Search

The relatively recent discovery of microRNAs (miRNAs) has exposed an extra layer of gene expression regulation that affects many physiological and pathological processes of biology. Dysregulation of miRNAs is a ubiquitous feature of cancer in general, including lymphomas. The identity of these aberrantly-expressed miRNAs has been thoroughly investigated in all but a few types of lymphomas, however their functional role in lymphomagenesis much less so. This review focuses on those miRNAs that have an experimentally confirmed functional role in the pathogenesis of the most frequent forms of lymphoma. In particular, the MIR15A/16-1 cluster, MIR21, MIR155, MIR17HG (MIR17-92 cluster), MIR34A and MIR125B, which have in vivo animal model evidence for their involvement in lymphomagenesis, are highlighted., (© 2012 Blackwell Publishing Ltd.)

MicroRNAs are a newly discovered class of short (approximately 22 nt) naturally occurring single-stranded RNA molecules that regulate the expression of target genes post-transcriptionally. Despite only being discovered 7 years ago, microRNAs have been implicated as key regulatory molecules in nearly every biological process examined so far and abnormal expression of microRNAs have been linked to many forms of disease including cancer where they can function as both tumour-suppressors and oncogenes. So why are microRNAs causing so much excitement? And will this excitement translate into new medical breakthroughs? This review attempts to answer these questions in the wider context of cancer, focusing on the role that microRNAs play in normal lymphoid development and malignancy.

MicroRNAs are a recently discovered class of short (approximately 22 nucleotide) naturally occurring RNA molecules that negatively regulate gene expression post-transcriptionally. There has been an explosion of interest in the microRNA field as these molecules have been found to play key roles in a wide range of biological processes and to be aberrantly expressed in many types of cancer, including haematological malignancies. Cancer-associated microRNAs can act as both tumour suppressor molecules (e.g., miR-15a and miR-16-1) and have oncogenic properties (e.g., miR-155 and miR-17-92 cluster). In this review the authors discuss the rapidly accumulating evidence for the central role that microRNAs play in both haematopoiesis and haematological malignancy, in particular focusing on their role in lymphoma.

B-cell lymphomas represent a group of more than 35 recognized mature B-cell neoplasms differentiated largely on the basis of immunohistochemical staining patterns that are often challenging to accurately diagnose. Despite having been only formally recognized just over 10 years ago, microRNAs (miRNAs) have become one of the trendiest topics in biology. Dysregulation of miRNAs is a ubiquitous feature of cancer in general, including B-cell lymphomas. Many of the miRNAs aberrantly expressed in B-cell lymphomas also play a crucial regulatory role in normal hematopoietic function. MiRNAs show great potential as novel biomarkers of cancer, as they can differentiate cancers according to diagnosis and developmental stage, even discriminating between cancers that are poorly separated histologically. Furthermore, they can be robustly measured from routinely prepared formalin-fixed paraffin-embedded biopsy material and biological fluids such as blood. Here, we consider the identity, function, and biomarker potential of miRNAs in B-cell lymphomas and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNAs (miRNAs) have become one of the hottest topics in biology over recent years, but remarkably have only been formally recognized for just over 10years. These endogenously produced short (19–24nt) non-coding RNAs have introduced an entirely new paradigm in our understanding of gene control and it is now evident that miRNAs play a crucial regulatory role in many, if not all, physiological and pathological processes. In this review we provide an overview of the role and potential clinical utility for miRNAs in hematological malignancies and their function in normal hematopoiesis. Although still in its infancy, the miRNA field has already added much to our understanding of hematological processes, and provides us with novel tools as both biomarkers and therapeutic agents for hematological malignancies. [Copyright &y& Elsevier]

Lawrie C H, Ballabio E, Soilleux E, Sington J, Hatton C S R, Dirnhofer S & Tzankov A (2012) Histopathology 61, 18-25 Inter- and intra-observational variability in immunohistochemistry: a multicentre analysis of diffuse large B-cell lymphoma staining Aims: Although many immunohistochemical (IHC) cancer biomarkers have been identified, very few have translated into routine clinical practice, primarily because of technical and observational inconsistencies between studies. However, despite the obvious need to address such variability, very few studies have done so. Methods and results: Using bcl-6, CD10, MUM1, GCET1 and FOXP1 antibody staining on diffuse large B-cell lymphoma cases ( n = 138) as a model, we employed Cronbach α analysis to quantify interobserver and intraobserver variability between four independent observers (two per institution), scoring two tissue microarrays (TMAs) stained at both institutions using differing staining procedures. The overall concordance between all observations irrespective of staining procedure or TMA source was high (average α = 0.951), with the highest level being reached for CD10 staining (average α = 0.967) and the lowest for bcl-6 (average α = 0.924). Interslide and interinstitutional reproducibility were similarly high (average α = 0.952 and average α = 0.934, respectively). Interobserver/intrainstitutional and interobserver/interinstitutional comparisons showed lower levels of concordance (average α = 0.870 and average α = 0.877, respectively), and intraobserver/interinstitutional comparisons showed the lowest levels of concordance (average α = 0.810), particularly for bcl-6 staining ( α = 0.658). Conclusions: This study suggests that most variability in IHC studies between centres results from inherent limitations of the biomarkers investigated rather than procedural or observational differences. [ABSTRACT FROM AUTHOR]

The identification of immunogenic cancer testis antigens (CTAs) as immunotherapeutic targets represents one approach to improve treatment options for diffuse large B-cell lymphoma (DLBCL). We previously identified PASD1 [PAS (Per ARNT Sim) domain containing 1 (PASD1)], a DLBCL-associated CTA that was expressed in a range of hematopoietic malignancies. The aim of the present study was to investigate the presence of a cytotoxic T-cell (CTL) response to PASD1 in DLBCL patients. A significant γ-interferon (IFN) release was detected in 21/29 HLA-A*0201-positive DLBCL patients (18 de novo DLBCL, two transformed DLBCL and one T-cell rich B-cell lymphoma) following short-term culture of their peripheral blood mononuclear cells stimulated with five HLA-A*0201-restricted PASD1 peptides. No significant responses were detected in 21 HLA-A*0201-negative DLBCL patients (12 de novo DLBCL, seven transformed DLBCL, two T-cell rich B-cell lymphoma) or six normal subjects. CTL cell lines were able to lyse PASD1-positive tumour cells in a major histocompatibility complex-Class I dependent manner. The presence of a γ-IFN response correlated with PASD1 protein expression in the tumour cells in 12/15 cases studied. This is the first report of a CTL response to a CTA in DLBCL. Our results provide additional valuable evidence supporting PASD1 as a potential immunotherapeutic target for the treatment of DLBCL and other malignancies. [ABSTRACT FROM AUTHOR]

MicroRNAs are naturally occurring small RNA species that regulate gene expression and are frequently abnormally expressed in cancers. However, the role of microRNAs in lymphoma is poorly understood. Therefore, we undertook a comprehensive study of microRNA expression in two of the most common lymphomas: diffuse large B-cell lymphoma (DLBCL) ( n = 80) and follicular lymphoma (FCL) ( n= 18) using microarrays containing probes for 464 human microRNAs. Unsupervised cluster analysis revealed distinct expression patterns between these two lymphomas and specific microRNA signatures (including members of the miR-17–92 cluster) were derived that correctly predicted lymphoma type in >95% of cases. Furthermore, we identified microRNAs in de novo DLBCL ( n = 64) associated with germinal centre-like and non-germinal centre-like immunophenotypes, international prognostic index status and event-free survival in CHOP and rituximab (R)-CHOP treated patients. Despite the indolent nature of FCL a significant proportion of cases undergo high-grade transformation to more aggressive DLBCL. In order to see if transformation is associated with changes in microRNA expression we compared transformed DLBCL cases ( n= 16) with de novo DLBCL, as well as FCL cases that underwent subsequent transformation ( n = 7) with FCL cases that had not transformed at a median follow-up of 60 months ( n = 11). Differential expression of 12 microRNAs correctly predicted >85% of transformed versus de novo DLBCL cases; six microRNAs ( miR-223, 217, 222, 221 and let-7i and 7b) were found which could similarly predict or transformation in FCL ( P < 0.05). These data suggest that microRNAs have potential as diagnostic and prognostic markers in these lymphomas and may be used to identify FCL patients at risk of high-grade transformation. [ABSTRACT FROM AUTHOR]

The article discusses aspects of MicroRNAs. The article focuses specifically on several aberrant expressions of some MicroRNAs including the MIR17-92 cluster and the MIR15A/MIR16. The cause of these aberrant expression in cancers is unknown. Aspects of RNASEN expression in relation to B cells and T cells are discussed.

Circulating nucleic acids have been shown to have potential as non-invasive diagnostic markers in cancer. We therefore investigated whether microRNAs also have diagnostic utility by comparing levels of tumour-associated MIRN155 ( miR-155), MIRN210 ( miR-210) and MIRN21 ( miR-21) in serum from diffuse large B-cell lymphoma (DLBCL) patients ( n = 60) with healthy controls ( n = 43). Levels were higher in patient than control sera ( P = 0·009, 0·02 and 0·04 respectively). Moreover, high MIRN21 expression was associated with relapse-free survival ( P = 0·05). This is the first description of circulating microRNAs and suggests that microRNAs have potential as non-invasive diagnostic markers for DLBCL and possibly other cancers. [ABSTRACT FROM AUTHOR]

The OX-TES-4 antigen originally elicited an antibody response in 50% of diffuse large B-cell lymphoma (DLBCL) patients but not in control subjects. OX-TES-4 is encoded by a novel gene, MORC4, located at chromosome Xq22.3. The MORC4 protein contains a HATPase-c domain, CW zinc finger motif, nuclear localisation signals and a nuclear matrix-binding domain, together with a coiled-coil region. MORC4 mRNA is widely expressed at low levels in normal tissues, showing highest expression levels in placenta and testis. mRNA levels were increased in non-germinal centre-derived DLBCL and Hodgkin lymphoma cell lines, compared with germinal centre-derived DLBCL cell lines and normal B cells. Nineteen DLBCL patients (66%) expressed significantly higher levels of MORC4 mRNA than normal B cells ( P = 0·0031). The differential expression of MORC4 identifies this molecule as a potential lymphoma biomarker, whose overexpression may contribute to the immunological recognition of MORC4 by a subgroup of DLBCL patients. [ABSTRACT FROM AUTHOR]

MicroRNAs are a recently discovered class of small (∼22nt) endogenously expressed translational-repressor RNAs that play key roles in many cellular pathways and whose aberrant expression appears to be a common feature of malignancy. MicroRNAs are expressed in specific haematological cell types and play important regulatory roles in early haematopoietic differentiation, erythropoiesis, granulocytosis, megakaryocytosis and lymphoid development. Additionally, there is an emerging body of research to suggest that microRNAs play an important role in the pathology of haematological malignancies. MicroRNAs have been found to act as both tumour suppressor molecules [e.g. MIRN15A ( miR-15a), MIRN16-1 ( miR-16-1)] in leukaemias and have oncogenic properties [e.g. MIRN155 ( miR-155) and MIRN17–92 ( miR-17– miR-92) cluster] in lymphomas. This review discusses the rapidly accumulating research that points to the major role microRNAs play in both haematopoiesis and haematological malignancy. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding RNAs that regulate many human genes including those involved in normal B-cell development. When these miRNAs are aberrantly expressed in B-cells they play key pathogenetic roles in the development and maintenance of B-cell lymphomas and by association may serve as useful biomarkers. In this review, we provide an overview of the importance of miRNAs to B-cell lymphomagenesis, as well as considering their use as biomarkers, and their potential usefulness for the clinic. [ABSTRACT FROM AUTHOR]