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MicroRNAs in Cutaneous T-Cell Lymphoma: The Future of Therapy

  • Rebecca Kohnken
    Affiliations
    Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA

    Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA
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  • Anjali Mishra
    Correspondence
    Correspondence: Anjali Mishra, 233 South 10th Street, Bluemle Life Sciences Building Room 330, Philadelphia, Pennsylvania 19107, USA.
    Affiliations
    Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA

    Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio USA

    Department of Medical Oncology, Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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Open ArchivePublished:January 24, 2019DOI:https://doi.org/10.1016/j.jid.2018.10.035
      MicroRNAs (miRs) are small, noncoding RNAs with numerous cellular functions. With advancing knowledge of the many functions of miRs in cancer pathogenesis, there is emerging interest in miRs as therapeutic targets in cancers. One disease that poses an intriguing model for miR therapy is cutaneous T-cell lymphoma, a rare disease featuring malignant CD4+ T cells that proliferate in the skin. The hallmark of cutaneous T-cell lymphoma progression is epigenetic dysregulation, with aberrant miR levels being a common feature. This review aims to summarize the rapidly emerging advances in the development of miR-based therapies in cancers, with a special emphasis on CTCL.

      Graphical abstract

      Abbreviations:

      CTCL (cutaneous T-cell lymphoma), MF (mycosis fungoides), miR (microRNA), SS (Sézary syndrome)

      Introduction

      MicroRNAs (miRs) are small (18–22-nucleotide), single-stranded RNA molecules with diverse cellular and extracellular activities. A single miR can interact with and regulate numerous targets (>100 on average), and most transcripts of protein-coding genes can be regulated by multiple mature miRs (
      • Di Leva G.
      • Garofalo M.
      • Croce C.M.
      MicroRNAs in cancer.
      ,
      • Friedman J.M.
      • Jones P.A.
      MicroRNAs: critical mediators of differentiation, development and disease.
      ). Because of the complex and critical function of miRs, their expression and activity are tightly regulated in the cell.
      Profiling of miR expression, which will be discussed in the context of cancer, has shown expansive changes in miR expression in disease states, including cancers. These changes in expression are accomplished via transcriptional regulation and posttranscriptional changes, as well as in response to cellular signaling pathways such as cytokine binding (
      • Obernosterer G.
      • Leuschner P.J.
      • Alenius M.
      • Martinez J.
      Post-transcriptional regulation of microRNA expression.
      ,
      • Yang Z.
      • Wang L.
      Regulation of microRNA expression and function by nuclear receptor signaling.
      ). Transcriptional regulation of miR expression can be accomplished through altered epigenetic modifications such as methylation or histone acetylation at the promoter of the host gene (
      • Deneberg S.
      • Kanduri M.
      • Ali D.
      • Bengtzen S.
      • Karimi M.
      • Qu Y.
      • et al.
      microRNA-34b/c on chromosome 11q23 is aberrantly methylated in chronic lymphocytic leukemia.
      ,
      • Gulyaeva L.F.
      • Kushlinskiy N.E.
      Regulatory mechanisms of microRNA expression.
      ). Notably, miRs themselves can regulate the expression of these epigenetic modifiers and therefore affect the expression of other miRs in the cell (
      • Garzon R.
      • Heaphy C.E.
      • Havelange V.
      • Fabbri M.
      • Volinia S.
      • Tsao T.
      • et al.
      MicroRNA 29b functions in acute myeloid leukemia.
      ,
      • Varambally S.
      • Cao Q.
      • Mani R.S.
      • Shankar S.
      • Wang X.
      • Ateeq B.
      • et al.
      Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer.
      ).
      Many miRs map to genomic regions frequently altered in cancer, such as loss of heterozygosity regions, amplified regions, breakpoint regions, and fragile sites. These fragile sites are common sites for chromosomal breaks, translocations, and rearrangements, as well as deletion or viral integration (
      • Calin G.A.
      • Sevignani C.
      • Dumitru C.D.
      • Hyslop T.
      • Noch E.
      • Yendamuri S.
      • et al.
      Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.
      ,
      • Laganà A.
      • Russo F.
      • Sismeiro C.
      • Giugno R.
      • Pulvirenti A.
      • Ferro A.
      Variability in the incidence of miRNAs and genes in fragile sites and the role of repeats and CpG islands in the distribution of genetic material.
      ). Incredibly, losses or gains in single miRs can have dramatic effects on cellular function, such as deletion of miR-15a/16-1 in lymphomagenesis (
      • Calin G.A.
      • Dumitru C.D.
      • Shimizu M.
      • Bichi R.
      • Zupo S.
      • Noch E.
      • et al.
      Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.
      ,
      • Raveche E.S.
      • Salerno E.
      • Scaglione B.J.
      • Manohar V.
      • Abbasi F.
      • Lin Y.C.
      • et al.
      Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice.
      ). This observation highlights the importance of miR dysregulation in the initiation and progression of cancers, and thus forms the basis of their potential use as cancer therapies.

      miR Therapy in Cancer

      Targeted therapy is emerging as the most promising therapeutic approach in cancer treatment. Nonspecific cytotoxic therapies have given way to small molecules, biologics, and immunotherapies. In addition to having more specific cellular targets, these approaches have improved safety profiles and improved efficacy for many patients. However, therapeutic resistance has been limiting to the overall success of many targeted therapies. miRs represent intriguing targets for cancer therapy for multiple reasons. A single miR likely has numerous cellular targets and, therefore, wide-ranging effects on cellular function. Additionally, miRs have significant context specificity, meaning that their expression and activity differ in different tissues. Thus, using miRs as targets for therapy represents an opportunity for patient/tumor specificity and cell-type specificity while affecting multiple cellular targets that may cooperate to result in impaired malignant cell proliferation and survival. Because of this hope of therapeutic success, there are currently several early-phase clinical trials for miR-based therapies and miR-targeting therapies for cancer and other diseases.
      Depending on the tissue type or cell type, a particular miR may have tumor-suppressive, oncogenic, or mixed functions. The complex biology of miRs necessitates extensive mechanistic study and preclinical assessment to support early development of miR-based therapies. Based on the disease miR expression profile, it may be advantageous to either rescue or inhibit the expression of a single miR.
      Tumor-suppressive miRs are those that maintain basal cellular function through regulation of genes involved in the cell cycle, proliferation, and apoptosis. In many tumors, the expression of these protective miRs may be lost through multiple mechanisms, including genomic losses or deletion, transcriptional repression, or loss or dysfunction of miR biogenesis proteins (
      • Williams M.
      • Cheng Y.Y.
      • Blenkiron C.
      • Reid G.
      Exploring mechanisms of microRNA downregulation in cancer.
      ).
      It has been established in a laboratory setting and in preclinical models that restoring miR levels can inhibit tumor growth (
      • Ji Q.
      • Hao X.
      • Meng Y.
      • Zhang M.
      • Desano J.
      • Fan D.
      • et al.
      Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres.
      ,
      • Ofek P.
      • Calderón M.
      • Mehrabadi F.S.
      • Krivitsky A.
      • Ferber S.
      • Tiram G.
      • et al.
      Restoring the oncosuppressor activity of microRNA-34a in glioblastoma using a polyglycerol-based polyplex.
      ). The significant challenge for miR mimic therapy has been inefficient cellular delivery. Several ongoing preclinical studies of miR mimics in lung cancer use delivery strategies such as EDV nanocells (EnGeneIC Dream Vector; EnGeneIC Ltd, New South Wales, Australia), viral vectors, and liposomes (
      • MacDiarmid J.A.
      • Mugridge N.B.
      • Weiss J.C.
      • Phillips L.
      • Burn A.L.
      • Paulin R.P.
      • et al.
      Bacterially derived 400 nm particles for encapsulation and cancer cell targeting of chemotherapeutics.
      ,
      • Reid G.
      • Kao S.C.
      • Pavlakis N.
      • Brahmbhatt H.
      • MacDiarmid J.
      • Clarke S.
      • et al.
      Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer.
      ). EDV nanocells feature nonviable minicells coated with bispecific antibody to target cancer cells. This technology has been used in the preclinical setting for delivery of miR mimics to tumors in vivo for mesothelioma (
      • Reid G.
      • Pel M.E.
      • Kirschner M.B.
      • Cheng Y.Y.
      • Mugridge N.
      • Weiss J.
      • et al.
      Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma.
      ,
      • Williams M.
      • Kirschner M.B.
      • Cheng Y.Y.
      • Hanh J.
      • Weiss J.
      • Mugridge N.
      • et al.
      miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma.
      ) and adrenal cortical carcinoma (
      • Glover A.R.
      • Zhao J.T.
      • Gill A.J.
      • Weiss J.
      • Mugridge N.
      • Kim E.
      • et al.
      MicroRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma.
      ). EDV nanocells have already been used safely in first-in-human studies for delivery of chemotherapeutics (
      • Whittle J.R.
      • Lickliter J.D.
      • Gan H.K.
      • Scott A.M.
      • Simes J.
      • Solomon B.J.
      • et al.
      First in human nanotechnology doxorubicin delivery system to target epidermal growth factor receptors in recurrent glioblastoma.
      ).
      Two recently initiated phase I trials include a miR-34 mimic with an indication for several types of cancer and a miR-16 mimic for non-small cell lung cancer. The former uses a liposomal delivery system but has been halted because of immune-related adverse events (
      • Bouchie A.
      First microRNA mimic enters clinic.
      ,
      • Chakraborty C.
      • Sharma A.R.
      • Sharma G.
      • Doss C.G.P.
      • Lee S.S.
      Therapeutic miRNA and siRNA: moving from bench to clinic as next generation medicine.
      ). The latter uses a delivery system termed a targomiR, in which the double-stranded synthetic mimic RNA is coupled with a nanoparticle and a targeting moiety—in this case, directing the minicell to EGFR-expressing cells (
      • Reid G.
      • Kao S.C.
      • Pavlakis N.
      • Brahmbhatt H.
      • MacDiarmid J.
      • Clarke S.
      • et al.
      Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer.
      ).
      Several oncogenic miRs have been identified in different cancer cell types that target tumor suppressors for degradation. These miRs are up-regulated and overexpressed through several mechanisms, including chromosomal or gene duplication, amplification, and transcriptional up-regulation (
      • Jansson M.D.
      • Lund A.H.
      MicroRNA and cancer.
      ,
      • Zhang B.
      • Pan X.
      • Cobb G.P.
      • Anderson T.A.
      microRNAs as oncogenes and tumor suppressors.
      ).
      AntagomiRs are single-stranded antisense oligonucleotides that are complementary to the endogenous miR (
      • Czech M.P.
      MicroRNAs as therapeutic targets.
      ). AntagomiRs block binding of the specific miR to endogenous mRNA targets. These have a strong affinity for their target and are resistant to nucleases, and they have been used successfully in animal models (
      • Elmén J.
      • Lindow M.
      • Schütz S.
      • Lawrence M.
      • Petri A.
      • Obad S.
      • et al.
      LNA-mediated microRNA silencing in non-human primates.
      ,
      • Elmén J.
      • Lindow M.
      • Silahtaroglu A.
      • Bak M.
      • Christensen M.
      • Lind-Thomsen A.
      • et al.
      Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver.
      ).
      More recently developed strategies include the use of miR sponge and miR masking. Specific sponges selectively sequester the endogenous miR, thus allowing expression of the target mRNAs (
      • Ebert M.S.
      • Neilson J.R.
      • Sharp P.A.
      MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells.
      ,
      • Li J.
      • Yu H.
      • Xi M.
      • Ma D.
      • Lu X.
      The SNAI1 3′UTR functions as a sponge for multiple migration-/invasion-related microRNAs.
      ). miR masking involves the use of a chemically modified antisense oligonucleotide complementary to the mRNA target of an endogenous miR. Thus, the mask de-represses the target gene and does not interact with the target miR (
      • Wang Z.
      The principles of miRNA-masking antisense oligonucleotides technology.
      ).

      miRs in Cutaneous T-Cell Lymphoma

      The largest category of primary cutaneous lymphomas (∼70%) derives from mature skin-resident or skin-homing T cells, referred to as cutaneous T-cell lymphoma (CTCL). Mycosis fungoides (MF), the most common subtype of CTCL, may progress slowly through skin-limited stages, but in a portion of patients the disease will advance and may spread to involve lymph nodes, viscera, and blood, known as Sézary syndrome (SS). SS may arise de novo in some patients, the disease course is often very rapid, and it is uniformly fatal (
      • Benner M.F.
      • Jansen P.M.
      • Vermeer M.H.
      • Willemze R.
      Prognostic factors in transformed mycosis fungoides: a retrospective analysis of 100 cases.
      ,
      • Kohnken R.
      • Fabbro S.
      • Hastings J.
      • Porcu P.
      • Mishra A.
      Sézary syndrome: clinical and biological aspects.
      ).
      Patients with early-stage disease can benefit from skin-directed therapies; however, for most patients the disease will progress despite these treatments. At the time of tumor stage or visceral spread, systemic therapies are initiated. These include immune-modulatory therapies and, recently, histone deacetylase inhibitors. These systemic therapies have variable responses, around 30% for most (
      • Olsen E.A.
      • Kim Y.H.
      • Kuzel T.M.
      • Pacheco T.R.
      • Foss F.M.
      • Parker S.
      • et al.
      Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma.
      ,
      • Virmani P.
      • Hwang S.H.
      • Hastings J.G.
      • Haverkos B.M.
      • Kohnken B.
      • Gru A.A.
      • et al.
      Systemic therapy for cutaneous T-cell lymphoma: who, when, what, and why?.
      ), but with high rates of relapse and development of clinical resistance. These challenges highlight the need for better understanding of disease pathogenesis, early diagnosis, and identification of innovative therapeutic targets.
      The new age of personalized medicine has yielded side-by-side advancement in diagnosis and treatment of individual tumors. miR profiling, the investigation of differential miR expression in CTCL patients, has emerged as a useful tool to study the biology of tumor cells and tissues and to aid in diagnosis of disease (
      • Ralfkiaer U.
      • Hagedorn P.H.
      • Bangsgaard N.
      • Løvendorf M.B.
      • Ahler C.B.
      • Svensson L.
      • et al.
      Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL).
      ,
      • Ralfkiaer U.
      • Lindahl L.M.
      • Lindal L.
      • Litman T.
      • Gjerdrum L.M.
      • Ahler C.B.
      • et al.
      MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma.
      ). Furthermore, miR profiling has also been suggested for use in prognostication and monitoring of therapeutic response in CTCL (
      • Lindahl L.M.
      • Besenbacher S.
      • Rittig A.H.
      • Celis P.
      • Willerslev-Olsen A.
      • Gjerdrum L.M.R.
      • et al.
      Prognostic miRNA classifier in early-stage mycosis fungoides: development and validation in a Danish nationwide study.
      ,
      • Shen X.
      • Wang B.
      • Li K.
      • Wang L.
      • Zhao X.
      • Xue F.
      • et al.
      MicroRNA signatures in diagnosis and prognosis of cutaneous T-cell lymphoma.
      ).
      Several studies have been done in recent years to explore the miRnome of CTCL patients. Epigenetic dysregulation in general is a hallmark feature of CTCL progression, and many miRs have been shown to be altered in this disease (
      • de Silva S.
      • Wang F.
      • Hake T.S.
      • Porcu P.
      • Wong H.K.
      • Wu L.
      Downregulation of SAMHD1 expression correlates with promoter DNA methylation in Sézary syndrome patients.
      ,
      • Ralfkiaer U.
      • Hagedorn P.H.
      • Bangsgaard N.
      • Løvendorf M.B.
      • Ahler C.B.
      • Svensson L.
      • et al.
      Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL).
      ) (Table 1).
      Table 1MicroRNA Profiling in CTCL
      ApplicationMethodologyUp-regulated miRsDown-regulated miRsReference
      Diagnosis of CTCL vs. BIDMicroarray followed by PCR326

      663b

      711

      155
      203

      205
      • Ralfkiaer U.
      • Hagedorn P.H.
      • Bangsgaard N.
      • Løvendorf M.B.
      • Ahler C.B.
      • Svensson L.
      • et al.
      Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL).
      Diagnosis of CTCL vs. BIDMicroarray155

      21

      142

      146

      181a/b
      141/200c
      • Sandoval J.
      • Díaz-Lagares A.
      • Salgado R.
      • Servitje O.
      • Climent F.
      • Ortiz-Romero P.L.
      • et al.
      MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma.
      Diagnosis of SSMicroarray21

      214

      486
      • Narducci M.G.
      • Arcelli D.
      • Picchio M.C.
      • Lazzeri C.
      • Pagani E.
      • Sampogna F.
      • et al.
      MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sézary syndrome.
      Diagnosis of C-ALCL vs. BIDMicroarray followed by PCR155

      27b

      30c

      29b
      • Benner M.F.
      • Ballabio E.
      • van Kester M.S.
      • Saunders N.J.
      • Vermeer M.H.
      • Willemze R.
      • et al.
      Primary cutaneous anaplastic large cell lymphoma shows a distinct miRNA expression profile and reveals differences from tumor-stage mycosis fungoides.
      Diagnosis of aggressive CTCL variantsPCR181a

      93

      34a
      • Marosvári D.
      • Téglási V.
      • Csala I.
      • Marschalkó M.
      • Bödör C.
      • Timár B.
      • et al.
      Altered microRNA expression in folliculotropic and transformed mycosis fungoides.
      Abbreviations: BID, benign inflammatory dermatoses; C-ALCL: cutaneous anaplastic large cell lymphoma; CTCL, cutaneous T-cell lymphoma; miR, microRNA; SS, Sézary syndrome.
      Because of the diverse targets of miRs and their critical role in cellular function, restoration of basal miR expression poses an intriguing therapeutic strategy. miR-based therapies may represent favorable adjunct treatment options to enhance sensitivity to chemotherapy or other targeted drugs.
      As examples, miRs known to play a role in the clinical response to chemotherapy in different cancer types include miR-203 for tyrosine kinase inhibitors in lung cancer based on its targeting of Src kinase (
      • Garofalo M.
      • Romano G.
      • Di Leva G.
      • Nuovo G.
      • Jeon Y.J.
      • Ngankeu A.
      • et al.
      EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers.
      ), miR-155 for doxorubicin and others based on its targeting of FOXO3A (
      • Kong W.
      • He L.
      • Coppola M.
      • Guo J.
      • Esposito N.N.
      • Coppola D.
      • et al.
      MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer.
      ), miR-214 for cisplatin in ovarian cancer based on its targeting of PTEN (
      • Yang H.
      • Kong W.
      • He L.
      • Zhao J.J.
      • O’Donnell J.D.
      • Wang J.
      • et al.
      MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN.
      ), miR-181a/b for nucleoside analogs in leukemia based on their targeting of anti-apoptotic proteins such as Bcl-2 (
      • Zhu D.X.
      • Zhu W.
      • Fang C.
      • Fan L.
      • Zou Z.J.
      • Wang Y.H.
      • et al.
      miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes.
      ), and miR-29b for gemcitabine in cholangiocarcinoma based on its targeting of promigratory proteinase MMP2 (
      • Okamoto K.
      • Miyoshi K.
      • Murawaki Y.
      miR-29b, miR-205 and miR-221 enhance chemosensitivity to gemcitabine in HuH28 human cholangiocarcinoma cells.
      ). miR/mRNA network analyses on resistant and sensitive cells may assist in the identification of more of these potentially targetable pathways (
      • Hiddingh L.
      • Raktoe R.S.
      • Jeuken J.
      • Hulleman E.
      • Noske D.P.
      • Kaspers G.J.
      • et al.
      Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis.
      ).

      miR Targets in CTCL

      CTCL provides a unique and desirable disease setting for testing innovative miR-based therapies (Figure 1 and Table 2). First, it is a severe and uniformly fatal disease with few effective therapeutic options, and therefore there is abundant potential for improved therapies to make a significant clinical impact. Second, the tumor is in the skin, making it easily visible and accessible for therapeutic delivery. Finally, therapeutic improvement can be readily monitored clinically and by relatively noninvasive means such as skin biopsy. Indeed, several miR-based therapies in development rely on intradermal or subcutaneous injection of their lead compounds, largely addressing bioavailability challenges for MF patients.
      Figure thumbnail gr1
      Figure 1MicroRNAs in CTCL. IL-2 family cytokines signal through the common γ receptor with downstream signaling mediated by JAK/STAT proteins. JAK3 activates STAT5 by inducing its phosphorylation. STAT5 induces increased expression of miR-155, which then has numerous effects on cellular proliferation. JAK inhibitors have been shown to reduce miR-155 level. MRG-106 (miR-155 inhibitor) is in clinical trials for the treatment of CTCL. STAT3 is constitutively activated in many CTCL patients, but it may also be activated by IL-2 signaling. STAT3 induces miR-21 expression, which then supports cellular survival. There is currently no known regulation of miR-214 level by IL-2. Elevated miR-214 in CTCL contributes to cellular survival, and miR-214 inhibition has been investigated as a therapy for CTCL. IL-2 family signaling induces transcriptional repression of miR-29b, a mechanism that can be inhibited by bortezomib. miR-29b has many epigenetic modifiers as downstream targets. Rescue of miR-29b level is proposed as a potential therapeutic strategy for CTCL. CTCL, cutaneous T-cell lymphoma; miR, microRNA, P, phosphorylation.
      Table 2MicroRNA Targets in CTCL
      CharacteristicsmiR-21miR-155miR-214miR-29b
      TypeOncogenicOncogenicOncogenicTumor suppressive
      Profile in CTCL patientsUp-regulatedUp-regulated, stage-dependentUp-regulatedDown-regulated
      SpecificityPoorHigh
      Association with outcomeN/AN/AYesN/A
      Important targetsPTENFOXO3APTEN

      LHX6

      Bcl2

      KLF12
      MMP-2

      DNMT3

      SP-1

      BRD4
      Cellular effectsProliferation, invasion, migrationSurvival, response to therapyEpigenetic dysregulation
      Role in resistanceHigh expression imparts resistance to TKIsHigh expression imparts resistance to doxorubicinKnockdown resensitizes to TKIs, high expression imparts resistance to cisplatinHigh expression imparts resistance to gemcitabine
      Results of preclinical targetingSilencing in SS cells results in apoptosisInhibition decreases malignant cell proliferationInhibition is efficacious in CTCL miceRescue by bortezomib reduces cellular survival and proliferation
      Abbreviations: CTCL, cutaneous T-cell lymphoma; miR, microRNA; N/A, not applicable; SS, Sézary syndrome; TKI, tyrosine kinase inhibitor.
      Cytokine signaling and tumor microenvironment are thought to contribute to miR dysregulation in multiple disease states, including multiple sclerosis (
      • de Faria Jr., O.
      • Moore C.S.
      • Kennedy T.E.
      • Antel J.P.
      • Bar-Or A.
      • Dhaunchak A.S.
      MicroRNA dysregulation in multiple sclerosis.
      ) and colorectal cancer (
      • Pucci S.
      • Mazzarelli P.
      MicroRNA dysregulation in colon cancer microenvironment interactions: the importance of small things in metastases.
      ). In CTCL, almost all members of the IL-2Rγ cytokine family have been implicated in the disease pathogenesis and progression, and downstream signaling of these cytokines may influence the tumor microenvironment (
      • Krejsgaard T.
      • Lindahl L.M.
      • Mongan N.P.
      • Wasik M.A.
      • Litvinov I.V.
      • Iversen L.
      • et al.
      Malignant inflammation in cutaneous T-cell lymphoma—a hostile takeover.
      ). One such γ-chain cytokine, IL-15, is a chronic inflammatory cytokine that is known to play a critical role in oncogenesis of cancers including CTCL (
      • Mishra A.
      • Sullivan L.
      • Caligiuri M.A.
      Molecular pathways: interleukin-15 signaling in health and in cancer.
      ,
      • Mishra A.
      • La Perle K.
      • Kwiatkowski S.
      • Sullivan L.A.
      • Sams G.H.
      • Johns J.
      • et al.
      Mechanism, consequences and therapeutic targeting of abnormal IL-15 signaling in cutaneous T-cell lymphoma.
      ,
      • Waldmann T.A.
      The biology of IL-15: implications for cancer therapy and the treatment of autoimmune disorders.
      ). IL-15 is up-regulated in CTCL patients in a stage-dependent manner and results in a host of downstream effects that contribute to CTCL pathogenesis. It has been shown that some of the effects of IL-15 signaling are epigenetic (
      • Kohnken R.
      • Wen J.
      • Mundy-Bosse B.
      • McConnell K.
      • Keiter A.
      • Grinshpun L.
      • et al.
      Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T-cell lymphoma.
      ,
      • Mishra A.
      • Liu S.
      • Sams G.H.
      • Curphey D.P.
      • Santhanam R.
      • Rush L.J.
      • et al.
      Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation.
      ). In the following sections, we discuss four miRs that have well-described roles in CTCL pathogenesis and thus serve as potential therapeutic targets. The expression of three of these miRs is known to be affected by IL-15 signaling, providing a disease setting that allows further study of this mechanistic interaction between microenvironment and miR expression in cancer.

       miR-21

      miR-21 is considered oncogenic in several tumor types, including SS. Indeed, miR-21 is aberrantly expressed in malignant skin lymphocytes of CTCL patients (
      • Lindahl L.M.
      • Fredholm S.
      • Joseph C.
      • Nielsen B.S.
      • Jønson L.
      • Willerslev-Olsen A.
      • et al.
      STAT5 induces miR-21 expression in cutaneous T cell lymphoma.
      ). The overexpression of miR-21 imparts tumorigenic effects such as enhanced proliferation, invasion, and migration in solid tumors such as breast, cervical, and colorectal cancer, in part through its targeted degradation of tumor suppressor PTEN (
      • Li C.
      • Song L.
      • Zhang Z.
      • Bai X.X.
      • Cui M.F.
      • Ma L.J.
      MicroRNA-21 promotes TGF-β1-induced epithelial-mesenchymal transition in gastric cancer through up-regulating PTEN expression.
      ,
      • Xu J.
      • Zhang W.
      • Lv Q.
      • Zhu D.
      Overexpression of miR-21 promotes the proliferation and migration of cervical cancer cells via the inhibition of PTEN.
      ,
      • Yan L.X.
      • Wu Q.N.
      • Zhang Y.
      • Li Y.Y.
      • Liao D.Z.
      • Hou J.H.
      • et al.
      Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth.
      ). Furthermore, overexpression of miR-21 is associated with acquired resistance to tyrosine kinase inhibitors in lung cancer, also related to its effect on PTEN expression (
      • Shen H.
      • Zhu F.
      • Liu J.
      • Xu T.
      • Pei D.
      • Wang R.
      • et al.
      Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer.
      ).
      It has been shown in several recent genomic studies that signaling molecule STAT3, which is downstream of cytokine signaling, such as with IL-2 family members, is constitutively activated in CTCL neoplastic cells (
      • Nielsen M.
      • Kaltoft K.
      • Nordahl M.
      • Röpke C.
      • Geisler C.
      • Mustelin T.
      • et al.
      Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines.
      ,
      • Sommer V.H.
      • Clemmensen O.J.
      • Nielsen O.
      • Wasik M.
      • Lovato P.
      • Brender C.
      • et al.
      In vivo activation of STAT3 in cutaneous T-cell lymphoma. Evidence for an antiapoptotic function of STAT3.
      ,
      • Zhang Q.
      • Nowak I.
      • Vonderheid E.C.
      • Rook A.H.
      • Kadin M.E.
      • Nowell P.C.
      • et al.
      Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome.
      ). miR-21 was shown to be a direct target of STAT3 in SS, such that signaling through the common γ chain results in activation of STAT3 and up-regulation of miR-21 (
      • van der Fits L.
      • van Kester M.S.
      • Qin Y.
      • Out-Luiting J.J.
      • Smit F.
      • Zoutman W.H.
      • et al.
      MicroRNA-21 expression in CD4+ T cells is regulated by STAT3 and is pathologically involved in Sézary syndrome.
      ). STAT5, also downstream of IL-2 cytokines including IL-15, was also shown to induce miR-21 expression by binding to its promoter region (
      • Lindahl L.M.
      • Fredholm S.
      • Joseph C.
      • Nielsen B.S.
      • Jønson L.
      • Willerslev-Olsen A.
      • et al.
      STAT5 induces miR-21 expression in cutaneous T cell lymphoma.
      ). Silencing of miR-21 in primary SS cells, as well as the use of antagomir to miR-21, resulted in apoptosis (
      • Narducci M.G.
      • Arcelli D.
      • Picchio M.C.
      • Lazzeri C.
      • Pagani E.
      • Sampogna F.
      • et al.
      MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sézary syndrome.
      ,
      • Ralfkiaer U.
      • Hagedorn P.H.
      • Bangsgaard N.
      • Løvendorf M.B.
      • Ahler C.B.
      • Svensson L.
      • et al.
      Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL).
      ,
      • van der Fits L.
      • van Kester M.S.
      • Qin Y.
      • Out-Luiting J.J.
      • Smit F.
      • Zoutman W.H.
      • et al.
      MicroRNA-21 expression in CD4+ T cells is regulated by STAT3 and is pathologically involved in Sézary syndrome.
      ).
      miR-21 overexpression was also described in other inflammatory conditions and is thus not useful in CTCL diagnosis. Important to the consideration of miR-21 as a potential therapeutic target in CTCL are the data showing aberrant overexpression of miR-21 in skin stroma (
      • Lindahl L.M.
      • Fredholm S.
      • Joseph C.
      • Nielsen B.S.
      • Jønson L.
      • Willerslev-Olsen A.
      • et al.
      STAT5 induces miR-21 expression in cutaneous T cell lymphoma.
      ) of CTCL patients. Thus, its dysregulation is not specific to the neoplastic population. This may limit any therapeutic inhibition of miR-21 that does not specifically target the neoplastic population via some modification of the drug compound.

       miR-155

      miR-155 is constitutively overexpressed in malignant cells from CTCL patients, which has been associated with specific action of STAT5. Indeed, supplementation of primary cells with IL-15 induces miR-155 expression, whereas use of a JAK inhibitor decreases it (
      • Kopp K.L.
      • Ralfkiaer U.
      • Gjerdrum L.M.
      • Helvad R.
      • Pedersen I.H.
      • Litman T.
      • et al.
      STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma.
      ). Inhibition of miR-155 inhibits proliferation of malignant T cells (
      • Kopp K.L.
      • Ralfkiaer U.
      • Gjerdrum L.M.
      • Helvad R.
      • Pedersen I.H.
      • Litman T.
      • et al.
      STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma.
      ).
      Disease progression is of particular research and clinical interest in CTCL, because stage of disease significantly affects prognosis (
      • Kohnken R.
      • Fabbro S.
      • Hastings J.
      • Porcu P.
      • Mishra A.
      Sézary syndrome: clinical and biological aspects.
      ,
      • Virmani P.
      • Hwang S.H.
      • Hastings J.G.
      • Haverkos B.M.
      • Kohnken B.
      • Gru A.A.
      • et al.
      Systemic therapy for cutaneous T-cell lymphoma: who, when, what, and why?.
      ). Two studies have noted higher miR-155 levels in advanced-stage MF patients (
      • Fava P.
      • Bergallo M.
      • Astrua C.
      • Brizio M.
      • Galliano I.
      • Montanari P.
      • et al.
      miR-155 expression in Primary Cutaneous T-Cell Lymphomas (CTCL).
      ,
      • Moyal L.
      • Barzilai A.
      • Gorovitz B.
      • Hirshberg A.
      • Amariglio N.
      • Jacob-Hirsch J.
      • et al.
      miR-155 is involved in tumor progression of mycosis fungoides.
      ) and suggest that miR-155 may be involved in the progression of CTCL. STAT5 was shown to decrease expression of putative tumor suppressor SATB1 via induction of miR-155 in a disease stage-dependent manner (
      • Fredholm S.
      • Willerslev-Olsen A.
      • Met Ö.
      • Kubat L.
      • Gluud M.
      • Mathiasen S.L.
      • et al.
      SATB1 in malignant T cells.
      ). Furthermore, it was shown using in situ hybridization that miR-155 was more highly expressed in malignant cells than in non-neoplastic infiltrating lymphocytes (
      • Kopp K.L.
      • Ralfkiaer U.
      • Nielsen B.S.
      • Gniadecki R.
      • Woetmann A.
      • Ødum N.
      • et al.
      Expression of miR-155 and miR-126 in situ in cutaneous T-cell lymphoma.
      ).
      One of the few current clinical trials involving the targeting of miR in cancer is a miR-155 inhibitor, currently being investigated for the indication of CTCL (
      • Querfeld C.
      • Foss F.M.
      • Pinter-Brown L.C.
      • Porcu P.
      • William B.M.
      • Pacheco T.
      • et al.
      Phase 1 study of the safety and efficacy of MRG-106, a synthetic inhibitor of microRNA-155, in CTCL patients.
      ). An oligonucleotide developed by miRagen Therapeutics (Boulder, CO) is currently being evaluated in a first-in-human study in MF patients. Administration of this drug is intratumoral or subcutaneous, highlighting the benefits of MF as an indication for this type of therapy, because the neoplasm is readily accessible for practical and efficient delivery of the compound. Thus far, the drug has been well tolerated. Furthermore, early data suggest efficacy with increased tumor cell death (
      • Querfeld C.
      • Foss F.M.
      • Pinter-Brown L.C.
      • Porcu P.
      • William B.M.
      • Pacheco T.
      • et al.
      Phase 1 study of the safety and efficacy of MRG-106, a synthetic inhibitor of microRNA-155, in CTCL patients.
      ). This ongoing clinical trial provides a prime example of the use of preclinical data to support the development of a miR-based therapy and further highlights the benefits of a cutaneous neoplasm as an early potential indication for these types of therapies.

       miR-214

      miR-214 expression is often significantly correlated with overall survival in various cancer types (
      • Feng Y.
      • Duan F.
      • Liu W.
      • Fu X.
      • Cui S.
      • Yang Z.
      Prognostic value of the microRNA-214 in multiple human cancers: a meta-analysis of observational studies.
      ). As mentioned, miR-214 has extensive implications for diagnosis and prognostication of CTCL. In fact, miR-214 represents one of the four most differentially expressed miRs in SS patients (
      • Qin Y.
      • Buermans H.P.
      • van Kester M.S.
      • van der Fits L.
      • Out-Luiting J.J.
      • Osanto S.
      • et al.
      Deep-sequencing analysis reveals that the miR-199a2/214 cluster within DNM3os represents the vast majority of aberrantly expressed microRNAs in Sézary syndrome.
      ).
      Through its targeting of anti-apoptotic Bcl-2 (
      • Wang F.
      • Liu M.
      • Li X.
      • Tang H.
      MiR-214 reduces cell survival and enhances cisplatin-induced cytotoxicity via down-regulation of Bcl2l2 in cervical cancer cells.
      ) and tumor-suppressor PTEN (
      • Wang Y.-S.
      • Wang Y.-H.
      • Xia H.-P.
      • Zhou S.-W.
      • Schmid-Bindert G.
      • Zhou C.-C.
      MicroRNA-214 regulates the acquired resistance to gefitinib via the PTEN/AKT pathway in EGFR-mutant cell lines.
      ), miR-214 has effects on cellular survival and response to chemotherapy. Because of the multitude of critical cellular targets of miR-214, it has been characterized as a master miRNA with regard to essential drug resistance pathways (
      • An X.
      • Sarmiento C.
      • Tan T.
      • Zhu H.
      Regulation of multidrug resistance by microRNAs in anti-cancer therapy.
      ). Thus, targeting miR-214 may improve sensitivity of cancer cells to numerous types of anticancer drugs. For example, a recent study in non-small cell lung cancer showed reversal of resistance to erlotinib through down-regulation of miR-214 (
      • Liao J.
      • Lin J.
      • Lin D.
      • Zou C.
      • Kurata J.
      • Lin R.
      • et al.
      Down-regulation of miR-214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression.
      ).
      Because of increased expression of miR-214 and its proposed oncogenic role in CTCL, we sought to explore the potential efficacy of inhibiting its expression. We used a miR-214 inhibitor in vivo in a mouse model of CTCL that is highly translatable to the human disease (
      • Mishra A.
      • La Perle K.
      • Kwiatkowski S.
      • Sullivan L.A.
      • Sams G.H.
      • Johns J.
      • et al.
      Mechanism, consequences and therapeutic targeting of abnormal IL-15 signaling in cutaneous T-cell lymphoma.
      ). Administered by subcutaneous injection, a specific inhibitor to miR-214 resulted in clinical improvement of gross disease in CTCL mice compared with scrambled control (
      • Kohnken R.
      • Wen J.
      • McConnell K.
      • Grinshpun L.
      • Keiter A.
      • McNeil B.
      • et al.
      Therapeutic targeting of microRNA-214 in cutaneous T-cell lymphoma.
      ). On examination of the lesions histologically, miR-214 inhibitor–treated mice were significantly improved compared with control animals. This preclinical efficacy study supports the future investigation of inhibiting miR-214 as a therapeutic strategy in CTCL.

       miR-29b

      A recent characterization of miRs as epi-miRs is an apt description for miR-29b. Epi-miRs are those that have extensive effects on epigenetic regulators, thus influencing the overall epigenetic landscape of the cell. miR-29b is known to target and down-regulate histone deacetylase HDAC4 in multiple myeloma (
      • Amodio N.
      • Leotta M.
      • Bellizzi D.
      • Di Martino M.T.
      • D’Aquila P.
      • Lionetti M.
      • et al.
      DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma.
      ,
      • Amodio N.
      • Stamato M.A.
      • Gullà A.M.
      • Morelli E.
      • Romeo E.
      • Raimondi L.
      • et al.
      Therapeutic targeting of miR-29b/HDAC4 epigenetic loop in multiple myeloma.
      ) and DNA methyltransferase DNMT3 in acute myeloid leukemia (
      • Cui H.
      • Wang L.
      • Gong P.
      • Zhao C.
      • Zhang S.
      • Zhang K.
      • et al.
      Deregulation between miR-29b/c and DNMT3A is associated with epigenetic silencing of the CDH1 gene, affecting cell migration and invasion in gastric cancer.
      ). Additionally, miR-29b targets prosurvival genes such as SP-1 (
      • Eiring A.M.
      • Harb J.G.
      • Neviani P.
      • Garton C.
      • Oaks J.J.
      • Spizzo R.
      • et al.
      miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts.
      ). Associated with these many functions, miR-29b is often considered to act as a tumor suppressor, and its expression is down-regulated in many cancer types (
      • Yan B.
      • Guo Q.
      • Fu F.J.
      • Wang Z.
      • Yin Z.
      • Wei Y.B.
      • et al.
      The role of miR-29b in cancer: regulation, function, and signaling.
      ).
      Epigenetic dysregulation is an important hallmark of CTCL disease progression. We recently described decreased miR-29b expression in CTCL patients compared with normal donors (
      • Kohnken R.
      • Wen J.
      • Mundy-Bosse B.
      • McConnell K.
      • Keiter A.
      • Grinshpun L.
      • et al.
      Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T-cell lymphoma.
      ). We have shown the role of IL-15 signaling in driving the decrease in expression of miR-29b in large granular lymphocytic leukemia and CTCL, both neoplasms driven by IL-15 (
      • Mishra A.
      • Liu S.
      • Sams G.H.
      • Curphey D.P.
      • Santhanam R.
      • Rush L.J.
      • et al.
      Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation.
      ). IL-15 and miR-29b seem to cooperate to contribute to widespread epigenetic dysregulation in these neoplasms. Adding to the known targets of miR-29b that affect the epigenetic landscape of neoplastic cells, we describe BRD4, which has been shown to be a survival factor in several types of tumors (
      • Delmore J.E.
      • Issa G.C.
      • Lemieux M.E.
      • Rahl P.B.
      • Shi J.
      • Jacobs H.M.
      • et al.
      BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
      ,
      • Herrmann H.
      • Blatt K.
      • Shi J.
      • Gleixner K.V.
      • Cerny-Reiterer S.
      • Müllauer L.
      • et al.
      Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML.
      ). Indeed, pharmacologic rescue of miR-29b by bortezomib or direct transfection of neoplastic cells with a miR-29b mimic results in reduced cellular survival and proliferation with decreased protein expression of BRD4 (
      • Kohnken R.
      • Wen J.
      • Mundy-Bosse B.
      • McConnell K.
      • Keiter A.
      • Grinshpun L.
      • et al.
      Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T-cell lymphoma.
      ).

      Conclusion

      Mechanisms of regulation of miRs and emerging mechanisms of miR function are being discovered at a rapid pace. This review seeks to provide a comprehensive yet approachable summary of the emerging world of miR therapeutics. miR-based therapy represents the latest example of the capacity for improving the lives of people through the benefit of basic science. The success of these programs, which seek to integrate the complexities of RNA biology with the necessity of a cure, will rely on the successful cooperation of researchers, clinicians, and pharmacologists in advancing of the future of therapy.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      Support for this study was provided by Spatz Foundation (A.M.) , American Skin Association (A.M.) , Cutaneous Lymphoma Foundation (A.M.) , Pelotonia (A.M.) , DeStefano Lymphoma Research funds (A.M.) , and a National Institutes of Health T32 fellowship from the Office of the Director ( OD010429 ) (R.K.), and in part by National Institutes of Health, National Cancer Institute grant CA016058 .

      References

        • Amodio N.
        • Leotta M.
        • Bellizzi D.
        • Di Martino M.T.
        • D’Aquila P.
        • Lionetti M.
        • et al.
        DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma.
        Oncotarget. 2012; 3: 1246-1258
        • Amodio N.
        • Stamato M.A.
        • Gullà A.M.
        • Morelli E.
        • Romeo E.
        • Raimondi L.
        • et al.
        Therapeutic targeting of miR-29b/HDAC4 epigenetic loop in multiple myeloma.
        Mol Cancer Ther. 2016; 15: 1364-1375
        • An X.
        • Sarmiento C.
        • Tan T.
        • Zhu H.
        Regulation of multidrug resistance by microRNAs in anti-cancer therapy.
        Acta Pharm Sin B. 2017; 7: 38-51
        • Benner M.F.
        • Ballabio E.
        • van Kester M.S.
        • Saunders N.J.
        • Vermeer M.H.
        • Willemze R.
        • et al.
        Primary cutaneous anaplastic large cell lymphoma shows a distinct miRNA expression profile and reveals differences from tumor-stage mycosis fungoides.
        Exp Dermatol. 2012; 21: 632-634
        • Benner M.F.
        • Jansen P.M.
        • Vermeer M.H.
        • Willemze R.
        Prognostic factors in transformed mycosis fungoides: a retrospective analysis of 100 cases.
        Blood. 2012; 119: 1643-1649
        • Bouchie A.
        First microRNA mimic enters clinic.
        Nat Biotechnol. 2013; 31: 577
        • Calin G.A.
        • Dumitru C.D.
        • Shimizu M.
        • Bichi R.
        • Zupo S.
        • Noch E.
        • et al.
        Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.
        Proc Natl Acad Sci USA. 2002; 99: 15524-15529
        • Calin G.A.
        • Sevignani C.
        • Dumitru C.D.
        • Hyslop T.
        • Noch E.
        • Yendamuri S.
        • et al.
        Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.
        Proc Natl Acad Sci USA. 2004; 101: 2999-3004
        • Chakraborty C.
        • Sharma A.R.
        • Sharma G.
        • Doss C.G.P.
        • Lee S.S.
        Therapeutic miRNA and siRNA: moving from bench to clinic as next generation medicine.
        Mol Ther Nucleic Acids. 2017; 8: 132-143
        • Cui H.
        • Wang L.
        • Gong P.
        • Zhao C.
        • Zhang S.
        • Zhang K.
        • et al.
        Deregulation between miR-29b/c and DNMT3A is associated with epigenetic silencing of the CDH1 gene, affecting cell migration and invasion in gastric cancer.
        PLoS One. 2015; 10: e0123926
        • Czech M.P.
        MicroRNAs as therapeutic targets.
        N Engl J Med. 2006; 354: 1194-1195
        • de Faria Jr., O.
        • Moore C.S.
        • Kennedy T.E.
        • Antel J.P.
        • Bar-Or A.
        • Dhaunchak A.S.
        MicroRNA dysregulation in multiple sclerosis.
        Front Genet. 2012; 3: 311
        • de Silva S.
        • Wang F.
        • Hake T.S.
        • Porcu P.
        • Wong H.K.
        • Wu L.
        Downregulation of SAMHD1 expression correlates with promoter DNA methylation in Sézary syndrome patients.
        J Invest Dermatol. 2014; 134: 562-565
        • Delmore J.E.
        • Issa G.C.
        • Lemieux M.E.
        • Rahl P.B.
        • Shi J.
        • Jacobs H.M.
        • et al.
        BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
        Cell. 2011; 146: 904-917
        • Deneberg S.
        • Kanduri M.
        • Ali D.
        • Bengtzen S.
        • Karimi M.
        • Qu Y.
        • et al.
        microRNA-34b/c on chromosome 11q23 is aberrantly methylated in chronic lymphocytic leukemia.
        Epigenetics. 2014; 9: 910-917
        • Di Leva G.
        • Garofalo M.
        • Croce C.M.
        MicroRNAs in cancer.
        Annu Rev Pathol. 2014; 9: 287-314
        • Ebert M.S.
        • Neilson J.R.
        • Sharp P.A.
        MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells.
        Nat Methods. 2007; 4: 721-726
        • Eiring A.M.
        • Harb J.G.
        • Neviani P.
        • Garton C.
        • Oaks J.J.
        • Spizzo R.
        • et al.
        miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts.
        Cell. 2010; 140: 652-665
        • Elmén J.
        • Lindow M.
        • Schütz S.
        • Lawrence M.
        • Petri A.
        • Obad S.
        • et al.
        LNA-mediated microRNA silencing in non-human primates.
        Nature. 2008; 452: 896-899
        • Elmén J.
        • Lindow M.
        • Silahtaroglu A.
        • Bak M.
        • Christensen M.
        • Lind-Thomsen A.
        • et al.
        Antagonism of microRNA-122 in mice by systemically administered LNA-antimiR leads to up-regulation of a large set of predicted target mRNAs in the liver.
        Nucleic Acids Res. 2008; 36: 1153-1162
        • Fava P.
        • Bergallo M.
        • Astrua C.
        • Brizio M.
        • Galliano I.
        • Montanari P.
        • et al.
        miR-155 expression in Primary Cutaneous T-Cell Lymphomas (CTCL).
        J Eur Acad Dermatol Venereol. 2017; 31: e27-e29
        • Feng Y.
        • Duan F.
        • Liu W.
        • Fu X.
        • Cui S.
        • Yang Z.
        Prognostic value of the microRNA-214 in multiple human cancers: a meta-analysis of observational studies.
        Oncotarget. 2017; 8: 75350-75360
        • Fredholm S.
        • Willerslev-Olsen A.
        • Met Ö.
        • Kubat L.
        • Gluud M.
        • Mathiasen S.L.
        • et al.
        SATB1 in malignant T cells.
        J Invest Dermatol. 2018; 138: 1805-1815
        • Friedman J.M.
        • Jones P.A.
        MicroRNAs: critical mediators of differentiation, development and disease.
        Swiss Med Wkly. 2009; 139: 466-472
        • Garofalo M.
        • Romano G.
        • Di Leva G.
        • Nuovo G.
        • Jeon Y.J.
        • Ngankeu A.
        • et al.
        EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers.
        Nat Med. 2011; 18: 74-82
        • Garzon R.
        • Heaphy C.E.
        • Havelange V.
        • Fabbri M.
        • Volinia S.
        • Tsao T.
        • et al.
        MicroRNA 29b functions in acute myeloid leukemia.
        Blood. 2009; 114: 5331-5341
        • Glover A.R.
        • Zhao J.T.
        • Gill A.J.
        • Weiss J.
        • Mugridge N.
        • Kim E.
        • et al.
        MicroRNA-7 as a tumor suppressor and novel therapeutic for adrenocortical carcinoma.
        Oncotarget. 2015; 6: 36675-36688
        • Gulyaeva L.F.
        • Kushlinskiy N.E.
        Regulatory mechanisms of microRNA expression.
        J Transl Med. 2016; 14: 143
        • Herrmann H.
        • Blatt K.
        • Shi J.
        • Gleixner K.V.
        • Cerny-Reiterer S.
        • Müllauer L.
        • et al.
        Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML.
        Oncotarget. 2012; 3: 1588-1599
        • Hiddingh L.
        • Raktoe R.S.
        • Jeuken J.
        • Hulleman E.
        • Noske D.P.
        • Kaspers G.J.
        • et al.
        Identification of temozolomide resistance factors in glioblastoma via integrative miRNA/mRNA regulatory network analysis.
        Sci Rep. 2014; 4: 5260
        • Jansson M.D.
        • Lund A.H.
        MicroRNA and cancer.
        Mol Oncol. 2012; 6: 590-610
        • Ji Q.
        • Hao X.
        • Meng Y.
        • Zhang M.
        • Desano J.
        • Fan D.
        • et al.
        Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres.
        BMC Cancer. 2008; 8: 266
        • Kohnken R.
        • Fabbro S.
        • Hastings J.
        • Porcu P.
        • Mishra A.
        Sézary syndrome: clinical and biological aspects.
        Curr Hematol Malig Rep. 2016; 11: 468-479
        • Kohnken R.
        • Wen J.
        • McConnell K.
        • Grinshpun L.
        • Keiter A.
        • McNeil B.
        • et al.
        Therapeutic targeting of microRNA-214 in cutaneous T-cell lymphoma.
        Blood. 2017; 130: 4100
        • Kohnken R.
        • Wen J.
        • Mundy-Bosse B.
        • McConnell K.
        • Keiter A.
        • Grinshpun L.
        • et al.
        Diminished microRNA-29b level is associated with BRD4-mediated activation of oncogenes in cutaneous T-cell lymphoma.
        Blood. 2018; 131: 771-781
        • Kong W.
        • He L.
        • Coppola M.
        • Guo J.
        • Esposito N.N.
        • Coppola D.
        • et al.
        MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer.
        J Biol Chem. 2010; 285: 17869-17879
        • Kopp K.L.
        • Ralfkiaer U.
        • Gjerdrum L.M.
        • Helvad R.
        • Pedersen I.H.
        • Litman T.
        • et al.
        STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma.
        Cell Cycle. 2013; 12: 1939-1947
        • Kopp K.L.
        • Ralfkiaer U.
        • Nielsen B.S.
        • Gniadecki R.
        • Woetmann A.
        • Ødum N.
        • et al.
        Expression of miR-155 and miR-126 in situ in cutaneous T-cell lymphoma.
        APMIS. 2013; 121: 1020-1024
        • Krejsgaard T.
        • Lindahl L.M.
        • Mongan N.P.
        • Wasik M.A.
        • Litvinov I.V.
        • Iversen L.
        • et al.
        Malignant inflammation in cutaneous T-cell lymphoma—a hostile takeover.
        Semin Immunopathol. 2017; 39: 269-282
        • Laganà A.
        • Russo F.
        • Sismeiro C.
        • Giugno R.
        • Pulvirenti A.
        • Ferro A.
        Variability in the incidence of miRNAs and genes in fragile sites and the role of repeats and CpG islands in the distribution of genetic material.
        PLoS One. 2010; 5: e11166
        • Li C.
        • Song L.
        • Zhang Z.
        • Bai X.X.
        • Cui M.F.
        • Ma L.J.
        MicroRNA-21 promotes TGF-β1-induced epithelial-mesenchymal transition in gastric cancer through up-regulating PTEN expression.
        Oncotarget. 2016; 7: 66989-67003
        • Li J.
        • Yu H.
        • Xi M.
        • Ma D.
        • Lu X.
        The SNAI1 3′UTR functions as a sponge for multiple migration-/invasion-related microRNAs.
        Tumor Biol. 2015; 36: 1067-1072
        • Liao J.
        • Lin J.
        • Lin D.
        • Zou C.
        • Kurata J.
        • Lin R.
        • et al.
        Down-regulation of miR-214 reverses erlotinib resistance in non-small-cell lung cancer through up-regulating LHX6 expression.
        Sci Rep. 2017; 7: 781
        • Lindahl L.M.
        • Besenbacher S.
        • Rittig A.H.
        • Celis P.
        • Willerslev-Olsen A.
        • Gjerdrum L.M.R.
        • et al.
        Prognostic miRNA classifier in early-stage mycosis fungoides: development and validation in a Danish nationwide study.
        Blood. 2018; 131: 759-770
        • Lindahl L.M.
        • Fredholm S.
        • Joseph C.
        • Nielsen B.S.
        • Jønson L.
        • Willerslev-Olsen A.
        • et al.
        STAT5 induces miR-21 expression in cutaneous T cell lymphoma.
        Oncotarget. 2016; 7: 45730-45744
        • MacDiarmid J.A.
        • Mugridge N.B.
        • Weiss J.C.
        • Phillips L.
        • Burn A.L.
        • Paulin R.P.
        • et al.
        Bacterially derived 400 nm particles for encapsulation and cancer cell targeting of chemotherapeutics.
        Cancer Cell. 2007; 11: 431-445
        • Marosvári D.
        • Téglási V.
        • Csala I.
        • Marschalkó M.
        • Bödör C.
        • Timár B.
        • et al.
        Altered microRNA expression in folliculotropic and transformed mycosis fungoides.
        Pathol Oncol Res. 2015; 21: 821-825
        • Mishra A.
        • La Perle K.
        • Kwiatkowski S.
        • Sullivan L.A.
        • Sams G.H.
        • Johns J.
        • et al.
        Mechanism, consequences and therapeutic targeting of abnormal IL-15 signaling in cutaneous T-cell lymphoma.
        Cancer Discov. 2016; 6: 986-1005
        • Mishra A.
        • Liu S.
        • Sams G.H.
        • Curphey D.P.
        • Santhanam R.
        • Rush L.J.
        • et al.
        Aberrant overexpression of IL-15 initiates large granular lymphocyte leukemia through chromosomal instability and DNA hypermethylation.
        Cancer Cell. 2012; 22: 645-655
        • Mishra A.
        • Sullivan L.
        • Caligiuri M.A.
        Molecular pathways: interleukin-15 signaling in health and in cancer.
        Clin Cancer Res. 2014; 20: 2044-2050
        • Moyal L.
        • Barzilai A.
        • Gorovitz B.
        • Hirshberg A.
        • Amariglio N.
        • Jacob-Hirsch J.
        • et al.
        miR-155 is involved in tumor progression of mycosis fungoides.
        Exp Dermatol. 2013; 22: 431-433
        • Narducci M.G.
        • Arcelli D.
        • Picchio M.C.
        • Lazzeri C.
        • Pagani E.
        • Sampogna F.
        • et al.
        MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sézary syndrome.
        Cell Death Dis. 2011; 2: e151
        • Nielsen M.
        • Kaltoft K.
        • Nordahl M.
        • Röpke C.
        • Geisler C.
        • Mustelin T.
        • et al.
        Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines.
        Proc Natl Acad Sci USA. 1997; 94: 6764-6769
        • Obernosterer G.
        • Leuschner P.J.
        • Alenius M.
        • Martinez J.
        Post-transcriptional regulation of microRNA expression.
        RNA. 2006; 12: 1161-1167
        • Ofek P.
        • Calderón M.
        • Mehrabadi F.S.
        • Krivitsky A.
        • Ferber S.
        • Tiram G.
        • et al.
        Restoring the oncosuppressor activity of microRNA-34a in glioblastoma using a polyglycerol-based polyplex.
        Nanomedicine. 2016; 12: 2201-2214
        • Okamoto K.
        • Miyoshi K.
        • Murawaki Y.
        miR-29b, miR-205 and miR-221 enhance chemosensitivity to gemcitabine in HuH28 human cholangiocarcinoma cells.
        PLoS One. 2013; 8: e77623
        • Olsen E.A.
        • Kim Y.H.
        • Kuzel T.M.
        • Pacheco T.R.
        • Foss F.M.
        • Parker S.
        • et al.
        Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma.
        J Clin Oncol. 2007; 25: 3109-3115
        • Pucci S.
        • Mazzarelli P.
        MicroRNA dysregulation in colon cancer microenvironment interactions: the importance of small things in metastases.
        Cancer Microenviron. 2011; 4: 155-162
        • Qin Y.
        • Buermans H.P.
        • van Kester M.S.
        • van der Fits L.
        • Out-Luiting J.J.
        • Osanto S.
        • et al.
        Deep-sequencing analysis reveals that the miR-199a2/214 cluster within DNM3os represents the vast majority of aberrantly expressed microRNAs in Sézary syndrome.
        J Invest Dermatol. 2012; 132: 1520-1522
        • Querfeld C.
        • Foss F.M.
        • Pinter-Brown L.C.
        • Porcu P.
        • William B.M.
        • Pacheco T.
        • et al.
        Phase 1 study of the safety and efficacy of MRG-106, a synthetic inhibitor of microRNA-155, in CTCL patients.
        Blood. 2017; 130: 820
        • Ralfkiaer U.
        • Hagedorn P.H.
        • Bangsgaard N.
        • Løvendorf M.B.
        • Ahler C.B.
        • Svensson L.
        • et al.
        Diagnostic microRNA profiling in cutaneous T-cell lymphoma (CTCL).
        Blood. 2011; 118: 5891-5900
        • Ralfkiaer U.
        • Lindahl L.M.
        • Lindal L.
        • Litman T.
        • Gjerdrum L.M.
        • Ahler C.B.
        • et al.
        MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma.
        Anticancer Res. 2014; 34: 7207-7217
        • Raveche E.S.
        • Salerno E.
        • Scaglione B.J.
        • Manohar V.
        • Abbasi F.
        • Lin Y.C.
        • et al.
        Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice.
        Blood. 2007; 109: 5079-5086
        • Reid G.
        • Kao S.C.
        • Pavlakis N.
        • Brahmbhatt H.
        • MacDiarmid J.
        • Clarke S.
        • et al.
        Clinical development of TargomiRs, a miRNA mimic-based treatment for patients with recurrent thoracic cancer.
        Epigenomics. 2016; 8: 1079-1085
        • Reid G.
        • Pel M.E.
        • Kirschner M.B.
        • Cheng Y.Y.
        • Mugridge N.
        • Weiss J.
        • et al.
        Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma.
        Ann Oncol. 2013; 24: 3128-3135
        • Sandoval J.
        • Díaz-Lagares A.
        • Salgado R.
        • Servitje O.
        • Climent F.
        • Ortiz-Romero P.L.
        • et al.
        MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma.
        J Invest Dermatol. 2015; 135: 1128-1137
        • Shen H.
        • Zhu F.
        • Liu J.
        • Xu T.
        • Pei D.
        • Wang R.
        • et al.
        Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer.
        PLoS One. 2014; 9: e103305
        • Shen X.
        • Wang B.
        • Li K.
        • Wang L.
        • Zhao X.
        • Xue F.
        • et al.
        MicroRNA signatures in diagnosis and prognosis of cutaneous T-cell lymphoma.
        J Invest Dermatol. 2018; 138: 2024-2032
        • Sommer V.H.
        • Clemmensen O.J.
        • Nielsen O.
        • Wasik M.
        • Lovato P.
        • Brender C.
        • et al.
        In vivo activation of STAT3 in cutaneous T-cell lymphoma. Evidence for an antiapoptotic function of STAT3.
        Leukemia. 2004; 18: 1288-1295
        • van der Fits L.
        • van Kester M.S.
        • Qin Y.
        • Out-Luiting J.J.
        • Smit F.
        • Zoutman W.H.
        • et al.
        MicroRNA-21 expression in CD4+ T cells is regulated by STAT3 and is pathologically involved in Sézary syndrome.
        J Invest Dermatol. 2011; 131: 762-768
        • Varambally S.
        • Cao Q.
        • Mani R.S.
        • Shankar S.
        • Wang X.
        • Ateeq B.
        • et al.
        Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer.
        Science. 2008; 322: 1695-1699
        • Virmani P.
        • Hwang S.H.
        • Hastings J.G.
        • Haverkos B.M.
        • Kohnken B.
        • Gru A.A.
        • et al.
        Systemic therapy for cutaneous T-cell lymphoma: who, when, what, and why?.
        Expert Rev Hematol. 2017; 10: 111-121
        • Waldmann T.A.
        The biology of IL-15: implications for cancer therapy and the treatment of autoimmune disorders.
        J Investig Dermatol Symp Proc. 2013; 16: S28-S30
        • Wang F.
        • Liu M.
        • Li X.
        • Tang H.
        MiR-214 reduces cell survival and enhances cisplatin-induced cytotoxicity via down-regulation of Bcl2l2 in cervical cancer cells.
        FEBS Lett. 2013; 587: 488-495
        • Wang Y.-S.
        • Wang Y.-H.
        • Xia H.-P.
        • Zhou S.-W.
        • Schmid-Bindert G.
        • Zhou C.-C.
        MicroRNA-214 regulates the acquired resistance to gefitinib via the PTEN/AKT pathway in EGFR-mutant cell lines.
        Asian Pac J Cancer Prev. 2012; 13: 255-260
        • Wang Z.
        The principles of miRNA-masking antisense oligonucleotides technology.
        Methods Mol Biol. 2011; 676: 43-49
        • Whittle J.R.
        • Lickliter J.D.
        • Gan H.K.
        • Scott A.M.
        • Simes J.
        • Solomon B.J.
        • et al.
        First in human nanotechnology doxorubicin delivery system to target epidermal growth factor receptors in recurrent glioblastoma.
        J Clin Neurosci. 2015; 22: 1889-1894
        • Williams M.
        • Cheng Y.Y.
        • Blenkiron C.
        • Reid G.
        Exploring mechanisms of microRNA downregulation in cancer.
        MicroRNA. 2016; 6: 2-16
        • Williams M.
        • Kirschner M.B.
        • Cheng Y.Y.
        • Hanh J.
        • Weiss J.
        • Mugridge N.
        • et al.
        miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma.
        Oncotarget. 2015; 6: 23480-23495
        • Xu J.
        • Zhang W.
        • Lv Q.
        • Zhu D.
        Overexpression of miR-21 promotes the proliferation and migration of cervical cancer cells via the inhibition of PTEN.
        Oncol Rep. 2015; 33: 3108-3116
        • Yan B.
        • Guo Q.
        • Fu F.J.
        • Wang Z.
        • Yin Z.
        • Wei Y.B.
        • et al.
        The role of miR-29b in cancer: regulation, function, and signaling.
        Onco Targets Ther. 2015; 8: 539-548
        • Yan L.X.
        • Wu Q.N.
        • Zhang Y.
        • Li Y.Y.
        • Liao D.Z.
        • Hou J.H.
        • et al.
        Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth.
        Breast Cancer Res. 2011; 13: R2
        • Yang H.
        • Kong W.
        • He L.
        • Zhao J.J.
        • O’Donnell J.D.
        • Wang J.
        • et al.
        MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN.
        Cancer Res. 2008; 68: 425-433
        • Yang Z.
        • Wang L.
        Regulation of microRNA expression and function by nuclear receptor signaling.
        Cell Biosci. 2011; 1: 31
        • Zhang B.
        • Pan X.
        • Cobb G.P.
        • Anderson T.A.
        microRNAs as oncogenes and tumor suppressors.
        Dev Biol. 2007; 302: 1-12
        • Zhang Q.
        • Nowak I.
        • Vonderheid E.C.
        • Rook A.H.
        • Kadin M.E.
        • Nowell P.C.
        • et al.
        Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome.
        Proc Natl Acad Sci USA. 1996; 93: 9148-9153
        • Zhu D.X.
        • Zhu W.
        • Fang C.
        • Fan L.
        • Zou Z.J.
        • Wang Y.H.
        • et al.
        miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes.
        Carcinogenesis. 2012; 33: 1294-1301