and function [13,14,15,16,17]
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