The role of miRNAs in the pathogenesis and diagnosis of B-cell lymphomas

Abstract

There is a demand to understand B-cell lymphoma pathogenesis better, to identify new markers, and to define multiple lymphoproliferative disorders more accurately. MicroRNAs (miRNAs) are regulators of protein translation, comprising a group of more than 1500 short noncoding single-strand RNA molecules of approximately 22 nucleotides in length. They are easily detectable in fresh or paraffinembedded diagnostic tissue and serum. Expression of individual miRNAs and miRNA signatures allows specific celldifferentiation stages to be identified, and is a powerful diagnostic and prognostic method. Here we review what is known about the pathogenic relevance of miRNAs, and use of miRNAs for the diagnosis and prognosis of B-cell lymphomas. Most of the published data concern chronic lymphocytic lymphoma and diffuse large B-cell lymphoma, and implicate miRNAs in the pathogenesis of these diseases. They identify miRNAs that could be used for diagnosis, prognosis, or prediction of response to specific therapies. (Blood. 2012;120(9):1782-1790) Introduction B-cell lymphomas make up a heterogeneous group of lymphoproliferative disorders that originate from B cells and whose pathogenesis is still largely unknown. Classification of B-cell lymphomas has essentially been based on the recognition of characteristic gene translocations that deregulate the expression of oncogenes or tumor suppressor genes. 1 B-cell lymphoma classification has made it possible to recognize and successfully treat a range of disorders, but a significant proportion of B-cell lymphoma patients still fail to respond to therapy.Although the accuracy with which the various B-cell disorders are recognized has improved through the use of new immunohistochemical and molecular markers, there is still a demand to understand lymphoma pathogenesis better, to identify new markers, and to define the range of lymphoproliferative disorders more accurately. Lymphoma classification is largely based on the assumption that lymphoma cells derive from specific cell populations, thereby making it possible to correlate the phenotype of particular lymphoma types with that of the normal counterpart B-cell subpopulations. Nevertheless, there is a growing understanding that lymphoma-specific markers also recapitulate the history of lymphoma pathogenesis, expressing additional markers that provide information about specific molecular events.The potential number of specific molecular markers for lymphoma diagnosis and prognostication has improved in the last few years thanks to the recognition of microRNAs (miRNAs) as central players in B-cell differentiation and oncogenesis. miRNAs are a recently identified class of noncoding single-strand RNA molecules of 21-23 nt that function as posttranscriptional regulators of gene expression, targeting their corresponding messenger RNAs for degradation or translational repression. MicroRNAs miRNAs were first described in 1993 in Caenorhabditis elegans, 2,3 although it took several years to confirm the supposition that miRNAs are essential compone...

A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas

“…Downregulation of a subset of miRNAs is a commonly observed feature of cancers, suggesting that these miRNAs, such as miR-548m, may act as tumor suppressors. Recent studies revealed that c-Myc activation resulted in widespread direct repression of miRNA expression and c-Myc-induced miRNA repression contributes to lymphoma aggressive progression (43)(44)(45). The stroma-induced miR-548m repression can be the result of c-Myc overexpression.…”

B-cell lymphoma mutations: improving diagnostics and enabling targeted therapies

“…It seems that highly proliferative lymphomas like BL or specific cases of MM 112 may be excellent case scenarios for therapeutic targeting of this pathway with rapamycin or its derivatives. 113 3) Playing a key role in downstream signaling from BCR, TLR and other co-receptors, NF-kB activity seems to be deregulated in the majority of B-cell lymphomas, although J.P. Vaqué et al 228 haematologica | 2014; 99 (2) © F e r r a t a S t o r t i F o u n d a t i o n specific features of activation and potential inhibition may differ among specific entities and even tumor subgroups. Deregulated NF-kB can be elicited by the numerous activating mutations found in NF-kB upstream regulators including those found in MYD 88 (in CLL, DLBCL, LPL) or in NIK/TNFAIP3 in SMLZ, to name but a few.…”

“…1 Moreover, specific gene expression and miRNA profiling signatures have also helped to distinguish between particular tumor types as the consequence of the deregulation of specific genes or pathways. 2 In addition to this, we now know that signaling from the B-cell receptor 3,4 and co-receptors (CD19, Toll-like receptors) 5,6 can be considered as triggers for activating critical signaling pathways that regulate a range of biological activities in B-cell lymphomas, including altered metabolism, 7 enhanced proliferation and survival, 1 and cell migration in response to soluble factors. 8 These highlight the increasing interest in developing BCR downstream signaling inhibitors with the potential for use in clinical practice.…”

Dysregulation of microRNAs and their association in the pathogenesis of T-cell lymphoma/leukemias

“…At present, over 4,500 miRNAs have been identified in humans, and it is known that nearly all human protein-encoding genes can be controlled by miRNAs in both healthy and malignant cells. Abnormal expression of miRNA is now known to occur in many cancers, including malignant lymphomas (MLs) [6][7][8][9][10][11][12][13][14].…”

“…In B-cell lymphomas, molecular-based classifications of the subtypes have been successfully conducted, leading to the development of understanding of their pathogenesis. Subtype-based miRNA classification has also been successfully conducted in B-cell lymphomas [11][12][13][14]. In T-cell lymphomas, however, attempts at translocation-or molecular-based classification have been unsuccessful to date, and as a result, understanding of molecular-based pathogenesis of T-cell lymphoma has been insufficiently established.…”