1 6146 122 THE EXPRESSION OF ENDOTHELIN-1 IN CHRONIC LYMPHOCYTIC LEUKEMIA IS CONTROLLED BY EPIGENETIC MECHANISMS AND EXTRACELLULAR STIMULI. ENDOTHELIN-1 (ET-1) IS A HORMONE PEPTIDE WIDELY EXPRESSED AND IS INVOLVED IN SEVERAL BIOLOGICAL PROCESSES, IMPORTANT NOT ONLY FOR NORMAL CELL FUNCTION BUT ALSO FOR TUMOR DEVELOPMENT, INCLUDING CELL PROLIFERATION, INVASION, METASTASIS, ANGIOGENESIS AND OSTEOGENESIS. IN ACCORDANCE, ET-1 WAS ALREADY SHOWN TO CONTRIBUTE TO THE GROWTH AND PROGRESSION OF MANY DIFFERENT SOLID CANCERS. WE RECENTLY DEMONSTRATED THAT ET-1 HAS A ROLE IN THE PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WHERE IT IS ABNORMALLY EXPRESSED. IN THE CONTEXT OF THIS MALIGNANCY, ET-1 IS ABLE TO MEDIATE SURVIVAL, DRUG-RESISTANCE AND GROWTH SIGNALS IN LEUKEMIC CELLS. PREVIOUS STUDIES, NOT CONDUCTED IN CLL, HAVE SHOWN THAT ET-1 REGULATORY MECHANISMS ARE NUMEROUS AND CELL SPECIFIC. HERE, WE VALUED THE EXPRESSION OF ET-1 IN CLL, IN RELATION TO DNA METHYLATION BUT ALSO IN RESPONSE TO STIMULATION OF SOME IMPORTANT PATHWAYS FOR THE DIALOGUE BETWEEN CLL AND MICROENVIRONMENT. WE FOUND THAT A HIGH METHYLATION OF ET-1 FIRST INTRON AFFECTS THE BASAL EXPRESSION OF ET-1 IN CLL. MOREOVER, WE SHOWED THAT THE ACTIVATION OF CD40 OR TOLL-LIKE RECEPTOR (TLR) BY EXTRACELLULAR STIMULI PRODUCES AN AUGMENT OF ET-1 LEVEL IN CLL CELLS. FINALLY, WE DEMONSTRATED THE FUNDAMENTAL ROLE OF NF-KB SIGNALLING PATHWAY IN PROMOTING AND MAINTAINING ET-1 EXPRESSION IN CLL CELLS, BOTH IN BASAL CONDITIONS AND AFTER CD40 ACTIVATION. 2017 2 4695 44 NF-KAPPAB ACTIVATION IN CHRONIC LYMPHOCYTIC LEUKEMIA: A POINT OF CONVERGENCE OF EXTERNAL TRIGGERS AND INTRINSIC LESIONS. THE NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) PATHWAY IS CONSTITUTIVELY ACTIVATED IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS, AND HENCE PLAYS A MAJOR ROLE IN DISEASE DEVELOPMENT AND EVOLUTION. IN CONTRAST TO MANY OTHER MATURE B-CELL LYMPHOMAS, ONLY A FEW RECURRENTLY MUTATED GENES INVOLVED IN CANONICAL OR NON-CANONICAL NF-KAPPAB ACTIVATION HAVE BEEN IDENTIFIED IN CLL (I.E. BIRC3, MYD88 AND NFKBIE MUTATIONS) AND OFTEN AT A LOW FREQUENCY. ON THE OTHER HAND, CLL B CELLS SEEM 'ADDICTED' TO THE TUMOR MICROENVIRONMENT FOR THEIR SURVIVAL AND PROLIFERATION, WHICH IS PRIMARILY MEDIATED BY INTERACTION THROUGH A NUMBER OF CELL SURFACE RECEPTORS, E.G. THE B-CELL RECEPTOR (BCR), TOLL-LIKE RECEPTORS AND CD40, THAT IN TURN ACTIVATE DOWNSTREAM NF-KAPPAB. THE IMPORTANCE OF CELL-EXTRINSIC TRIGGERING FOR CLL PATHOPHYSIOLOGY WAS RECENTLY ALSO HIGHLIGHTED BY THE CLINICAL EFFICACY OF NOVEL DRUGS TARGETING MICROENVIRONMENTAL INTERACTIONS THROUGH THE INHIBITION OF BCR SIGNALING. IN OTHER WORDS, CLL CAN BE CONSIDERED A PROTOTYPE DISEASE FOR STUDYING THE INTRICATE INTERPLAY BETWEEN EXTERNAL TRIGGERS AND INTRINSIC ABERRATIONS AND THEIR COMBINED IMPACT ON DISEASE EVOLUTION. IN THIS REVIEW, WE WILL DISCUSS THE CURRENT UNDERSTANDING OF MECHANISMS UNDERLYING NF-KAPPAB DEREGULATION IN CLL, INCLUDING MICRO-ENVIRONMENTAL, GENETIC AND EPIGENETIC EVENTS, AND SUMMARIZE DATA GENERATED IN MURINE MODELS RESEMBLING HUMAN CLL. FINALLY, WE WILL ALSO DISCUSS DIFFERENT STRATEGIES UNDERTAKEN TO INTERVENE WITH THE NF-KAPPAB PATHWAY AND ITS UPSTREAM MEDIATORS. 2016 3 2380 34 EPIGENETIC REGULATION OF WNT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. CERTAIN WNT AND WNT NETWORK TARGET GENES ARE EXPRESSED AT HIGHER OR LOWER LEVELS IN CHRONIC LYMPHOCYTIC LEUKEMIA COMPARED WITH NORMAL B-CELLS. THIS INCLUDES UPREGULATION OF NUCLEAR COMPLEX GENES, AS WELL AS GENES FOR CYTOPLASMIC PROTEINS AND WNT LIGANDS AND THEIR COGNATE RECEPTORS. IN ADDITION, EPIGENETIC SILENCING OF SEVERAL NEGATIVE REGULATORS OF THE WNT PATHWAY HAVE BEEN IDENTIFIED. THE BALANCE BETWEEN EPIGENETIC DOWNREGULATION OF NEGATIVE EFFECTOR GENES AND INCREASED EXPRESSION OF POSITIVE EFFECTOR GENES DEMONSTRATE THAT THE EPIGENETIC DOWNREGULATION OF WNT ANTAGONISTS IS ONE MECHANISM, PERHAPS THE MAIN MECHANISM, THAT IS PERMISSIVE TO ACTIVE WNT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. MOREOVER, CONSTITUTIVE ACTIVATION OF THE WNT NETWORK AND TARGET GENES IS LIKELY TO IMPACT ON ADDITIONAL INTERACTING SIGNALING PATHWAYS. BASED ON PUBLISHED STUDIES, WE PROPOSE A MODEL OF WNT SIGNALING THAT INVOLVES MAINLY PERMISSIVE EXPRESSION, AND SOMETIMES OVEREXPRESSION, OF POSITIVE EFFECTORS AND DOWNREGULATION OF NEGATIVE REGULATORS IN THE NETWORK. IN THIS MODEL, DNA METHYLATION, HISTONE MODIFICATIONS AND ALTERED EXPRESSION OF MICRORNA MOLECULES INTERACT TO ALLOW CONTINUOUS WNT SIGNALING. 2010 4 1542 41 DNA METHYLATION IN HAEMATOLOGICAL MALIGNANCIES: THE ROLE OF DECITABINE. NORMAL CELL DEVELOPMENT AND FUNCTION IS DEPENDENT UPON CONTROLLED GENE EXPRESSION. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT CAN PLAY AN IMPORTANT ROLE IN THE CONTROL OF GENE EXPRESSION. DNA METHYLATION AT CYTOSINE RESIDUES IN GENE PROMOTER CPG SEQUENCES IS KNOWN TO INHIBIT GENE TRANSCRIPTION. INAPPROPRIATE INHIBITION OF THE TRANSCRIPTION OF TUMOUR SUPPRESSOR GENES, GENES THAT INHIBIT ANGIOGENESIS AND METASTASIS AND GENES INVOLVED IN DNA REPAIR BY UNCONTROLLED METHYLATION, CAN LEAD TO UNREGULATED GROWTH AND PROLIFERATION OF A CELL AND CARCINOGENESIS. PROMOTER HYPERMETHYLATION AFFECTING THE P16 GENE, RESULTING IN GENE SILENCING, HAS BEEN SHOWN TO OCCUR IN MANY HUMAN SOLID TUMOURS AND A 'HYPERMETHYLATION PROFILE' IN SOME LEUKAEMIAS HAS BEEN DEFINED. THE MOLECULAR MECHANISMS BY WHICH ABERRANT DNA METHYLATION TAKES PLACE DURING CARCINOGENESIS ARE STILL NOT CLEAR. HOWEVER, THE LARGE NUMBER OF TARGET GENES (INVOLVED IN TUMORIGENESIS) THAT ARE SILENCED BY ABERRANT METHYLATION SUGGESTS THAT INHIBITION OF THIS PROCESS MAY HAVE POTENTIAL AS CANCER THERAPY. DECITABINE (NSC-127716, DACOGEN; SUPERGEN) IS A POTENT AND SPECIFIC HYPOMETHYLATING AGENT AND AN INHIBITOR OF THE DNA METHYLTRANSFERASE ACTIVITY THAT MEDIATES DNA METHYLATION. DECITABINE HAS BEEN SHOWN TO HAVE A BROAD RANGE OF ANTINEOPLASTIC ACTIVITY IN PRECLINICAL STUDIES. THIS AGENT HAS EXHIBITED SIGNIFICANT ACTIVITY IN THE TREATMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROME, CHRONIC MYELOID LEUKAEMIA AND ACUTE MYELOID LEUKAEMIA, ALTHOUGH CLINICAL PHASE I AND II STUDIES WITH SOLID TUMOURS HAVE NOT BEEN VERY PROMISING. PHASE II AND III STUDIES ARE CURRENTLY ONGOING TO EVALUATE DECITABINE, BOTH ALONE AND IN COMBINATION, IN VARIOUS STAGES OF THESE HAEMATOLOGICAL MALIGNANCIES. 2003 5 6773 28 [ADVANCES OF RESEARCH ON DEMETHYLATION THERAPY FOR HEMATOLOGIC MALIGNANCIES]. DNA METHYLATION IS AN IMPORTANT AND REVERSIBLE EPIGENETIC MODIFICATION WHICH REGULATES GENOMIC STABILITY. METHYLATION IS ESSENTIAL FOR MAMMALIAN DEVELOPMENT. GENERALLY, GENE EXPRESSION LEVEL AND DNA METHYLATION ARE NEGATIVE CORRELATION. TRANSCRIPTIONAL SILENCING VIA METHYLATION OF CPG ISLANDS IN THE PROMOTER IS IMPORTANT FOR CELL GROWTH AND DIFFERENTIATION AND PLAYS A KEY ROLE IN TUMORIGENESIS. DEMETHYLATION DRUG CAN MODIFY CHROMATIN AND RESTORE THE ABILITY OF ANTI-ONCOGENE. DEMETHYLATION THERAPY AS A NEW THERAPY MAY TREAT EFFICIENTLY HEMATOLOGICAL MALIGNANCIES WITH RESISTANCE AND RELAPSE. IN THIS REVIEW, DNA METHYLATION MECHANISM, RELATIONSHIP BETWEEN ABERRANT METHYLATION AND HEMATOLOGIC MALIGNANCIES, MECHANISM OF DEMETHYLATION THERAPY, THE ADVANCE OF RESEARCH ON THE DEMETHYLATION THERAPY OF HEMATOLOGICAL MALIGNANCIES, SUCH AS ACUTE AND CHRONIC LEUKEMIA, LYMPHOMA, MYELODYSPLASTIC SYNDROME WERE SUMMARIZED. 2009 6 4284 29 MICRORNA CIRCUITS REGULATE THE CANCER-INFLAMMATION LINK. GENETIC AND EPIGENETIC PERTURBATIONS ARE REQUIRED TO TRANSFORM NORMAL CELLS INTO CANCER CELLS. INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN VARIOUS CANCERS, LINKING CHRONIC INFLAMMATION TO ONCOGENESIS. HOWEVER, THE MOLECULAR CIRCUITS THAT RESULT IN SUSTAINED ACTIVATION OF THESE INFLAMMATORY FACTORS ARE NOT YET WELL UNDERSTOOD. IN THE 28 JANUARY 2014 ISSUE OF SCIENCE SIGNALING, XIANG ET AL. IDENTIFIED A MICRORNA-MEDIATED ANTI-INFLAMMATORY CIRCUIT THAT IS REPRESSED EPIGENETICALLY IN RECEPTOR-NEGATIVE BREAST CANCERS. A HIGH-THROUGHPUT SCREEN FOR SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3)-REGULATED MICRORNAS REVEALED MICRORNA MIR-146B AS A DIRECT STAT3 TARGET IN MAMMARY EPITHELIAL CELLS, BUT DNA METHYLATION IN ITS PROMOTER AREA SUPPRESSED MIR-146B EXPRESSION IN CANCER CELLS. OVEREXPRESSION OF MIR-146B SUPPRESSED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT EXPRESSION OF IL6 AND SUBSEQUENT STAT3 ACTIVATION AND DECREASED THE STAT3-INDUCED INVASIVENESS AND MESENCHYMAL PHENOTYPE OF BREAST CANCER CELLS. OVERALL, THIS STUDY CONTRIBUTES TO OUR UNDERSTANDING OF HOW INFLAMMATION IS INVOLVED IN ONCOGENIC TRANSFORMATION. FURTHER STUDIES COULD EVALUATE THE THERAPEUTIC POTENTIAL OF TARGETING THIS CIRCUIT IN ESTROGEN RECEPTOR-NEGATIVE BREAST CANCERS. 2014 7 4111 42 MECHANISMS CONTRIBUTING TO PERSISTENTLY ACTIVATED CELL PHENOTYPES IN PULMONARY HYPERTENSION. CHRONIC PULMONARY HYPERTENSION (PH) IS CHARACTERIZED BY THE ACCUMULATION OF PERSISTENTLY ACTIVATED CELL TYPES IN THE PULMONARY VESSEL EXHIBITING ABERRANT EXPRESSION OF GENES INVOLVED IN APOPTOSIS RESISTANCE, PROLIFERATION, INFLAMMATION AND EXTRACELLULAR MATRIX (ECM) REMODELLING. CURRENT THERAPIES FOR PH, FOCUSING ON VASODILATATION, DO NOT NORMALIZE THESE ACTIVATED PHENOTYPES. FURTHERMORE, CURRENT APPROACHES TO DEFINE ADDITIONAL THERAPEUTIC TARGETS HAVE FOCUSED ON DETERMINING THE INITIATING SIGNALS AND THEIR DOWNSTREAM EFFECTORS THAT ARE IMPORTANT IN PH ONSET AND DEVELOPMENT. ALTHOUGH THESE APPROACHES HAVE PRODUCED A LARGE NUMBER OF COMPELLING PH TREATMENT TARGETS, MANY PROMISING HUMAN DRUGS HAVE FAILED IN PH CLINICAL TRIALS. HEREIN, WE PROPOSE THAT ONE CONTRIBUTING FACTOR TO THESE FAILURES IS THAT PROCESSES IMPORTANT IN PH DEVELOPMENT MAY NOT BE GOOD TREATMENT TARGETS IN THE ESTABLISHED PHASE OF CHRONIC PH. WE HYPOTHESIZE THAT THIS IS DUE TO ALTERATIONS OF CHROMATIN STRUCTURE IN PH CELLS, RESULTING IN FUNCTIONAL DIFFERENCES BETWEEN THE SAME FACTOR OR PATHWAY IN NORMAL OR EARLY PH CELLS VERSUS CELLS IN CHRONIC PH. WE PROPOSE THAT THE HIGH EXPRESSION OF GENES INVOLVED IN THE PERSISTENTLY ACTIVATED PHENOTYPE OF PH VASCULAR CELLS IS PERPETUATED BY AN OPEN CHROMATIN STRUCTURE AND MULTIPLE TRANSCRIPTION FACTORS (TFS) VIA THE RECRUITMENT OF HIGH LEVELS OF EPIGENETIC REGULATORS INCLUDING THE HISTONE ACETYLASES P300/CBP, HISTONE ACETYLATION READERS INCLUDING BRDS, THE MEDIATOR COMPLEX AND THE POSITIVE TRANSCRIPTION ELONGATION FACTOR (ABSTRACT FIGURE). THUS, DETERMINING HOW GENE EXPRESSION IS CONTROLLED BY EXAMINING CHROMATIN STRUCTURE, TFS AND EPIGENETIC REGULATORS ASSOCIATED WITH ABERRANTLY EXPRESSED GENES IN PULMONARY VASCULAR CELLS IN CHRONIC PH, MAY UNCOVER NEW PH THERAPEUTIC TARGETS. 2019 8 160 36 ABERRANT PROMOTER HYPOMETHYLATION IN CLL: DOES IT MATTER FOR DISEASE DEVELOPMENT? OVER THE LAST 30 YEARS, STUDIES OF ABERRANT DNA METHYLATION IN HEMATOLOGIC MALIGNANCIES HAVE BEEN DOMINATED BY THE PRIMARY FOCUS OF UNDERSTANDING PROMOTER HYPERMETHYLATION. THESE EFFORTS NOT ONLY RESULTED IN A BETTER UNDERSTANDING OF THE BASIS OF EPIGENETIC SILENCING OF TUMOR SUPPRESSOR GENES BUT ALSO RESULTED IN APPROVAL OF HYPOMETHYLATING AGENTS FOR THE TREATMENT OF SEVERAL MALIGNANCIES, SUCH AS MYELODYSPLASTIC SYNDROME AND ACUTE MYELOID LEUKEMIA. RECENT ADVANCES IN GLOBAL METHYLATION PROFILING COUPLED WITH THE USE OF MOUSE MODELS SUGGEST THAT ABERRANT PROMOTER HYPOMETHYLATION IS ALSO A FREQUENT EVENT IN HEMATOLOGIC MALIGNANCIES, PARTICULARLY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). PROMOTER HYPOMETHYLATION AFFECTS GENE EXPRESSION AND, THEREFORE, MAY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. HERE, WE REVIEW RECENT FINDINGS AND DISCUSS THE POTENTIAL INVOLVEMENT OF ABERRANT PROMOTER HYPOMETHYLATION IN CLL. 2016 9 1232 47 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 10 4693 25 NEXT GENERATION OF TARGETED MOLECULES FOR NON-HODGKIN LYMPHOMAS: SMALL-MOLECULE INHIBITORS OF INTRACELLULAR TARGETS AND SIGNALING PATHWAYS. ADVANCES IN OUR UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF B-CELL LYMPHOMA HAVE GUIDED THE DEVELOPMENT OF TARGETED THERAPIES THAT DISRUPT ABERRANT SIGNALING PATHWAYS IMPORTANT FOR COMMUNICATION WITHIN LYMPHOMA CELLS AND FOR THEIR INTERACTIONS WITH THE TUMOR MICROENVIRONMENT. THIS HAS LED TO UNPRECEDENTED THERAPEUTIC PROGRESS, WITH BIOLOGIC AGENTS THAT HAVE BEGUN TO TRANSFORM THE CARE OF PATIENTS WITH LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA. THIS REVIEW DISCUSSES THE MECHANISMS OF ACTION, CLINICAL DEVELOPMENT, AND EMERGING APPLICATIONS OF SMALL-MOLECULE INHIBITORS THAT TARGET B-CELL RECEPTOR SIGNALING PATHWAYS, B-CELL LYMPHOMA-2 INHIBITORS, SELECTIVE INHIBITORS OF NUCLEAR EXPORT, AND EPIGENETIC MODIFIERS. 2016 11 1562 37 DNA METHYLATION OF ENHANCER ELEMENTS IN MYELOID NEOPLASMS: THINK OUTSIDE THE PROMOTERS? GENE REGULATION THROUGH DNA METHYLATION IS A WELL DESCRIBED PHENOMENON THAT HAS A PROMINENT ROLE IN PHYSIOLOGICAL AND PATHOLOGICAL CELL-STATES. THIS EPIGENETIC MODIFICATION IS USUALLY GROUPED IN REGIONS DENOMINATED CPG ISLANDS, WHICH FREQUENTLY CO-LOCALIZE WITH GENE PROMOTERS, SILENCING THE TRANSCRIPTION OF THOSE GENES. RECENT GENOME-WIDE DNA METHYLATION STUDIES HAVE CHALLENGED THIS PARADIGM, DEMONSTRATING THAT DNA METHYLATION OF REGULATORY REGIONS OUTSIDE PROMOTERS IS ABLE TO INFLUENCE CELL-TYPE SPECIFIC GENE EXPRESSION PROGRAMS UNDER PHYSIOLOGIC OR PATHOLOGIC CONDITIONS. COUPLING GENOME-WIDE DNA METHYLATION ASSAYS WITH HISTONE MARK ANNOTATION HAS ALLOWED FOR THE IDENTIFICATION OF SPECIFIC EPIGENOMIC CHANGES THAT AFFECT ENHANCER REGULATORY REGIONS, REVEALING AN ADDITIONAL LAYER OF COMPLEXITY TO THE EPIGENETIC REGULATION OF GENE EXPRESSION. IN THIS REVIEW, WE SUMMARIZE THE NOVEL EVIDENCE FOR THE MOLECULAR AND BIOLOGICAL REGULATION OF DNA METHYLATION IN ENHANCER REGIONS AND THE DYNAMISM OF THESE CHANGES CONTRIBUTING TO THE FINE-TUNING OF GENE EXPRESSION. WE ALSO ANALYZE THE CONTRIBUTION OF ENHANCER DNA METHYLATION ON THE EXPRESSION OF RELEVANT GENES IN ACUTE MYELOID LEUKEMIA AND CHRONIC MYELOPROLIFERATIVE NEOPLASMS. THE CHARACTERIZATION OF THE ABERRANT ENHANCER DNA METHYLATION PROVIDES NOT ONLY A NOVEL PATHOGENIC MECHANISM FOR DIFFERENT TUMORS BUT ALSO HIGHLIGHTS NOVEL POTENTIAL THERAPEUTIC TARGETS FOR MYELOID DERIVED NEOPLASMS. 2019 12 1568 33 DNA METHYLATION OF TUMOR-SUPPRESSOR MIRNA GENES IN CHRONIC LYMPHOCYTIC LEUKEMIA. DNA METHYLATION IS ONE OF THE MOST IMPORTANT EPIGENETIC MODIFICATIONS OF THE GENOME INVOLVED IN THE REGULATION OF NUMEROUS CELLULAR PROCESSES THROUGH GENE SILENCING WITHOUT ALTERING DNA SEQUENCES. MIRNAS, A CLASS OF SINGLE-STRANDED NONCODING RNAS OF 19-25 NUCLEOTIDES IN LENGTH, FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS OF GENE EXPRESSION LEADING TO MRNA CLEAVAGE OR TRANSLATIONAL REPRESSION OF THEIR CORRESPONDING TARGET PROTEIN-CODING GENES. RECENTLY, DYSREGULATION OF TUMOR SUPPRESSOR MIRNAS MEDIATED BY PROMOTER DNA HYPERMETHYLATION IS IMPLICATED IN HUMAN CANCERS, INCLUDING B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). MOREOVER, IT APPEARS THAT METHYLATED MIRNA GENES COULD BE POTENTIAL BIOMARKERS FOR CLL DIAGNOSIS OR THERAPY. THIS REVIEW WILL HIGHLIGHT THE ROLE OF ABERRANT METHYLATION OF MIRNA GENES IN THE PATHOGENESIS OF CLL. 2015 13 6428 34 THE TUMOR MICROENVIRONMENT AND METASTATIC DISEASE. THE MICROENVIRONMENT OF SOLID TUMORS IS A HETEROGENEOUS, COMPLEX MILIEU FOR TUMOR GROWTH AND SURVIVAL THAT INCLUDES FEATURES SUCH AS ACIDIC PH, LOW NUTRIENT LEVELS, ELEVATED INTERSTITIAL FLUID PRESSURE (IFP) AND CHRONIC AND FLUCTUATING LEVELS OF OXYGENATION THAT RELATE TO THE ABNORMAL VASCULAR NETWORK THAT EXISTS IN TUMORS. THE METASTATIC POTENTIAL OF TUMOR CELLS IS BELIEVED TO BE REGULATED BY INTERACTIONS BETWEEN THE TUMOR CELLS AND THEIR EXTRACELLULAR ENVIRONMENT (EXTRACELLULAR MATRIX (ECM)). THESE INTERACTIONS CAN BE MODIFIED BY THE ACCUMULATION OF GENETIC CHANGES AND BY THE TRANSIENT ALTERATIONS IN GENE EXPRESSION INDUCED BY THE LOCAL TUMOR MICROENVIRONMENT. CLINICAL AND EXPERIMENTAL EVIDENCE SUGGESTS THAT ALTERED GENE EXPRESSION IN RESPONSE TO THE HYPOXIC MICROENVIRONMENT IS A CONTRIBUTING FACTOR TO INCREASED METASTATIC EFFICIENCY. A NUMBER OF GENES THAT HAVE BEEN IMPLICATED IN THE METASTATIC PROCESS, INVOLVING ANGIOGENESIS, INTRA/EXTRAVASATION, SURVIVAL AND GROWTH, HAVE BEEN FOUND TO BE HYPOXIA-RESPONSIVE. THE VARIOUS METASTATIC DETERMINANTS, GENETIC AND EPIGENETIC, SOMATIC AND INHERITED MAY SERVE AS PRECEDENTS FOR THE FUTURE IDENTIFICATION OF MORE GENES THAT ARE INVOLVED IN METASTASIS. MUCH RESEARCH HAS FOCUSED ON GENETIC AND MOLECULAR PROPERTIES OF THE TUMOR CELLS THEMSELVES. IN THE PRESENT REVIEW WE DISCUSS THE EPIGENETIC AND PHYSIOLOGICAL REGULATION OF METASTASIS AND EMPHASIZE THE NEED FOR FURTHER STUDIES ON THE INTERACTIONS BETWEEN THE PATHOPHYSIOLOGIC TUMOR MICROENVIRONMENT AND THE TUMOR EXTRACELLULAR MATRIX. 2009 14 2033 31 EPIGENETIC CHANGES IN SOLID AND HEMATOPOIETIC TUMORS. THERE ARE THREE CONNECTED MOLECULAR MECHANISMS OF EPIGENETIC CELLULAR MEMORY IN MAMMALIAN CELLS: DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA INTERFERENCE. THE FIRST TWO HAVE NOW BEEN FIRMLY LINKED TO NEOPLASTIC TRANSFORMATION. HYPERMETHYLATION OF CPG-RICH PROMOTERS TRIGGERS LOCAL HISTONE CODE MODIFICATIONS RESULTING IN A CELLULAR CAMOUFLAGE MECHANISM THAT SEQUESTERS GENE PROMOTERS AWAY FROM TRANSCRIPTION FACTORS AND RESULTS IN STABLE SILENCING. THIS NORMALLY RESTRICTED MECHANISM IS UBIQUITOUSLY USED IN CANCER TO SILENCE HUNDREDS OF GENES, AMONG WHICH SOME CRITICALLY CONTRIBUTE TO THE NEOPLASTIC PHENOTYPE. VIRTUALLY EVERY PATHWAY IMPORTANT TO CANCER FORMATION IS AFFECTED BY THIS PROCESS. METHYLATION PROFILING OF HUMAN CANCERS REVEALS TISSUE-SPECIFIC EPIGENETIC SIGNATURES, AS WELL AS TUMOR-SPECIFIC SIGNATURES, REFLECTING IN PARTICULAR THE PRESENCE OF EPIGENETIC INSTABILITY IN A SUBSET OF CANCERS AFFECTED BY THE CPG ISLAND METHYLATOR PHENOTYPE. GENERALLY, METHYLATION PATTERNS CAN BE TRACED TO A TISSUE-SPECIFIC, PROLIFERATION-DEPENDENT ACCUMULATION OF ABERRANT PROMOTER METHYLATION IN AGING TISSUES, A PROCESS THAT CAN BE ACCELERATED BY CHRONIC INFLAMMATION AND LESS WELL-DEFINED MECHANISMS INCLUDING, POSSIBLY, DIET AND GENETIC PREDISPOSITION. THE EPIGENETIC MACHINERY CAN ALSO BE ALTERED IN CANCER BY SPECIFIC LESIONS IN EPIGENETIC EFFECTOR GENES, OR BY ABERRANT RECRUITMENT OF THESE GENES BY MUTANT TRANSCRIPTION FACTORS AND COACTIVATORS. EPIGENETIC PATTERNS ARE PROVING CLINICALLY USEFUL IN HUMAN ONCOLOGY VIA RISK ASSESSMENT, EARLY DETECTION, AND PROGNOSTIC CLASSIFICATION. PHARMACOLOGIC MANIPULATION OF THESE PATTERNS-EPIGENETIC THERAPY-IS ALSO POISED TO CHANGE THE WAY WE TREAT CANCER IN THE CLINIC. 2005 15 3659 37 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT. 2010 16 1336 25 DESCRIBING A TRANSCRIPTION FACTOR DEPENDENT REGULATION OF THE MICRORNA TRANSCRIPTOME. WHILE THE TRANSCRIPTION REGULATION OF PROTEIN CODING GENES WAS EXTENSIVELY STUDIED, LITTLE IS KNOWN ON HOW TRANSCRIPTION FACTORS ARE INVOLVED IN TRANSCRIPTION OF NON-CODING RNAS, SPECIFICALLY OF MICRORNAS. HERE, WE PROPOSE A STRATEGY TO STUDY THE POTENTIAL ROLE OF TRANSCRIPTION FACTOR IN REGULATING TRANSCRIPTION OF MICRORNAS USING PUBLICALLY AVAILABLE DATA, COMPUTATIONAL RESOURCES AND HIGH THROUGHPUT DATA. WE USE THE H3K4ME3 EPIGENETIC SIGNATURE TO IDENTIFY MICRORNA PROMOTERS AND CHROMATIN IMMUNOPRECIPITATION (CHIP)-SEQUENCING DATA FROM THE ENCODE PROJECT TO IDENTIFY MICRORNA PROMOTERS THAT ARE ENRICHED WITH TRANSCRIPTION FACTOR BINDING SITES. BY TRANSFECTING CELLS OF INTEREST WITH SHRNA TARGETING A TRANSCRIPTION FACTOR OF INTEREST AND SUBJECTING THE CELLS TO MICRORNA ARRAY, WE STUDY THE EFFECT OF THIS TRANSCRIPTION FACTOR ON THE MICRORNA TRANSCRIPTOME. AS AN ILLUSTRATIVE EXAMPLE WE USE OUR STUDY ON THE EFFECT OF STAT3 ON THE MICRORNA TRANSCRIPTOME OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS. 2016 17 3822 30 INVESTIGATING EPIGENETIC EFFECTS OF ACTIVATION-INDUCED DEAMINASE IN CHRONIC LYMPHOCYTIC LEUKEMIA. ACTIVATION INDUCED DEAMINASE (AID) HAS TWO DISTINCT AND WELL DEFINED ROLES, BOTH RELYING ON ITS DEOXYCYTIDINE (DC) DEAMINATING FUNCTION: ONE AS A DNA MUTATOR AND ANOTHER IN DNA DEMETHYLATION. IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), AID WAS PREVIOUSLY SHOWN TO BE AN INDEPENDENT NEGATIVE PROGNOSTIC FACTOR. WHILE THERE IS SUBSTANTIAL IMPACT ON DNA MUTATIONS, EFFECTS OF AID ON GENE EXPRESSION BY PROMOTER DEMETHYLATION OF DISEASE RELATED TARGET GENES IN LEUKEMIA HAS NOT BEEN ADDRESSED. TO SHED LIGHT ON THIS QUESTION, WE AIMED AT DETERMINING GENOME WIDE METHYLATION CHANGES AS WELL AS GENE EXPRESSION CHANGES IN RESPONSE TO AID EXPRESSION IN CLL. ALTHOUGH WE FOUND MINOR DIFFERENCES IN INDIVIDUAL METHYLATION VARIABLE POSITIONS FOLLOWING AID EXPRESSION, WE COULD NOT FIND RECURRENT METHYLATION CHANGES OF SPECIFIC TARGET SITES OR CHANGES IN GLOBAL METHYLATION. 2018 18 3795 40 INTERLEUKIN-6 CONTRIBUTES TO GROWTH IN CHOLANGIOCARCINOMA CELLS BY ABERRANT PROMOTER METHYLATION AND GENE EXPRESSION. THE ASSOCIATION BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT AND PROGRESSION OF MALIGNANCY IS EXEMPLIFIED IN THE BILIARY TRACT WHERE PERSISTENT INFLAMMATION STRONGLY PREDISPOSES TO CHOLANGIOCARCINOMA. THE INFLAMMATORY CYTOKINE INTERLEUKIN-6 (IL-6) ENHANCES TUMOR GROWTH IN CHOLANGIOCARCINOMA BY ALTERED GENE EXPRESSION VIA AUTOCRINE MECHANISMS. IL-6 CAN REGULATE THE ACTIVITY OF DNA METHYLTRANSFERASES, AND MOREOVER, ABERRANT DNA METHYLATION CAN CONTRIBUTE TO CARCINOGENESIS. WE THEREFORE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO IL-6 ON METHYLATION-DEPENDENT GENE EXPRESSION AND TRANSFORMED CELL GROWTH IN HUMAN CHOLANGIOCARCINOMA. THE RELATIONSHIP BETWEEN AUTOCRINE IL-6 PATHWAYS, DNA METHYLATION, AND TRANSFORMED CELL GROWTH WAS ASSESSED USING MALIGNANT CHOLANGIOCYTES STABLY TRANSFECTED TO OVEREXPRESS IL-6. TREATMENT WITH THE DNA METHYLATION INHIBITOR 5-AZA-2'-DEOXYCYTIDINE DECREASED CELL PROLIFERATION, GROWTH IN SOFT AGAR, AND METHYLCYTOSINE CONTENT OF MALIGNANT CHOLANGIOCYTES. HOWEVER, THIS EFFECT WAS NOT OBSERVED IN IL-6-OVEREXPRESSING CELLS. IL-6 OVEREXPRESSION RESULTED IN THE ALTERED EXPRESSION AND PROMOTER METHYLATION OF SEVERAL GENES, INCLUDING THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR). EGFR PROMOTER METHYLATION WAS DECREASED AND GENE AND PROTEIN EXPRESSION WAS INCREASED BY IL-6. THUS, EPIGENETIC REGULATION OF GENE EXPRESSION BY IL-6 CAN CONTRIBUTE TO TUMOR PROGRESSION BY ALTERING PROMOTER METHYLATION AND GENE EXPRESSION OF GROWTH-REGULATORY PATHWAYS, SUCH AS THOSE INVOLVING EGFR. MOREOVER, ENHANCED IL-6 EXPRESSION MAY DECREASE THE SENSITIVITY OF TUMOR CELLS TO THERAPEUTIC TREATMENTS USING METHYLATION INHIBITORS. THESE OBSERVATIONS HAVE IMPORTANT IMPLICATIONS FOR CANCER TREATMENT AND PROVIDE A MECHANISM BY WHICH PERSISTENT CYTOKINE STIMULATION CAN PROMOTE TUMOR GROWTH. 2006 19 3799 29 INTERPLAY BETWEEN INFLAMMATION AND EPIGENETIC CHANGES IN CANCER. IMMUNE RESPONSES CAN SUPPRESS TUMORIGENESIS, BUT ALSO CONTRIBUTE TO CANCER INITIATION AND PROGRESSION SUGGESTING A COMPLEX INTERACTION BETWEEN THE IMMUNE SYSTEM AND CANCER. EPIGENETIC ALTERATIONS, WHICH ARE HERITABLE CHANGES IN GENE EXPRESSION WITHOUT CHANGES TO THE DNA SEQUENCE, ALSO PLAY A ROLE IN CARCINOGENESIS THROUGH SILENCING EXPRESSION OF TUMOR SUPPRESSOR GENES AND ACTIVATING ONCOGENIC SIGNALING. INTERESTINGLY, EPITHELIAL CELLS AT SITES OF CHRONIC INFLAMMATION UNDERGO DNA METHYLATION ALTERATIONS THAT ARE SIMILAR TO THOSE PRESENT IN CANCER CELLS, SUGGESTING THAT INFLAMMATION MAY INITIATE CANCER-SPECIFIC EPIGENETIC CHANGES IN EPITHELIAL CELLS. FURTHERMORE, EPIGENETIC CHANGES OCCUR DURING IMMUNE CELL DIFFERENTIATION AND PARTICIPATE IN REGULATING THE IMMUNE RESPONSE, INCLUDING THE REGULATION OF INFLAMMATORY CYTOKINES. CANCER CELLS UTILIZE EPIGENETIC SILENCING OF IMMUNE-RELATED GENES TO EVADE THE IMMUNE RESPONSE. THIS CHAPTER WILL DETAIL THE INTERACTIONS BETWEEN INFLAMMATION AND EPIGENETICS IN TUMOR INITIATION, PROMOTION, AND IMMUNE EVASION AND HOW THESE CONNECTIONS ARE BEING LEVERAGED IN CANCER PREVENTION AND TREATMENT. 2016 20 6326 29 THE ROLE OF BCL-2 FAMILY PROTEINS IN CHRONIC LYMPHOCYTIC LEUKAEMIA. BCL-2 FAMILY PROTEINS HAVE LONG BEEN IMPLICATED IN THE PATHOLOGY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). INDEED, A NUMBER OF THESE PROTEINS HAVE BEEN SHOWN TO HAVE PROGNOSTIC IMPORTANCE IN THIS DISEASE. THE PRECISE WAYS IN WHICH THESE PROTEINS IMPACT UPON CLL AND THE WAYS IN WHICH THEY ARE REGULATED REMAIN INCOMPLETELY RESOLVED. HOWEVER, SIGNIFICANT ADVANCES HAVE BEEN RECENTLY MADE IN OUR UNDERSTANDING OF HOW THESE PROTEINS ARE CONTROLLED BY GENETIC, EPIGENETIC AND MICROENVIRONMENTAL CUES. FURTHERMORE, MAJOR PROGRESS HAS BEEN MADE IN TRYING TO TARGET THESE PROTEINS THERAPEUTICALLY. HERE WE REVIEW THE CURRENT KNOWLEDGE ABOUT THIS FAMILY OF APOPTOSIS-REGULATING PROTEINS AND HOW THEY IMPACT UPON DRUG RESISTANCE AND DISEASE PROGRESSION. WE ALSO SUMMARISE EVOLUTION IN THE DEVELOPMENT OF BCL-2 FAMILY INHIBITORS FOR THE TREATMENT OF CLL AND OTHER CANCERS. 2010