miRNA-Based Therapies in B Cell Non-Hodgkin Lymphoma

Modulation of the expression of the oncomiRs miR-17-92, miR-21, and miR-155 and the tumor suppressor miRNAs miR-144/451, miR-181a, miR-27, miR-28-5p, and miR-34a has shown therapeutic potential in xenograft mouse models of human B-cell non-Hodgkin lymphoma (B-NHL) in vivo.Changing the expression of various miRNAs can increase sensitivity to R-CHOP chemotherapy components and B-NHL-targeted drugs such as bortezomib and imatinib in certain B-NHLs.Several miRNAs have been identified as regulators of the expression of the inhibitory receptor programmed cell death-1 (PD-1) and its ligand PD-L1. Shifting the expression of these miRNAs might contribute to the improvement of immunotherapy-based B-NHL treatments.miRNA expression patterns might be used as putative biomarkers for certain B-NHLs to predict survival, relapse, remission, and responsiveness to specific treatments.MRX34 (miR-34 mimic), mesomiR-1 (miR-16 mimic), and cobomarsen (anti-miR-155) have shown antitumor activity in Phase I clinical trials. Although not specifically designed for B-NHL, these trials included B-NHL patients. Non-Hodgkin lymphoma (NHL) is a diverse class of hematological cancers, many of which arise from germinal center (GC)-experienced B cells. Thus GCs, the sites of antibody affinity maturation triggered during immune responses, also provide an environment that facilitates B cell oncogenic transformation. miRNAs provide attractive and mechanistically different strategies to treat these malignancies based on their potential for simultaneous modulation of multiple targets. Here, we discuss the scientific rationale for miRNA-based therapeutics in B cell neoplasias and review recent advances that may help establish a basis for novel candidate miRNA-based therapies for B cell-NHL (B-NHL). Non-Hodgkin lymphoma (NHL) is a diverse class of hematological cancers, many of which arise from germinal center (GC)-experienced B cells. Thus GCs, the sites of antibody affinity maturation triggered during immune responses, also provide an environment that facilitates B cell oncogenic transformation. miRNAs provide attractive and mechanistically different strategies to treat these malignancies based on their potential for simultaneous modulation of multiple targets. Here, we discuss the scientific rationale for miRNA-based therapeutics in B cell neoplasias and review recent advances that may help establish a basis for novel candidate miRNA-based therapies for B cell-NHL (B-NHL). Lymphomas arise from the neoplastic transformation of either T or B lymphocytes. About 95% of all human lymphomas originate in B cells, rather than T cells, and most of them (75–85%) arise from mature B cells that are germinal center (GC, see Glossary) experienced [1.Armitage J.O. et al.Non-Hodgkin lymphoma.Lancet. 2017; 390: 298-310Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar]. GCs are unique structures in which Ig genes are remodeled and are thus essential for the generation of high-affinity antibodies required for a proficient immune response. The production of high-affinity antibodies entails the introduction of mutations and DNA double-strand breaks in Ig genes and thus increases the risk of generating oncogenic events in mature B cells that transit through the GC [2.Robbiani D.F. Nussenzweig M.C. Chromosome translocation, B cell lymphoma, and activation-induced cytidine deaminase.Annu. Rev. Pathol. 2013; 8: 79-103Crossref PubMed Scopus (87) Google Scholar,3.Alvarez-Prado A.F. et al.A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets.J. Exp. Med. 2018; 215: 761-771Crossref PubMed Scopus (0) Google Scholar]. Mature B cell neoplasia underlies the vast majority of lymphocyte-derived cancers, including most B-NHLs, such as diffuse large B cell lymphomas (DLBCLs), follicular lymphoma (FL), Burkitt lymphoma (BL), multiple myeloma (MM), and B cell chronic lymphocytic leukemia (CLL) [4.Shaffer III, A.L. et al.Pathogenesis of human B cell lymphomas.Annu. Rev. Immunol. 2012; 30: 565-610Crossref PubMed Scopus (253) Google Scholar]. It is estimated that B-NHL affects 1.3 million people worldwide [Global Cancer Observatory (GCO), World Health Organizationi]. While some types of B-NHL progress relatively slowly and are considered indolent cancers, about 60% of them, including BL and DLBCL, are aggressive and require immediate intervention [1.Armitage J.O. et al.Non-Hodgkin lymphoma.Lancet. 2017; 390: 298-310Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar]. In general, the main treatments for mature B-NHL are chemotherapy, immunochemotherapy, and radiation therapy; however, a significant fraction of these cancers are refractory to these interventions or relapse after treatment [1.Armitage J.O. et al.Non-Hodgkin lymphoma.Lancet. 2017; 390: 298-310Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar,5.Klener P. Klanova M. Drug resistance in non-Hodgkin lymphomas.Int. J. Mol. Sci. 2020; 21: 2081Crossref Scopus (3) Google Scholar]. There is therefore an urgent need for alternative therapeutic strategies to replace or complement current approaches. Advances in knowledge of the molecular mechanisms underlying lymphomagenesis have led to the design of promising new drugs that target specific genes and proteins involved in neoplasia development or maintenance. Clinically available strategies targeting B-NHL currently include: (i) immunotherapy with cell-directed monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapy; and (ii) signal transduction inhibitors, including proteasome inhibitors, histone deacetylase (HDAC) inhibitors, and B cell receptor (BCR) signaling kinase inhibitors [6.Chaudhari K. et al.Non-Hodgkin lymphoma therapy landscape.Nat. Rev. Drug Discov. 2019; 18: 663-664Crossref PubMed Scopus (0) Google Scholar]. The availability of targeted therapies has improved treatment options for certain B cell neoplasias in some patients. However, current targeted therapies have important limitations; most notably, treatment failure due to the selective pressure to generate drug-resistant mutations in tumor cells [5.Klener P. Klanova M. Drug resistance in non-Hodgkin lymphomas.Int. J. Mol. Sci. 2020; 21: 2081Crossref Scopus (3) Google Scholar]. In recent years, miRNAs have emerged as new therapeutic tools for mature B cell malignancies due to their unique molecular features, as described below. A high proportion of human miRNAs are located in cancer-associated genomic regions, and dysregulated miRNA expression is a hallmark of most cancers, including lymphomas [7.Lu J. et al.MicroRNA expression profiles classify human cancers.Nature. 2005; 435: 834-838Crossref PubMed Scopus (7340) Google Scholar]. In B cell neoplasia, miRNAs can function both as oncogenes (oncomiRs) and as tumor suppressor genes (reviewed in [8.de Yebenes V.G. et al.Regulation of B-cell development and function by microRNAs.Immunol. Rev. 2013; 253: 25-39Crossref PubMed Scopus (0) Google Scholar]), and the possibility of delivering synthetic miRNA mimics or miRNA inhibitors to manipulate miRNA expression in vivo has opened new and exciting therapeutic perspectives [9.Rupaimoole R. Slack F.J. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases.Nat. Rev. Drug Discov. 2017; 16: 203-222Crossref PubMed Scopus (1286) Google Scholar]. Notably, the ability of miRNAs to target multiple protein-coding genes in the same pathways is expected to limit the generation of drug resistance [10.Si W. et al.The role and mechanisms of action of microRNAs in cancer drug resistance.Clin. Epigenetics. 2019; 11: 25Crossref PubMed Scopus (42) Google Scholar, 11.Leivonen S.K. et al.MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma.Blood Cancer J. 2017; 7654Crossref PubMed Scopus (9) Google Scholar, 12.Zhao B. et al.Exploiting temporal collateral sensitivity in tumor clonal evolution.Cell. 2016; 165: 234-246Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. Here, we review the oncogenic and tumor suppressor actions of miRNAs in B-NHL, with particular emphasis on in vivo studies addressing the therapeutic potential of miRNA modulation. We also discuss studies exploring miRNA-based combination strategies to treat B cell neoplasias and the use of miRNAs as putative biomarkers to track responses to novel treatments for B cell malignancies, describing ongoing miRNA-based clinical trials for specific cancers (Figure 1, Key Figure). Finally, we comment on the current challenges and future directions of this exciting and promising field. miRNAs are noncoding RNAs (ncRNAs) that drive post-transcriptional negative regulation of gene expression by promoting the degradation or translational blockade of their target mRNAs. miRNAs are 21–24-nucleotide-long RNA molecules that are processed from longer RNA precursors (pri-miRNAs) [13.Bartel D.P. MicroRNAs: genomics, biogenesis, mechanism, and function.Cell. 2004; 116: 281-297Abstract Full Text Full Text PDF PubMed Scopus (24900) Google Scholar], and either the 5′ or the 3′ strand of the mature miRNA duplex is loaded into the Argonaute (AGO) family of proteins to form a miRNA-induced silencing complex (miRISC) [13.Bartel D.P. MicroRNAs: genomics, biogenesis, mechanism, and function.Cell. 2004; 116: 281-297Abstract Full Text Full Text PDF PubMed Scopus (24900) Google Scholar]. When bound to AGO proteins, mature miRNAs destabilize or inhibit the translation of partially complementary target mRNAs [13.Bartel D.P. MicroRNAs: genomics, biogenesis, mechanism, and function.Cell. 2004; 116: 281-297Abstract Full Text Full Text PDF PubMed Scopus (24900) Google Scholar]. Animal miRNAs promote subtle changes in gene expression through imperfect pairing with their target mRNAs. Each miRNA can bind numerous different target mRNAs and can act as a regulator of gene networks rather than of individual genes (reviewed in [14.Ebert M.S. Sharp P.A. Roles for microRNAs in conferring robustness to biological processes.Cell. 2012; 149: 515-524Abstract Full Text Full Text PDF PubMed Google Scholar, 15.Bartel D.P. MicroRNAs: target recognition and regulatory functions.Cell. 2009; 136: 215-233Abstract Full Text Full Text PDF PubMed Scopus (12973) Google Scholar, 16.Gosline S.J. et al.Elucidating microRNA regulatory networks using transcriptional, post-transcriptional, and histone modification measurements.Cell Rep. 2016; 14: 310-319Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]). However, genetic studies involving mutation of miRNA-binding sites in individual target genes have identified key target genes, demonstrating that individual miRNA–target mRNA interactions can play important roles in a cell- and context-dependent manner [17.Dorsett Y. et al.MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation.Immunity. 2008; 28: 630-638Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar, 18.Teng G. et al.MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase.Immunity. 2008; 28: 621-629Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar, 19.Jin H.Y. et al.Differential sensitivity of target genes to translational repression by miR-17~92.PLoS Genet. 2017; 13e1006623Crossref PubMed Scopus (0) Google Scholar, 20.Lu L.F. et al.A single miRNA–mRNA interaction affects the immune response in a context- and cell-type-specific manner.Immunity. 2015; 43: 52-64Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar]. miRNA-mediated post-transcriptional regulation of gene expression is cell-type specific [21.Hsin J.P. et al.The effect of cellular context on miR-155-mediated gene regulation in four major immune cell types.Nat. Immunol. 2018; 19: 1137-1145Crossref PubMed Scopus (34) Google Scholar], is influenced by the relative abundance of mRNA targets in the cell, and can be balanced by other ncRNAs such as circular RNAs and long-ncRNAs, which have been described to function as miRNA sponges [22.Hansen T.B. et al.Natural RNA circles function as efficient microRNA sponges.Nature. 2013; 495: 384-388Crossref PubMed Scopus (2826) Google Scholar,23.Paraskevopoulou M.D. Hatzigeorgiou A.G. Analyzing miRNA–lncRNA interactions.Methods Mol. Biol. 2016; 1402: 271-286Crossref PubMed Scopus (232) Google Scholar]. miRNAs can also regulate gene expression in a paracrine manner through transfer in exosomes to neighboring or synaptically linked cells [24.Gutierrez-Vazquez C. et al.Transfer of extracellular vesicles during immune cell-cell interactions.Immunol. Rev. 2013; 251: 125-142Crossref PubMed Scopus (145) Google Scholar]. Recent work demonstrated the key role of exosomal miRNA transfer in the regulation of GC responses [25.Fernandez-Messina L. et al.Transfer of extracellular vesicle-microRNA controls germinal center reaction and antibody production.EMBO Rep. 2020; 21e48925Crossref PubMed Scopus (1) Google Scholar] and in intercellular communication in solid-tumor microenvironments [26.Amit M. et al.Loss of p53 drives neuron reprogramming in head and neck cancer.Nature. 2020; 578: 449-454Crossref PubMed Scopus (10) Google Scholar] in mice. Since the oncogenic potential of miRNAs for B cell lymphoma development was first reported in 2005 [27.He L. et al.A microRNA polycistron as a potential human oncogene.Nature. 2005; 435: 828-833Crossref PubMed Scopus (2918) Google Scholar], numerous studies have advanced our understanding of the molecular mechanisms underlying the roles of miRNA in B cell transformation. Here, we cover representative miRNAs for which the therapeutic potential of miRNA modulation has been established in in vivo preclinical models. These studies are summarized in Table 1, together with other studies that have established a role for miRNAs in B cell neoplasias in vivo but these are not discussed here.Table 1miRNAs in B Cell NeoplasiasaAbbreviations: KO, knockout; ; MALT, extranodal marginal zone lymphoma; MDS, myelodysplastic syndrome; NA, not assessed.miRNAExpression in B cell neoplasiaEffect of miRNA modulation on B cell neoplasia developmentmiRNA target in B lymphocytes and B cell lymphomaTherapy potential in B-NHLmiR-17∼92 polycistron (miR-17, miR-18a, miR-19a, miR-20a, miR-19b, and miR-92a)OncomiRIncreased expression in primary human B-NHL [27.He L. et al.A microRNA polycistron as a potential human oncogene.Nature. 2005; 435: 828-833Crossref PubMed Scopus (2918) Google Scholar] due to gene amplifications [111.Ota A. et al.Identification and characterization of a novel gene, C13orf25, as a target for 13q31–q32 amplification in malignant lymphoma.Cancer Res. 2004; 64: 3087-3095Crossref PubMed Scopus (575) Google Scholar] and Myc-mediated transcriptional upregulation [112.O’Donnell K.A. et al.c-Myc-regulated microRNAs modulate E2F1 expression.Nature. 2005; 435: 839-843Crossref PubMed Scopus (2294) Google Scholar,113.Ji M. et al.The miR-17-92 microRNA cluster is regulated by multiple mechanisms in B-cell malignancies.Am. J. Pathol. 2011; 179: 1645-1656Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]Accelerates preB lymphoma development in Eμ-MYC transgenic mice [27.He L. et al.A microRNA polycistron as a potential human oncogene.Nature. 2005; 435: 828-833Crossref PubMed Scopus (2918) Google Scholar]Induces GC-derived lymphomas in WT-background mice [30.Jin H.Y. et al.MicroRNA-17~92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways.EMBO J. 2013; 32: 2377-2391Crossref PubMed Scopus (96) Google Scholar]Inhibits expression of Pten, P21 [34.Xiao C. et al.Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes.Nat. Immunol. 2008; 9: 405-414Crossref PubMed Scopus (953) Google Scholar,35.Inomata M. et al.MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes.Blood. 2009; 113: 396-402Crossref PubMed Scopus (205) Google Scholar], Bim [34.Xiao C. et al.Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes.Nat. Immunol. 2008; 9: 405-414Crossref PubMed Scopus (953) Google Scholar], and c-Myc [36.Mihailovich M. et al.miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth.Nat. Commun. 2015; 68725Crossref PubMed Scopus (49) Google Scholar,37.Olive V. et al.A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis.Elife. 2013; 2e00822Crossref PubMed Google Scholar] in miceRegulates cell survival and proliferation [30.Jin H.Y. et al.MicroRNA-17~92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways.EMBO J. 2013; 32: 2377-2391Crossref PubMed Scopus (96) Google Scholar, 31.Sandhu S.K. et al.B-cell malignancies in microRNA Eμ-miR-17~92 transgenic mice.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 18208-18213Crossref PubMed Scopus (0) Google Scholar, 32.Olive V. et al.miR-19 is a key oncogenic component of miR-17-92.Genes Dev. 2009; 23: 2839-2849Crossref PubMed Scopus (462) Google Scholar,114.Jiang C. et al.The miR-17~92 cluster activates mTORC1 in mantle cell lymphoma by targeting multiple regulators in the STK11/AMPK/TSC/mTOR pathway.Br. J. Haematol. 2019; 185: 616-620Crossref PubMed Scopus (1) Google Scholar], apoptosis inhibition [115.Li Y. et al.MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state.Cancer Cell. 2014; 26: 262-272Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar], chromatin regulation [115.Li Y. et al.MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state.Cancer Cell. 2014; 26: 262-272Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar], BCR signaling amplification [116.Psathas J.N. et al.The Myc-miR-17-92 axis amplifies B-cell receptor signaling via inhibition of ITIM proteins: a novel lymphomagenic feed-forward loop.Blood. 2013; 122: 4220-4229Crossref PubMed Scopus (45) Google Scholar,117.Jablonska E. et al.miR-17-92 represses PTPROt and PP2A phosphatases and amplifies tonic BCR signaling in DLBCL cells.Exp. Hematol. 2017; 46 (e51): 56-61Abstract Full Text Full Text PDF PubMed Google Scholar], and tumor metabolism [118.Izreig S. et al.The miR-17 approximately 92 microRNA Cluster is a global regulator of tumor metabolism.Cell Rep. 2016; 16: 1915-1928Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] in human and mouse B cellsSimultaneous inhibition of 13 oncomiRsb limits human SUDHL-4 DLBCL xenograft growth [38.Su Y. et al.Therapeutic strategy with artificially-designed i-lncRNA targeting multiple oncogenic microRNAs exhibits effective antitumor activity in diffuse large B-cell lymphoma.Oncotarget. 2016; 7: 49143-49155Crossref PubMed Scopus (8) Google Scholar]bIncludes miR-21, miR-155, miR-221/222, miR-125a-5p/125b, and miR-146a/146b-5p as well as the miR-17-92 family members miR-17, miR-19a/19b, and miR-20a/20bmiR-19bOncomiRIncreased expression in primary human B-NHL [27.He L. et al.A microRNA polycistron as a potential human oncogene.Nature. 2005; 435: 828-833Crossref PubMed Scopus (2918) Google Scholar] due to gene amplifications [111.Ota A. et al.Identification and characterization of a novel gene, C13orf25, as a target for 13q31–q32 amplification in malignant lymphoma.Cancer Res. 2004; 64: 3087-3095Crossref PubMed Scopus (575) Google Scholar] and Myc-mediated transcriptional upregulation [112.O’Donnell K.A. et al.c-Myc-regulated microRNAs modulate E2F1 expression.Nature. 2005; 435: 839-843Crossref PubMed Scopus (2294) Google Scholar,113.Ji M. et al.The miR-17-92 microRNA cluster is regulated by multiple mechanisms in B-cell malignancies.Am. J. Pathol. 2011; 179: 1645-1656Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar]Accelerates preB lymphoma development in MYC transgenic mice [36.Mihailovich M. et al.miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth.Nat. Commun. 2015; 68725Crossref PubMed Scopus (49) Google Scholar,37.Olive V. et al.A component of the mir-17-92 polycistronic oncomir promotes oncogene-dependent apoptosis.Elife. 2013; 2e00822Crossref PubMed Google Scholar]Expression is required for c-Myc-induced mouse lymphomagenesis [33.Mu P. et al.Genetic dissection of the miR-17~92 cluster of microRNAs in Myc-induced B-cell lymphomas.Genes Dev. 2009; 23: 2806-2811Crossref PubMed Scopus (366) Google Scholar]Inhibits expression of Pten, Bcl7a, Rnf42, and Sbf2 [32.Olive V. et al.miR-19 is a key oncogenic component of miR-17-92.Genes Dev. 2009; 23: 2839-2849Crossref PubMed Scopus (462) Google Scholar,33.Mu P. et al.Genetic dissection of the miR-17~92 cluster of microRNAs in Myc-induced B-cell lymphomas.Genes Dev. 2009; 23: 2806-2811Crossref PubMed Scopus (366) Google Scholar] in mouse B cellsNAmiR-21OncomiRUpregulated expression in primary human B-NHL [39.Volinia S. et al.A microRNA expression signature of human solid tumors defines cancer gene targets.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 2257-2261Crossref PubMed Scopus (4506) Google Scholar], increased expression in ABC-DLBCL [40.Lawrie C.H. et al.MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma.Int. J. Cancer. 2007; 121: 1156-1161Crossref PubMed Scopus (0) Google Scholar], expression associated with low DLBCL survival [41.Go H. et al.MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma.Oncotarget. 2015; 6: 15035-15049Crossref PubMed Google Scholar]miR-21 induces preB lymphomas that are dependent on continuous miR-21 expression in mice [42.Medina P.P. et al.OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma.Nature. 2010; 467: 86-90Crossref PubMed Scopus (713) Google Scholar]Inhibits expression of PTEN, PDCD4 [119.Gu L. et al.Inhibition of miR-21 induces biological and behavioral alterations in diffuse large B-cell lymphoma.Acta Haematol. 2013; 130: 87-94Crossref PubMed Scopus (0) Google Scholar], and FOXO [41.Go H. et al.MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma.Oncotarget. 2015; 6: 15035-15049Crossref PubMed Google Scholar] in human B-NHL cell linesActivates the PI3K–AKT–mTOR pathway and resistance to chemotherapy in CRL2631 human DLBCL cell line [41.Go H. et al.MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma.Oncotarget. 2015; 6: 15035-15049Crossref PubMed Google Scholar]Synthetic miR-21 inhibitors impair human OPM-2 MM xenograft growth [43.Leone E. et al.Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth.Clin. Cancer Res. 2013; 19: 2096-2106Crossref PubMed Scopus (129) Google Scholar]miR-155OncomiRIncreased expression in primary human B-NHLs [44.Eis P.S. et al.Accumulation of miR-155 and BIC RNA in human B cell lymphomas.Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 3627-3632Crossref PubMed Scopus (1107) Google Scholar,45.Garzon R. et al.Targeting microRNAs in cancer: rationale, strategies and challenges.Nat. Rev. Drug Discov. 2010; 9: 775-789Crossref PubMed Scopus (1094) Google Scholar]miR-155 induces preB and mature B cell lymphomas [46.Costinean S. et al.Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in Eμ-miR155 transgenic mice.Proc. Natl. Acad. Sci. U. S. A. 2006; 103: 7024-7029Crossref PubMed Scopus (0) Google Scholar, 47.Costinean S. et al.Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein beta are targeted by miR-155 in B cells of Emicro-MiR-155 transgenic mice.Blood. 2009; 114: 1374-1382Crossref PubMed Scopus (232) Google Scholar, 48.Pedersen I.M. et al.Onco-miR-155 targets SHIP1 to promote TNFα-dependent growth of B cell lymphomas.EMBO Mol. Med. 2009; 1: 288-295Crossref PubMed Scopus (0) Google Scholar, 49.Babar I.A. et al.Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: E1695-E1704Crossref PubMed Scopus (0) Google Scholar] in miceInhibits expression of Spi1 [120.Vigorito E. et al.MicroRNA-155 regulates the generation of immunoglobulin class-switched plasma cells.Immunity. 2007; 27: 847-859Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar], Aicda [17.Dorsett Y. et al.MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation.Immunity. 2008; 28: 630-638Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar,18.Teng G. et al.MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase.Immunity. 2008; 28: 621-629Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar], Ship1, Bcl6, Smad2, Smad5, Ctla4 [121.Mashima R. Physiological roles of miR-155.Immunology. 2015; 145: 323-333Crossref PubMed Scopus (82) Google Scholar], Actr10, Hif1a, Jarid2, and Terf1 [21.Hsin J.P. et al.The effect of cellular context on miR-155-mediated gene regulation in four major immune cell types.Nat. Immunol. 2018; 19: 1137-1145Crossref PubMed Scopus (34) Google Scholar] in mouse B cellsmiR-155 inhibition impairs the growth of B-NHL human cell-line xenografts [50.Zhang Y. et al.LNA-mediated anti-miR-155 silencing in low-grade B-cell lymphomas.Blood. 2012; 120: 1678-1686Crossref PubMed Scopus (107) Google Scholar,51.Zhu F.Q. et al.MicroRNA-155 downregulation promotes cell cycle arrest and apoptosis in diffuse large B-cell lymphoma.Oncol. Res. 2016; 24: 415-427Crossref PubMed Scopus (0) Google Scholar] and primary mouse B cell lymphomas [49.Babar I.A. et al.Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma.Proc. Natl. Acad. Sci. U. S. A. 2012; 109: E1695-E1704Crossref PubMed Scopus (0) Google Scholar,52.Cheng C.J. et al.MicroRNA silencing for cancer therapy targeted to the tumour microenvironment.Nature. 2015; 518: 107-110Crossref PubMed Scopus (461) Google Scholar]miR-217OncomiRDNA amplifications in human DLBCL [122.Lenz G. et al.Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 13520-13525Crossref PubMed Scopus (672) Google Scholar] and increased expression in human B-NHL [123.de Yebenes V.G. et al.miR-217 is an oncogene that enhances the germinal center reaction.Blood. 2014; 124: 229-239Crossref PubMed Scopus (20) Google Scholar]Overexpression in B cells leads to clonal GC-derived lymphomas in mice [123.de Yebenes V.G. et al.miR-217 is an oncogene that enhances the germinal center reaction.Blood. 2014; 124: 229-239Crossref PubMed Scopus (20) Google Scholar]Downregulation of DNA damage and repair response through Nbs1, Xrcc2, Lig4, and Pds5b downregulation and Bcl6 stabilization in mouse primary GC B cells [123.de Yebenes V.G. et al.miR-217 is an oncogene that enhances the germinal center reaction.Blood. 2014; 124: 229-239Crossref PubMed Scopus (20) Google Scholar]NAmiR-181aTumor suppressorDownregulated expression in primary human ABC-DLBCL [55.Kozloski G.A. et al.miR-181a negatively regulates NF-κB signaling and affects activated B-cell-like diffuse large B-cell lymphoma pathogenesis.Blood. 2016; 127: 2856-2866Crossref PubMed Scopus (0) Google Scholar]NANF-κB signaling [55.Kozloski G.A. et al.miR-181a negatively regulates NF-κB signaling and affects activated B-cell-like diffuse large B-cell lymphoma pathogenesis.Blood. 2016; 127: 2856-2866Crossref PubMed Scopus (0) Google Scholar] and CARD11 [58.Zhu D. et al.MicroRNA-181a inhibits activated B-cell-like diffuse large B-cell lymphoma progression by repressing CARD11.J. Oncol. 2019; 2019Crossref Scopus (0) Google Scholar] in human B HNL cell linesmiR-181a slows tumor growth rate in human OCILY10 and U2932 ABC-like DLBCL xenograft models [58.Zhu D. et al.MicroRNA-181a inhibits activated B-cell-like diffuse large B-cell lymphoma progression by repressing CARD11.J. Oncol. 2019; 2019Crossref Scopus (0) Google Scholar,63.Lim E.L. et al.Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients.Genome Biol. 2015; 1618Crossref PubMed Scopus (60) Google Scholar]miR-144/451 gene locusTumor suppressorReduced expression of miR-144 and miR-451 in primary mouse Myc-driven B lymphomas and in highly expressing MYC human DLBCL [53.Ding L. et al.Activating and sustaining c-Myc by depletion of miR-144/451 gene locus contributes to B-lymphomagenesis.Oncogene. 2018; 37: 1293-1307Crossref PubMed Scopus (0) Google Scholar]; reduced expression of miR-144 in highly expressing BCL-6 human primary BL, DLBCL, and FL and in cell lines [54.Wang H. et al.A critical role of miR-144 in diffuse large B-cell lymphoma proliferation and invasion.Cancer Immunol. Res. 2016; 4: 337-344Crossref PubMed Scopus (0) Google Scholar]Depletion of miR-144/451 locus accelerates B lymphoma generation in aged mice [53.Ding L. et al.Activating and sustaining c-Myc by depletion of miR-144/451 gene locus contributes to B-lymphomagenesis.Oncogene. 2018; 37: 1293-1307Crossref PubMed Scopus (0) Google Scholar]miR-451 directly represses Myc [53.Ding L. et al.Activating and sustaining c-Myc by depletion of miR-144/451 gene locus contributes to B-lymphomagenesis.Oncogene. 2018; 37: 1293-1307Crossref PubMed Scopus (0) Google Scholar]; miR-144 directly represses Bcl6 [54.Wang H. et al.A critical role of miR-144 in diffuse large B-cell lymphoma proliferation and invasion.Cancer Immunol. Res. 2016; 4: 337-344Crossref PubMed Scopus (0) Google Scholar] in miceTransduction of miR-144 and miR-451 inhibits mouse Myc3 and human Daudi B cell line lymphoma grow