microRNAs (miRNAs) are small noncoding RNAs which regulate gene expression circuits and influence development, immune response, and disease pathogenesis and progression [1–4]. Initially, miRNA expression profiling studies revealed unique expression patterns in specific lymphomas that often matched the corresponding cell of origin [5–9]. These findings helped strengthen the emerging notion that despite the indistinguishable histological similarities among some lymphoma entities, they are molecularly heterogeneous [e.g., diffuse large B-cell lymphoma (DLBCL)] . Later studies helped establish miRNAs as markers for lymphoma pathogenesis, prognosis, and treatment response , and as biomarkers that can enhance the accuracy of patient risk-stratification . More recently, functional and structural studies accelerated our understanding of the role of miRNA in oncogenic mechanisms that drive lymphomagenesis and disease maintenance.
The term ‘lymphoma’ encompasses multiple distinct malignancies, which vary in clinical behavior, morphological appearance, and immunologic and molecular phenotype. In the present review, we focus primarily, but not exclusively, on the role of miRNA in mature B-cell lymphomas. These share common features that intrinsically predispose them to genome instability because of bystander DNA modification events (mutations and DNA double strand breaks) that commonly take place during the normal immune response of antibody selection and diversification in the germinal center [13,14]. Herein we review recent studies that illustrate the role of miRNA in lymphoma. Included are functional studies that establish in vivo causal role of miRNA in lymphoma development, maintenance, and progression, and examples of how miRNAs are involved in each of the well-established cancer hallmarks. Structural studies highlight our current knowledge of aberrations in miRNA genes, which display a role in lymphoma pathogenesis.
FUNCTIONAL STUDIES: MICRORNAS AS LYMPHOMA DRIVERS
The ultimate evidence of direct miRNA role in lymphoma development is provided in transgenic mouse models in which alterations of miRNA expression levels has an impact on lymphoma incidence. The expression of miR-155, miR-21, miR-17-92 cluster, and recently miR-217 have been implicated in lymphomagenesis, and illustrate a direct miRNA role in B-cell lymphomagenesis (Table 1[15–18,19▪▪]).
The miR-21, which is overexpressed in most tumor types including B-cell malignancies, was shown to contribute to the development of B-cell lymphoblastic lymphomas/leukemia and tumor maintenance . Importantly, switching off miR-21 expression in established tumors caused a rapid tumor regression that was mediated by a combination of apoptosis and proliferative arrest . These results demonstrate that miR-21 is a genuine oncogene and present the first case of ‘oncomiR addiction’.
Ectopic miR-155 expression in mice B cells has been shown to induce pre-B-cell proliferation followed by high-grade lymphoma/leukemia [16,20]. Babar et al. showed that miR-155 induction is sufficient for tumor initiation and survival in the hematopoietic system. These mice developed disseminated lymphoma, which rapidly regressed upon Doxycycline-induced withdrawal of miR-155, indicating that miR-155 is involved in lymphomagenesis . These studies corroborated previous data that demonstrated elevated expression of miR-155 in specific lymphoma subtypes (e.g., activated DLBCL and Hodgkin lymphoma).
The miR-17-92 polycistronic cluster (six miRNAs) accelerated the development of B-cell malignancies in Eμ-miR-17-92 transgenic mice. These mice developed DLBCL-like disease by age 12–18 months . A similar study that monitored for lymphoma development in the transgenic mice over the life span of animals reported the development of lymphoma with characteristics of DLBCL, follicular lymphoma, small B-cell lymphoma, Burkitt lymphoma, or high-grade mucosa-associated lymphoid tissue lymphoma by histological and immunohistochemistry analyses . Most of the lymphoma primary cells in the transgenic mice were also able to establish secondary lymphoma in Rag1−/− (immunodeficient) animals. Comparative genomic hybridization analyses revealed that the miR-17-92 cluster is recurrently amplified in human B-cell lymphomas, including mantle cell lymphoma (MCL), follicular lymphoma, Burkitt lymphoma, and in the germinal center B-cell like DLBCL . Overall, this cluster is currently considered to function as an ‘oncomiR’, because it acts to regulate the induction of apoptosis and lymphoproliferation by accelerating the expression of Myc and its target genes, and leading to lymphomas in animal studies .
Recently, miR-217 was added to the list of miRNA that can impact B-cell lymphoma development. De Yebenes et al.[19▪▪] monitored the incidence of B-cell lymphoma in knock-in miR-217 mice. Their data suggest that miR-217 is a positive regulator of the germinal center reaction, and an oncogene that promotes mature B-cell lymphomagenesis leading to clonal follicular lymphoma, DLBCL, and B-cell plasmacytomas. Of note, the authors reported that the genomic region that contains the miR-217 chromosomal location is amplified in a fraction of DLBCL, suggesting that miR-217 gain-of-function may be associated with human lymphomas. Together, these studies illustrate the direct and causal role of miRNA genes in lymphoma development.
FUNCTIONAL STUDIES: MICRORNAS AS MODULATORS OF LYMPHOMA CANCER HALLMARKS
Functional miRNA studies in lymphoma illustrate that miRNAs can also affect the cancer hallmarks, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. These were described by Hanahan and Weinberg as distinctive and complementary capabilities which enable tumor growth and metastatic dissemination . Below we discuss recent evidence that illustrates this idea, and summarize these findings in Fig. 1.
The most fundamental cancer hallmark is the ability to sustain chronic proliferation. This hallmark is often acquired by cell-surface receptors stimulation through a variety of molecular mechanisms that yield constitutive activation of downstream proliferative signaling pathways. In B-lymphocytes, this is mediated through B-cell receptor (BCR) activation and downstream proliferative signaling pathways . The Myc-miR-17-92 axis was shown to affect BCR stimulation through direct targeting of two negative regulators of the BCR, the immunoreceptor tyrosine inhibitory motifs-containing proteins CD22 and FCGR2B . miR-150 was shown to modulated the BCR signaling through targeting of the growth factor receptor bound protein 2-associated protein 1 (GAB1), an adaptor molecule that regulates BCR signal amplification by recruiting and assembling the BCR signal [27▪]. miR-155 was shown to enhance BCR signaling in chronic lymphocytic leukemia . These studies demonstrated that miRNAs may contribute to lymphomagenesis by enhancing the BCR signaling, which is necessary for initiation and maintenance of lymphoma.
The cancer hallmark of evading growth suppressors pertains to the ability to circumvent powerful programs that negatively regulate cell proliferation through modulation of tumor suppressor activity such as the retinoblastoma (RB), transforming growth factor beta, and the phosphatase and tensin homolog (PTEN). The miR-155-mediated perturbation of the RB/E2F axis through direct targeting of SMAD5 was shown to blunt the transforming growth factor beta-induced transcription of the cell-cycle inhibitors p15 and p21, which in turn sustained RB phosphorylation and inactivity [29▪]. These findings suggest a critical role for miR-155 in DLBCL pathogenesis and provide the rationale for the impaired immune function in the miR-155 knockout mice . In studies on the mechanism of the oncogenic miR-17-92 cluster in promoting lymphomagenesis, Xiao et al. showed that this cluster drives lymphoproliferative signaling by directly targeting two tumor suppressor genes, the PI-3K inhibitor PTEN, and the pro-apoptotic protein BIM. miRNAs may also function as lymphoma tumor suppressors. In Burkitt lymphoma, Schneider et al. showed that miR-28 acts as a tumor suppressor to impair cell proliferation and clonogenic properties via Myc regulation. In Epstein–Barr virus T-cell lymphoma, low expression of miR-15a, and high expression of LMP1, which promotes cell proliferation and predicts poor prognosis, was shown to decrease MYB and cyclin D1 levels and block G1 to S-phase transition and cell proliferation . The tumor suppressor PTEN is often mutated or underexpressed in T-cell lymphoma, leading to hyperproliferative signaling. In a recent study that simulated PTEN loss in-vivo by expression of the miRNAs miR-146a/b, Burger et al.[34▪▪] showed that these miRNAs act as barriers to transformation by targeting the nuclear factor (NF)-κB activator, Traf6, which in turn attenuated T-cell receptor signaling in the thymus and inhibited downstream NF-κB-dependent induction of c-Myc.
The cancer hallmark of resisting cell death refers to the ability of tumor cells to subvert programmed cell death by apoptosis, the natural barrier to cancer development. Several miRNAs were found to interfere with programed cell death by regulating members of the pro-apoptotic proteins. In radiation-induced thymic lymphoma cells, miR-467a was shown to target the pro-apoptotic proteins Fas and Bax, and to conferr growth advantage to tumor cells , and miR23-a/b was shown to target Fas . The oncogenic miR-17-92 cluster also maintains a neoplastic state through inhibition of the mitochondrial apoptosis pathway and by targeting the pro-apoptotic protein BIM [21,37▪]. Finally, in MCL, miR-16 was shown to targets BMI1, which acts to suppress the expression of the pro-apoptotic genes Pmaip1 and Bcl2l11.
Enabling replicative immortality refers to the required ability of cancer cell to undergo unlimited replicative potential in order to generate macroscopic tumors. Multiple lines of evidence indicate that telomeres, which protect the ends of chromosomes, are centrally involved in this capability . One link to the regulation of telomers and replicative immortality is provided through studies showing that induced telomerase expression by Myc extends the life span of cells . In an interesting study, Watanabe et al. showed that miR-150 acts as a tumor suppressor that inhibits immortalization of cancer cells. Induction of miR-150 in NK/T-cell lymphoma cells increased the incidence of apoptosis and reduced cell proliferation. These cells appeared senescent and displayed lower telomerase activity and shortened telomeric DNA .
Induction of angiogenesis is a hallmark that allows tumors to acquire sustained supply of nutrients and oxygen and to evacuate metabolic wastes and carbon dioxide. The tumor-associated neovasculature that is generated by the process of angiogenesis addresses these needs. The prototype of angiogenesis inducer is the vascular endothelial growth factor (VEGF), which is expressed in non-Hodgkin lymphomas, where it promotes the formation of new blood vessels [41,42]. Dejean et al. investigated the regulation of angiogenesis in anaplastic large cell lymphomas and found a strong inverse correlation between miR-16 and the VEGF levels. miR-16 directly decreased expression levels of VEGF, further suggesting that this miRNA has a role in regulating angiogenesis in lymphoma .
Activating invasion and metastasis refers to the ability of tumor cells to invade, resist apoptosis, and disseminate . One example of a miRNA role in inhibiting this hallmark capability was recently illustrated in T-cell lymphoma through the interplay between miR-150 and its target, CCR6, a member of the b-chemokine receptor family. Ito et al.[45▪▪] showed that the continuous receptor–chemokine interaction (CCL20–CCR6) in a low miR-150 background, driven by the IL-22 cytokine, leads to autocrine dissemination to distal organs. This study highlighted the role of miR-150 as a negative regulator of the IL–22–CCL20–CCR6 autocrine pathway in advanced cutaneous T-cell lymphoma. A direct link to cell motility by miRNA was also shown in our study that illustrated a direct miR-155 targeting of HGAL , an inhibitor of lymphocyte and lymphoma cell motility [47,48]. Together the evidence provided here suggests that miRNA are able to affect each one of the well-established cancer hallmarks and thus contribute to lymphomagenesis by regulating diverse biological processes in lymphomas.
Although each of these cancer hallmarks are directly linked to genetic aberrations, it is important to note that B-cell lymphomas are particularly prone to malignant transformation because of the inherent B-cell machinery that is used for antibody diversification during the germinal center reaction. This complex reaction involves multiple orchestrated processes that are commonly deregulated in lymphoma and include BCR affinity maturation by somatic mutations (SHM) and class switch recombination (CSR), and response to DNA double-strand break repair. SHM and CSR are initiated by activation-induced deaminase (AID), which deaminates the DNA base cytosine (C) into uracil (U), thus resulting in C > T transition mutations followed by DNA breaks. AID preferentially targets the Ig loci but is also capable of mutating other genes, including the proto-oncogenes BCL6, Pim1, Pax5, CD95, Myc, and others in human B-cell lymphomas and normal B cells [49–51]. Thus, any of the intermediate DNA lesions during antibody diversification (U, abasic sites, double-strand breaks) can be tumorigenic if not properly resolved. In mice, a direct role for AID in promoting lymphomagenesis was confirmed by analyses of transgenic animals lacking AID, in which germinal center-derived lymphomas did not develop. Thus, deregulation of AID expression may be pivotal for lymphomagenesis. AID is a direct target of miR-155 . Transgenic mice models with mutated miR-155 binding site in the 3’ UTR of the AID gene showed a modest increase in AID levels and increased CSR and c-/IgH translocation frequency in in-vitro stimulation assays . Deregulated AID expression enhanced the mutation rate in an off-target gene for AID activity, and was accompanied by impaired affinity maturation . Since miR-155 positively regulates several aspects of the germinal center reaction [30,54], the negative regulatory role of miR-155 on AID is puzzling. A potential reconciliation for this puzzle may be provided through BCL6, a transcription repressor that is also required for the germinal center reaction. A BCL6/miR-155 circuit was revealed in two different studies. BCL6 was shown to bind to the regulatory regions in MIR155HG and transcriptionally deregulate miR-155 expression,  and in turn, miR-155 was shown to regulate BCL6 indirectly by targeting its co-repressor partner, HDAC4 directly . Alternatively, the miR-155 regulatory circuit may be the result of distinct temporal and spatial regulation of miR155, AID, and BLC6 during the germinal center reaction and in lymphomas derived from germinal center lymphocytes. AID expression is also regulated by miR-181b, which is upregulated during the germinal center response . Following ectopic expression of miR-181b during B-cell activation, miR-181b decreased AID expression and the CSR rate. Further studies on the role of miRNAs in modulating AID and the germinal center reaction will help elucidate these circuits.
STRUCTURAL GENETIC ABERRATIONS OF MICRORNAS IN LYMPHOMA
Cancer is driven largely by somatic mutations and genetic aberrations that accumulate in the genome over an individual's lifetime. The widespread deregulation of the miRNA transcriptome appears to be a hallmark of cancer with additional contributions from epigenetic and transcriptomic alterations. Evidence linking large-scale genome aberrations that results in gain or loss of miRNA genes have been described and linked to lymphomagenesis [57,58]. Splenic marginal zone lymphoma (SMZL), for example, is characterized by a 7q32 deletion in approximately 40% of cases, and this chromosomal region contains the miR-29a/b-1 cluster that is commonly lost in SMZL . A key target of miR-29-a/b1 is TCL1, which is upregulated in SMZL and functions as a coactivator of the cell survival kinase AKT (also known as protein kinase b) .
At the level of single nucleotide variants (SNV), insights are gained from genomic landscape studies that utilize next-generation sequencing technologies that provide higher-resolution analyses of SNV in coding and noncoding genes. Although miRNAs should in principle be susceptible to similar types of somatic aberrations that are known to affect coding genes, the genomic evidence for mutations and SNV in miRNAs is sparse . The reason for this may be the choice of sequencing analyses coverage. The commonly utilized whole-exome sequencing studies identify only coding mutations (about 1% of the genome), which provide coverage of only a fraction of miRNA genes (exonic). Whole-genome sequencing is more costly and therefore fewer whole-genome sequencing studies are currently available in lymphoma malignancies. Consequently, to the best of our knowledge, only a single report on miRNA mutations currently exists in the literature. Mutation in pri-miR-16-1 was found in two chronic lymphocytic leukemia cases and has been postulated to have an impact on pri-miR processing .
Transcriptionally, miRNAs are regulated by the lymphoma oncogenes Myc and BCL-6, and by the catalytic subunit of polycomb repressive complex 2 (PRC2), which mediates transcriptional silencing through EZH2 activity. A Myc–miR–29–EZH2 feed-forward axis in MCL leads to persistent Myc and EZH2 overexpression, and miR-29 repression leads to induction of CDK6 and IGF-1R. This effect mediated lymphomagenesis and maintenance of tumorigenic potential of lymphoma cells . In a drug-resistance mechanism study in a cutaneous T-cell lymphoma model, Valentina Manfe et al. found that the proteasome inhibitor Bortezomib repressed Myc and simultaneously induced miR-125b-5p, which exerted a cyto-protective effect by targeting MAD4 (a Myc antagonist). Overexpression of Myc repressed miR-125b-5p transcription and sensitized lymphoma cells to Bortezomib. In a subsequent study, this group tested a strategy for inhibitor-mediated silencing of Myc and EZH2 and determined that these inhibitors synergistically disrupt the -miR-26–EZH2 regulatory circuitry and lead to increased miR-26a expression and greater suppression of lymphoma cell growth, thus highlighting miR-26 as a tumor suppressor . These studies provide evidence that miRNAs can be regulated in lymphomas by genetic, epigenetic, and transcriptional programs.
Functional studies firmly establish the role of miRNAs as drivers of lymphomagenesis and regulators of disease maintenance and progression. The mechanisms that are utilized by miRNAs seem to reflect modulation of known signaling pathways that characterize the normal lymphoma cell of origin. Expansion of these studies to functional in-vivo screens that examine specific physiological process and comprehensive analyses of gene targets of individual miRNAs in lymphomas are needed and may reveal additional novel mechanisms contributing to lymphomagenesis. Structural genomic studies are still lacking and present an area of research that is bound to yield more data in the near future as more recurrent miRNA gene mutations may be identified in the different lymphoma entities. These studies will help decipher which somatic mutations are critical drivers and define regulatory pathways to which lymphomas are addicted. It is likely that in the near future, miRNAs will not only be used as lymphoma markers and for better understanding lymphomagenesis mechanisms, but also as potent tools in lymphoma therapy.
Financial support and sponsorship
This work was supported by the Lymphoma Research Foundation and by the Dwoskin, Recio, and the Greg Olsen and Anthony Rizzo Family Foundations.
Conflicts of interest
There are no conflicts of interest.
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