1 1433 132 DIFFERENTIAL GENOME-WIDE ARRAY-BASED METHYLATION PROFILES IN PROGNOSTIC SUBSETS OF CHRONIC LYMPHOCYTIC LEUKEMIA. GLOBAL HYPOMETHYLATION AND REGIONAL HYPERMETHYLATION ARE WELL-KNOWN EPIGENETIC FEATURES OF CANCER; HOWEVER, IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), STUDIES ON GENOME-WIDE EPIGENETIC MODIFICATIONS ARE LIMITED. HERE, WE ANALYZED THE GLOBAL METHYLATION PROFILES IN CLL, BY APPLYING HIGH-RESOLUTION METHYLATION MICROARRAYS (27,578 CPG SITES) TO 23 CLL SAMPLES, BELONGING TO THE IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE (IGHV) MUTATED (FAVORABLE) AND IGHV UNMUTATED/IGHV3-21 (POOR-PROGNOSTIC) SUBSETS. OVERALL, RESULTS DEMONSTRATED SIGNIFICANT DIFFERENCES IN METHYLATION PATTERNS BETWEEN THESE SUBGROUPS. SPECIFICALLY, IN IGHV UNMUTATED CLL, WE IDENTIFIED METHYLATION OF 7 KNOWN OR CANDIDATE TUMOR SUPPRESSOR GENES (EG, VHL, ABI3, AND IGSF4) AS WELL AS 8 UNMETHYLATED GENES INVOLVED IN CELL PROLIFERATION AND TUMOR PROGRESSION (EG, ADORA3 AND PRF1 ENHANCING THE NUCLEAR FACTOR-KAPPAB AND MITOGEN-ACTIVATED PROTEIN KINASE PATHWAYS, RESPECTIVELY). IN CONTRAST, THESE LATTER GENES WERE SILENCED BY METHYLATION IN IGHV MUTATED PATIENTS. THE ARRAY DATA WERE VALIDATED FOR SELECTED GENES USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION, QUANTITATIVE REVERSE TRANSCRIPTASE-POLYMERASE CHAIN REACTION, AND BISULFITE SEQUENCING. FINALLY, THE SIGNIFICANCE OF DNA METHYLATION IN REGULATING GENE PROMOTERS WAS SHOWN BY REINDUCING 4 METHYLATED TUMOR SUPPRESSOR GENES (EG, VHL AND ABI3) IN IGHV UNMUTATED SAMPLES USING THE METHYL-INHIBITOR 5-AZA-2'-DEOXYCYTIDINE. TAKEN TOGETHER, OUR DATA FOR THE FIRST TIME REVEAL DIFFERENCES IN GLOBAL METHYLATION PROFILES BETWEEN PROGNOSTIC SUBSETS OF CLL, WHICH MAY UNFOLD EPIGENETIC SILENCING MECHANISMS INVOLVED IN CLL PATHOGENESIS. 2010 2 2378 21 EPIGENETIC REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING IN ATHEROSCLEROTIC ARTERY REMODELING: A MINI-REVIEW. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY EXTENSIVE REMODELING OF MEDIUM AND LARGE-SIZED ARTERIES. INWARD REMODELING (=LUMEN SHRINKAGE) OF THE VASCULAR WALLS IS THE UNDERLYING CAUSE FOR ISCHEMIA IN TARGET ORGANS. THEREFORE, INWARD REMODELING CAN BE CONSIDERED THE PREDOMINANT FEATURE OF ATHEROSCLEROTIC PATHOLOGY. OUTWARD REMODELING (=LUMEN ENLARGEMENT) IS A PHYSIOLOGICAL RESPONSE COMPENSATING FOR LUMEN SHRINKAGE CAUSED BY NEOINTIMAL HYPERPLASIA, BUT AS A PATHOLOGICAL RESPONSE TO CHANGES IN BLOOD FLOW, OUTWARD REMODELING LEADS TO SUBSTANTIAL ARTERIAL WALL THINNING. THINNED VASCULAR WALLS ARE PRONE TO RUPTURE, AND SUBSEQUENT THROMBUS FORMATION ACCOUNTS FOR THE MAJORITY OF ACUTE CARDIOVASCULAR EVENTS. PATHOLOGICAL REMODELING IS DRIVEN BY INFLAMMATORY CELLS WHICH INDUCE VASCULAR SMOOTH MUSCLE CELLS TO SWITCH FROM QUIESCENT TO A PROLIFERATIVE AND MIGRATORY PHENOTYPE. AFTER DECADES OF INTENSIVE RESEARCH, THE MOLECULAR MECHANISMS OF ARTERIAL REMODELING ARE STARTING TO UNFOLD. IN THIS MINI-REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF VASCULAR SMOOTH MUSCLE CELL PHENOTYPE SWITCHING FROM THE CONTRACTILE TO THE SYNTHETIC PHENOTYPE INVOLVED IN ARTERIAL REMODELING AND DISCUSS POTENTIAL THERAPEUTIC OPTIONS. 2021 3 4131 24 MECHANISMS OF HBV-INDUCED HEPATOCELLULAR CARCINOMA. HEPATITIS B VIRUS (HBV) CONTRIBUTES TO HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT THROUGH DIRECT AND INDIRECT MECHANISMS. HBV DNA INTEGRATION INTO THE HOST GENOME OCCURS AT EARLY STEPS OF CLONAL TUMOR EXPANSION AND INDUCES BOTH GENOMIC INSTABILITY AND DIRECT INSERTIONAL MUTAGENESIS OF DIVERSE CANCER-RELATED GENES. PROLONGED EXPRESSION OF THE VIRAL REGULATORY PROTEIN HBX AND/OR ALTERED VERSIONS OF THE PRES/S ENVELOPE PROTEINS DYSREGULATES CELL TRANSCRIPTION AND PROLIFERATION CONTROL AND SENSITIZES LIVER CELLS TO CARCINOGENIC FACTORS. ACCUMULATION OF PRES1 LARGE ENVELOPE PROTEINS AND/OR PRES2/S MUTANT PROTEINS ACTIVATES THE UNFOLD PROTEINS RESPONSE, THAT CAN CONTRIBUTE TO HEPATOCYTE TRANSFORMATION. EPIGENETIC CHANGES TARGETING THE EXPRESSION OF TUMOR SUPPRESSOR GENES OCCUR EARLY IN THE DEVELOPMENT OF HCC. A MAJOR ROLE IS PLAYED BY THE HBV PROTEIN, HBX, WHICH IS RECRUITED ON CELLULAR CHROMATIN AND MODULATES CHROMATIN DYNAMICS AT SPECIFIC GENE LOCI. COMPARED WITH TUMORS ASSOCIATED WITH OTHER RISK FACTORS, HBV-RELATED TUMORS HAVE A HIGHER RATE OF CHROMOSOMAL ALTERATIONS, P53 INACTIVATION BY MUTATIONS AND OVEREXPRESSION OF FETAL LIVER/HEPATIC PROGENITOR CELLS GENES. THE WNT/BETA-CATENIN PATHWAY IS ALSO OFTEN ACTIVATED BUT HBV-RELATED TUMORS DISPLAY A LOW RATE OF ACTIVATING BETA-CATENIN MUTATIONS. HBV-RELATED HCCS MAY ARISE ON NON-CIRRHOTIC LIVERS, FURTHER SUPPORTING THE NOTION THAT HBV PLAYS A DIRECT ROLE IN LIVER TRANSFORMATION BY TRIGGERING BOTH COMMON AND ETIOLOGY SPECIFIC ONCOGENIC PATHWAYS IN ADDITION TO STIMULATING THE HOST IMMUNE RESPONSE AND DRIVING LIVER CHRONIC NECRO-INFLAMMATION. 2016 4 4243 34 METHYLATION STATUS OF CEBPA GENE PROMOTER IN CHRONIC MYELOID LEUKEMIA. CCAAT/ENHANCER BINDING PROTEIN ALPHA IS ONE OF THE CRUCIAL TRANSCRIPTION FACTORS FOR MYELOID CELL DEVELOPMENT THAT HAS BEEN FOUND TO BE INVOLVED IN HEMATOPOIETIC DIFFERENTIATION AND LEUKEMIOGENESIS. RECENTLY, EPIGENETIC REGULATION OF CEBPA EXPRESSION THROUGH DNA METHYLATION HAS BEEN DEMONSTRATED IN LEUKEMIA. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE METHYLATION STATUS OF CEBPA GENE IN CHRONIC MYELOID LEUKEMIA (CML) PATIENTS. THE METHYLATION STATUS OF CEBPA PROMOTER WAS STUDIED IN 100 PATIENTS WITH CML AND 98 NORMAL HEALTHY INDIVIDUALS FROM HYDERABAD, INDIA, USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. THE ABERRANT METHYLATION OF CEBPA GENE PROMOTER WAS FOUND IN 32 OF THE 100 CML CASES. A HIGHLY SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN THE FREQUENCY OF CEBPA GENE PROMOTER HYPERMETHYLATION AND THE CML STAGES (P = 0.017), BUT ASSOCIATION WITH RESPECT TO AGE AND GENDER OF THE PATIENT WAS NOT FOUND. THE RESULTS SUGGEST THAT ABERRANT METHYLATION IN THE CPG ISLAND OF THE PROMOTER REGION OF THIS GENE MIGHT BE A COMMON EVENT IN CML, AND SYSTEMIC EXPRESSION STUDIES WILL BE NEEDED TO UNFOLD THE ROLE OF CEBPA PROMOTER METHYLATION IN THE DEVELOPMENT, PROGRESSION, AND PROGNOSIS OF CML. 2014 5 4826 20 OF PLEIOTROPY AND TRAJECTORIES: DOES THE TGF-BETA PATHWAY LINK CHILDHOOD ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE? THE STUDY OF DEVELOPMENTAL TRAJECTORIES IS WHERE EPIGENETICS TRULY SHINES. THE "EPI" IN EPIGENETICS CAPTURES THE FACT THAT ALTHOUGH EPIGENETIC PROCESSES ALSO PRESIDE OVER THE MAINTENANCE AND TERMINATION OF GENE EXPRESSION, THE UNFOLDING AND REMODELING OF CHROMATIN ARCHITECTURE ARE ESPECIALLY CRITICAL TO PREPARE GENES FOR REGULATED TRANSCRIPTION. THESE PROPERTIES IMPLY BEING ON A PATH, A TRAJECTORY TO EVENTS THAT WILL OCCUR LATER THANKS TO EPIGENETIC PROGRAMMING. THUS EPIGENETICS IS ABOUT TIMED AND TIMELY EVENTS. IN THIS ARTICLE WE DISCUSS EPIGENETIC AND GENETIC EVIDENCE FROM SEVERAL INDEPENDENT STUDIES OF ASTHMA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, AND LUNG FUNCTION, WHICH CONVERGE TO HIGHLIGHT A POTENTIAL ROLE OF THE TGF-BETA GENE PATHWAY IN THESE PROCESSES. THESE RESULTS RAISE THE POSSIBILITY THAT AT LEAST IN A SUBSET OF SUBJECTS, THESE CONDITIONS MIGHT BE FUNCTIONALLY CONNECTED IN WAYS THAT NEED TO BE FURTHER DEFINED BUT THAT LIKELY REFLECT THE UNIQUELY PLEIOTROPIC NATURE OF TGF-BETA PATHWAY GENES, PARTICULARLY THEIR ABILITY TO CONTROL BOTH LUNG DEVELOPMENT AND IMMUNE RESPONSES ESSENTIAL FOR REGULATION AND INFLAMMATION. FURTHER CHARACTERIZATION OF THIS PATHWAY IN LONGITUDINALLY PHENOTYPED POPULATIONS MIGHT UNMASK NOVEL TRAJECTORIES TO LUNG DISEASE THAT BEGIN IN UTERO AND UNFOLD INTO OLD AGE. 2018 6 6383 30 THE ROLE OF PHF6 IN HEMATOPOIESIS AND HEMATOLOGIC MALIGNANCIES. EPIGENETIC REGULATION OF GENE EXPRESSION REPRESENTS AN IMPORTANT MECHANISM IN THE MAINTENANCE OF STEM CELL FUNCTION. ALTERATIONS IN EPIGENETIC REGULATION CONTRIBUTE TO THE PATHOGENESIS OF HEMATOLOGICAL MALIGNANCIES. PLANT HOMEODOMAIN FINGER PROTEIN 6 (PHF6) IS A MEMBER OF THE PLANT HOMEODOMAIN (PHD)-LIKE ZINC FINGER FAMILY OF PROTEINS THAT IS INVOLVED IN TRANSCRIPTIONAL REGULATION THROUGH THE MODIFICATION OF THE CHROMATIN STATE. GERMLINE MUTATION OF PHF6 IS THE CAUSATIVE GENETIC ALTERATION OF THE X-LINKED MENTAL RETARDATION BORJESON-FORSSMAN-LEHMANN SYNDROME (BFLS). SOMATIC MUTATIONS IN PHF6 ARE IDENTIFIED IN HUMAN LEUKEMIA, SUCH AS ADULT T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL, ~ 38%), PEDIATRIC T-ALL (~ 16%), ACUTE MYELOID LEUKEMIA (AML, ~ 3%), CHRONIC MYELOID LEUKEMIA (CML, ~ 2.5%), MIXED PHENOTYPE ACUTE LEUKEMIA (MPAL, ~ 20%), AND HIGH-GRADE B-CELL LYMPHOMA (HGBCL, ~ 3%). MORE RECENT STUDIES IMPLY AN ONCOGENIC EFFECT OF PHF6 IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL) AND SOLID TUMORS. THESE DATA DEMONSTRATE THAT PHF6 COULD ACT AS A DOUBLE-EDGED SWORD, EITHER A TUMOR SUPPRESSOR OR AN ONCOGENE, IN A LINEAGE-DEPENDENT MANNER. HOWEVER, THE UNDERLYING MECHANISMS OF PHF6 IN NORMAL HEMATOPOIESIS AND LEUKEMOGENESIS REMAIN LARGELY UNKNOWN. IN THIS REVIEW, WE SUMMARIZE CURRENT KNOWLEDGE OF PHF6, EMPHASIZING THE ROLE OF PHF6 IN HEMATOLOGICAL MALIGNANCIES. EPIGENETIC REGULATION OF PHF6 IN B-ALL. PHF6 MAINTAINS A CHROMATIN STRUCTURE THAT IS PERMISSIVE TO B-CELL IDENTITY GENES, BUT NOT T-CELL-SPECIFIC GENES (LEFT). LOSS OF PHF6 LEADS TO ABERRANT EXPRESSION OF B-CELL- AND T-CELL-SPECIFIC GENES RESULTING FROM LINEAGE PROMISCUITY AND BINDING OF T-CELL TRANSCRIPTION FACTORS (RIGHT). 2023 7 2971 22 GENETIC AND EPIGENETIC SILENCING OF MICRORNA-203 ENHANCES ABL1 AND BCR-ABL1 ONCOGENE EXPRESSION. THE MAMMALIAN GENOME CONTAINS SEVERAL HUNDRED MICRORNAS THAT REGULATE GENE EXPRESSION THROUGH MODULATION OF TARGET MRNAS. HERE, WE REPORT A FRAGILE CHROMOSOMAL REGION LOST IN SPECIFIC HEMATOPOIETIC MALIGNANCIES. THIS 7 MB REGION ENCODES ABOUT 12% OF ALL GENOMIC MICRORNAS, INCLUDING MIR-203. THIS MICRORNA IS ADDITIONALLY HYPERMETHYLATED IN SEVERAL HEMATOPOIETIC TUMORS, INCLUDING CHRONIC MYELOGENOUS LEUKEMIAS AND SOME ACUTE LYMPHOBLASTIC LEUKEMIAS. A PUTATIVE MIR-203 TARGET, ABL1, IS SPECIFICALLY ACTIVATED IN THESE HEMATOPOIETIC MALIGNANCIES IN SOME CASES AS A BCR-ABL1 FUSION PROTEIN (PHILADELPHIA CHROMOSOME). RE-EXPRESSION OF MIR-203 REDUCES ABL1 AND BCR-ABL1 FUSION PROTEIN LEVELS AND INHIBITS TUMOR CELL PROLIFERATION IN AN ABL1-DEPENDENT MANNER. THUS, MIR-203 FUNCTIONS AS A TUMOR SUPPRESSOR, AND RE-EXPRESSION OF THIS MICRORNA MIGHT HAVE THERAPEUTIC BENEFITS IN SPECIFIC HEMATOPOIETIC MALIGNANCIES. 2008 8 1662 24 DOWNREGULATION OF DEATH-ASSOCIATED PROTEIN KINASE 1 (DAPK1) IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE HERITABILITY OF B CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS RELATIVELY HIGH; HOWEVER, NO PREDISPOSING MUTATION HAS BEEN CONVINCINGLY IDENTIFIED. WE SHOW THAT LOSS OR REDUCED EXPRESSION OF DEATH-ASSOCIATED PROTEIN KINASE 1 (DAPK1) UNDERLIES CASES OF HERITABLE PREDISPOSITION TO CLL AND THE MAJORITY OF SPORADIC CLL. EPIGENETIC SILENCING OF DAPK1 BY PROMOTER METHYLATION OCCURS IN ALMOST ALL SPORADIC CLL CASES. FURTHERMORE, WE DEFINED A DISEASE HAPLOTYPE, WHICH SEGREGATES WITH THE CLL PHENOTYPE IN A LARGE FAMILY. DAPK1 EXPRESSION OF THE CLL ALLELE IS DOWNREGULATED BY 75% IN GERMLINE CELLS DUE TO INCREASED HOXB7 BINDING. IN THE BLOOD CELLS FROM AFFECTED FAMILY MEMBERS, PROMOTER METHYLATION RESULTS IN ADDITIONAL LOSS OF DAPK1 EXPRESSION. THUS, REDUCED EXPRESSION OF DAPK1 CAN RESULT FROM GERMLINE PREDISPOSITION, AS WELL AS EPIGENETIC OR SOMATIC EVENTS CAUSING OR CONTRIBUTING TO THE CLL PHENOTYPE. 2007 9 4462 19 MOLECULAR MECHANISMS OF HBV-ASSOCIATED HEPATOCARCINOGENESIS. HEPATITIS B VIRUS (HBV) CONTRIBUTES TO HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT THROUGH DIRECT AND INDIRECT MECHANISMS. HBV-DNA INTEGRATION INTO THE HOST GENOME OCCURS AT EARLY STEPS OF CLONAL TUMOR EXPANSION AND INDUCES BOTH GENOMIC INSTABILITY AND DIRECT INSERTIONAL MUTAGENESIS OF DIVERSE CANCER-RELATED GENES. PROLONGED EXPRESSION OF THE VIRAL REGULATORY PROTEIN HBX AND THE LARGE ENVELOPE PROTEIN DEREGULATE THE CELLULAR TRANSCRIPTION PROGRAM AND PROLIFERATION CONTROL AND SENSITIZE LIVER CELLS TO CARCINOGENIC FACTORS. EPIGENETIC CHANGES TARGETING THE EXPRESSION OF TUMOR SUPPRESSOR GENES OCCUR EARLY IN THE DEVELOPMENT OF HCC. A MAJOR ROLE IS PLAYED BY HBX THAT IS RECRUITED ON CELLULAR CHROMATIN AND MODULATES CHROMATIN DYNAMICS AT SPECIFIC GENE LOCI. COMPARED WITH TUMORS ASSOCIATED WITH OTHER RISK FACTORS, HBV-RELATED TUMORS HAVE A HIGHER RATE OF CHROMOSOMAL ALTERATIONS AND P53 INACTIVATION BY MUTATIONS, OVEREXPRESS FETAL LIVER/HEPATIC PROGENITOR CELLS GENES, AND SHOW A SPECIFIC ACTIVATION OF THE AKT PATHWAY. THE WNT/BETA-CATENIN PATHWAY IS ALSO OFTEN ACTIVATED, BUT HBV-RELATED TUMORS DISPLAY A LOW RATE OF ACTIVATING BETA-CATENIN MUTATIONS. ALL AVAILABLE EVIDENCE STRONGLY SUPPORTS THE NOTION THAT CHRONIC HBV INFECTION TRIGGERS BOTH COMMON AND ETIOLOGY-SPECIFIC ONCOGENIC PATHWAYS, THUS PLAYING A DIRECT ROLE BEYOND STIMULATION OF HOST IMMUNE RESPONSES AND CHRONIC NECROINFLAMMATORY LIVER DISEASE. 2013 10 5871 36 SUSTAINED NF-KAPPAB ACTIVITY IN CHRONIC LYMPHOCYTIC LEUKEMIA IS INDEPENDENT OF GENETIC AND EPIGENETIC ALTERATIONS IN THE TNFAIP3 (A20) LOCUS. INAPPROPRIATE NUCLEAR FACTOR (NF) KAPPAB ACTIVITY IS ONE MAJOR HALLMARK OF B-CELL MALIGNANCIES AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). NFKAPPAB-DEPENDENT GENES ARE INVOLVED IN ANTIAPOPTOSIS, CELL PROLIFERATION AND METASTASIS AND ARE RESPONSIBLE FOR SURVIVAL AND PROLIFERATION OF TUMORS. HOWEVER, THE MECHANISMS OF NFKAPPAB ACTIVITY IN CLL STILL NEED TO BE ELUCIDATED. PREVIOUSLY, WE IDENTIFIED TRANSLOCATIONS IN A REGION ON CHROMOSOME 6Q THAT ENCODES TUMOR NECROSIS FACTOR ALPHA-INDUCED PROTEIN 3, WHICH IS A KEY PLAYER IN NEGATIVE FEEDBACK LOOP REGULATION OF NFKAPPAB. INACTIVATION OF THIS UBIQUITIN-EDITING ENZYME IS INVOLVED IN IMMUNOPATHOLOGIES AND IN TUMORIGENESIS. FREQUENT MUTATIONS IN THE A20 LOCUS--LEADING TO SUSTAINED NFKAPPAB ACTIVITY--COULD BE SHOWN TO PLAY A DOMINANT ROLE IN DEVELOPMENT OF DIFFERENT B-CELL MALIGNANCIES. TO CHECK IF A20 IS INVOLVED IN UPREGULATION OF NFKAPPAB ACTIVITY IN CLL, WE SEQUENCED EXONS 2-9 OF THE A20 GENE IN 55 CLL DNA SAMPLES. FURTHERMORE, WE DETERMINED THE METHYLATION STATUS OF THE PROMOTER REGION IN 63 CLL DNA SAMPLES AND COMPARED TO 10 CONTROL DNAS OF B CELLS FROM HEALTHY DONORS. CONTRARY TO REPORTS FROM OTHER B-CELL MALIGNANCIES, THE A20 REGION SHOWED NEITHER MUTATIONS NOR ABERRANT DNA METHYLATION. MOREOVER, ITS EXPRESSION COULD BE CONFIRMED BY IMMUNOBLOTTING AND SHOWING COMPARABLE RESULTS TO HEALTHY B CELLS. THESE RESULTS INDICATE THAT MALIGNANT DEVELOPMENT IN CLL DIFFERS FROM MOST OF OTHER B-CELL MALIGNANCIES, WHICH SHOW FREQUENT INACTIVATION OF A20. 2011 11 6307 28 THE REFERENCE EPIGENOME AND REGULATORY CHROMATIN LANDSCAPE OF CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A FREQUENT HEMATOLOGICAL NEOPLASM IN WHICH UNDERLYING EPIGENETIC ALTERATIONS ARE ONLY PARTIALLY UNDERSTOOD. HERE, WE ANALYZE THE REFERENCE EPIGENOME OF SEVEN PRIMARY CLLS AND THE REGULATORY CHROMATIN LANDSCAPE OF 107 PRIMARY CASES IN THE CONTEXT OF NORMAL B CELL DIFFERENTIATION. WE IDENTIFY THAT THE CLL CHROMATIN LANDSCAPE IS LARGELY INFLUENCED BY DISTINCT DYNAMICS DURING NORMAL B CELL MATURATION. BEYOND THIS, WE DEFINE EXTENSIVE CATALOGUES OF REGULATORY ELEMENTS DE NOVO REPROGRAMMED IN CLL AS A WHOLE AND IN ITS MAJOR CLINICO-BIOLOGICAL SUBTYPES CLASSIFIED BY IGHV SOMATIC HYPERMUTATION LEVELS. WE UNCOVER THAT IGHV-UNMUTATED CLLS HARBOR MORE ACTIVE AND OPEN CHROMATIN THAN IGHV-MUTATED CASES. FURTHERMORE, WE SHOW THAT DE NOVO ACTIVE REGIONS IN CLL ARE ENRICHED FOR NFAT, FOX AND TCF/LEF TRANSCRIPTION FACTOR FAMILY BINDING SITES. ALTHOUGH MOST GENETIC ALTERATIONS ARE NOT ASSOCIATED WITH CONSISTENT EPIGENETIC PROFILES, CLLS WITH MYD88 MUTATIONS AND TRISOMY 12 SHOW DISTINCT CHROMATIN CONFIGURATIONS. FURTHERMORE, WE OBSERVE THAT NON-CODING MUTATIONS IN IGHV-MUTATED CLLS ARE ENRICHED IN H3K27AC-ASSOCIATED REGULATORY ELEMENTS OUTSIDE ACCESSIBLE CHROMATIN. OVERALL, THIS STUDY PROVIDES AN INTEGRATIVE PORTRAIT OF THE CLL EPIGENOME, IDENTIFIES EXTENSIVE NETWORKS OF ALTERED REGULATORY ELEMENTS AND SHEDS LIGHT ON THE RELATIONSHIP BETWEEN THE GENETIC AND EPIGENETIC ARCHITECTURE OF THE DISEASE. 2018 12 787 18 CELLS OF ADULT T-CELL LEUKEMIA EVADE HTLV-1 TAX/NF-KAPPAB HYPERACTIVATION-INDUCED SENESCENCE. HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-1) IS THE ETIOLOGICAL AGENT OF ADULT T-CELL LEUKEMIA/LYMPHOMA (ATL). THE HTLV-1 VIRAL TRANS-ACTIVATOR/ONCOPROTEIN TAX IS A MAJOR DRIVER OF ATL, YET IT INDUCES RAPID P21(CIP1/WAF1) (P21)- AND P27(KIP1)-MEDIATED CELLULAR SENESCENCE THROUGH CONSTITUTIVE ACTIVATION (HYPERACTIVATION) OF NF-KAPPAB. ALTHOUGH CONSTITUTIVE NF-KAPPAB ACTIVATION IS A COMMON FEATURE OF T/B-CELL LEUKEMIA/LYMPHOMA, INCLUDING ATL, IT IS NOT KNOWN HOW ATL CELLS MAINTAIN CHRONIC NF-KAPPAB ACTIVATION WITHOUT UNDERGOING SENESCENCE. HERE, WE DEMONSTRATE THAT, IN CONTRAST TO HTLV-1(-) T-CELL LINES, ATL CELL LINES NO LONGER UNDERGO TAX-INDUCED SENESCENCE. ALTHOUGH TAX(+) AND TAX(-) ATL CELL LINES SHOWED SIGNATURES OF CONSTITUTIVE NF-KAPPAB ACTIVATION, THEIR ABILITY TO PROGRESS THROUGH THE CELL CYCLE WAS UNAFFECTED. IN SOME CASES, ATL CELL LINES CONTINUED TO PROLIFERATE DESPITE SIGNIFICANT UPREGULATION OF P21; ADDITIONALLY, MANY CELL LINES DISPLAYED ALTERED EXPRESSION OF G1 AND G1/S CYCLINS, PARTICULARLY OVEREXPRESSION OF CYCLIN D2. WE PROPOSE THAT, DURING THE COURSE OF ATL DEVELOPMENT, LEUKEMIA CELLS ACQUIRE GENETIC/EPIGENETIC CHANGES THAT CAN MITIGATE THE SENESCENCE RESPONSE TRIGGERED BY NF-KAPPAB HYPERACTIVATION. RESTORING THE NF-KAPPAB-INDUCED SENESCENCE RESPONSE WOULD LIKELY HELP TO CONTROL THE DEVELOPMENT AND PROGRESSION OF ATL AND SIMILAR LYMPHOID MALIGNANCIES. 2019 13 6268 24 THE NEUROEPIGENOME: IMPLICATIONS OF CHEMICAL AND PHYSICAL MODIFICATIONS OF GENOMIC DNA IN SCHIZOPHRENIA. SCHIZOPHRENIA IS A CHRONIC MENTAL ILLNESS WITH A SUBSTANTIAL GENETIC COMPONENT. TO UNFOLD THE COMPLEX ETIOLOGY OF SCHIZOPHRENIA, IT IS IMPORTANT TO UNDERSTAND THE INTERPLAY BETWEEN GENETIC AND NONGENETIC FACTORS. GENETIC FACTORS INVOLVE VARIATION IN THE DNA SEQUENCES OF PROTEIN-CODING GENES, WHICH DIRECTLY CONTRIBUTE TO PHENOTYPIC TRAITS, AND VARIATION IN NONCODING SEQUENCES, WHICH COMPRISE 98% OF THE GENOME AND CONTAIN DNA ELEMENTS KNOWN TO PLAY A ROLE IN REGULATING GENE EXPRESSION. THE EPIGENOME REFERS TO THE CHEMICAL MODIFICATIONS ON BOTH DNA AND THE STRUCTURAL PROTEINS THAT PACKAGE DNA INTO THE NUCLEUS, WHICH TOGETHER REGULATE GENE EXPRESSION IN SPECIFIC CELL TYPES, CONDITIONS, AND DEVELOPMENTAL STAGES. THE DYNAMIC NATURE OF THE EPIGENOME MAKES IT AN IDEAL TOOL TO INVESTIGATE THE RELATIONSHIP BETWEEN INHERITED GENETIC MUTATIONS ASSOCIATED WITH SCHIZOPHRENIA AND ALTERED GENE REGULATION THROUGHOUT THE COURSE OF BRAIN DEVELOPMENT. IN THIS REVIEW, WE FOCUS ON THE CURRENT UNDERSTANDING OF THE ROLE OF EPIGENETIC MARKS AND THEIR THREE-DIMENSIONAL NUCLEAR ORGANIZATION IN THE DEVELOPMENTAL TRAJECTORY OF DISTINCT BRAIN CELL TYPES TO DECIPHER THE COMPLEX GENE REGULATORY MECHANISMS THAT ARE DISRUPTED IN SCHIZOPHRENIA. 2022 14 6753 24 WILD TYPE HBX AND TRUNCATED HBX: PLEIOTROPIC REGULATORS DRIVING SEQUENTIAL GENETIC AND EPIGENETIC STEPS OF HEPATOCARCINOGENESIS AND PROGRESSION OF HBV-ASSOCIATED NEOPLASMS. HEPATITIS B VIRUS (HBV) IS ONE OF THE CAUSATIVE AGENTS OF HEPATOCELLULAR CARCINOMA. THE MOLECULAR MECHANISMS OF TUMORIGENESIS ARE COMPLEX. ONE OF THE HOST FACTORS INVOLVED IS APPARENTLY THE LONG-LASTING INFLAMMATORY REACTION WHICH ACCOMPANIES CHRONIC HBV INFECTION. ALTHOUGH HBV LACKS A TYPICAL VIRAL ONCOGENE, THE HBX GENE ENCODING A PLEIOTROPIC REGULATORY PROTEIN EMERGED AS A MAJOR PLAYER IN LIVER CARCINOGENESIS. HERE WE REVIEW THE TUMORIGENIC FUNCTIONS OF HBX WITH AN EMPHASIS ON WILD TYPE AND TRUNCATED HBX VARIANTS, AND THEIR ROLE IN THE TRANSCRIPTIONAL DYSREGULATION AND EPIGENETIC REPROGRAMMING OF THE HOST CELL GENOME. WE SUGGEST THAT HBX ACQUIRED BY THE HBV GENOME DURING EVOLUTION ACTS LIKE A CELLULAR PROTO-ONC GENE THAT IS ACTIVATED BY DELETION DURING HEPATOCARCINOGENESIS. THE RESULTING VIRAL ONCOGENE (V-ONC GENE) CODES FOR A TRUNCATED HBX PROTEIN THAT FACILITATES TUMOR PROGRESSION. COPYRIGHT (C) 2015 JOHN WILEY & SONS, LTD. 2016 15 6390 24 THE ROLE OF THE GENETIC ABNORMALITIES, EPIGENETIC AND MICRORNA IN THE PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS INCREASED PROLIFERATION OF B-CELLS WITH PERIPHERAL BLOOD AND BONE MARROW INVOLVEMENT, WHICH IS USUALLY OBSERVED IN OLDER PEOPLE. GENETIC MUTATIONS, EPIGENETIC CHANGES AND MIRS PLAY A ROLE IN CLL PATHOGENESIS. DEL 11Q, DEL L17Q, DEL 6Q, TRISOMY 12, P53 AND IGVH MUTATIONS ARE THE MOST IMPORTANT GENETIC CHANGES IN CLL. DELETION OF MIR-15A AND MIR-16A CAN INCREASE BCL2 GENE EXPRESSION, MIR-29 AND MIR-181 DELETIONS DECREASE THE EXPRESSION OF TCL1, AND MIR-146A DELETION PREVENTS TUMOR METASTASIS. EPIGENETIC CHANGES SUCH AS HYPO- AND HYPERMETHYLATION, UBIQUITINATION, HYPO- AND HYPERACETYLATION OF GENE PROMOTERS INVOLVED IN CLL PATHOGENESIS CAN ALSO PLAY A ROLE IN CLL. EXPRESSION OF CD38 AND ZAP70, PRESENCE OR ABSENCE OF MUTATION IN IGVH AND P53 MUTATION ARE AMONG THE FACTORS INVOLVED IN CLL PROGNOSIS. USE OF MONOCLONAL ANTIBODIES AGAINST SURFACE MARKERS OF B-CELLS LIKE ANTI-CD20 AS WELL AS TYROSINE KINASE INHIBITORS ARE THE MOST IMPORTANT THERAPEUTIC APPROACHES FOR CLL. 2018 16 1465 24 DISSECTING THE ROLE OF ABERRANT DNA METHYLATION IN HUMAN LEUKAEMIA. CHRONIC MYELOID LEUKAEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY THE GENETIC TRANSLOCATION T(9;22)(Q34;Q11.2) ENCODING FOR THE BCR-ABL FUSION ONCOGENE. HOWEVER, MANY MOLECULAR MECHANISMS OF THE DISEASE PROGRESSION STILL REMAIN POORLY UNDERSTOOD. A GROWING BODY OF EVIDENCE SUGGESTS THAT THE EPIGENETIC ABNORMALITIES ARE INVOLVED IN TYROSINE KINASE RESISTANCE IN CML, LEADING TO LEUKAEMIC CLONE ESCAPE AND DISEASE PROPAGATION. HERE WE SHOW THAT, BY APPLYING CELLULAR REPROGRAMMING TO PRIMARY CML CELLS, ABERRANT DNA METHYLATION CONTRIBUTES TO THE DISEASE EVOLUTION. IMPORTANTLY, USING A BCR-ABL INDUCIBLE MURINE MODEL, WE DEMONSTRATE THAT A SINGLE ONCOGENIC LESION TRIGGERS DNA METHYLATION CHANGES, WHICH IN TURN ACT AS A PRECIPITATING EVENT IN LEUKAEMIA PROGRESSION. 2015 17 15 44 450K-ARRAY ANALYSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA CELLS REVEALS GLOBAL DNA METHYLATION TO BE RELATIVELY STABLE OVER TIME AND SIMILAR IN RESTING AND PROLIFERATIVE COMPARTMENTS. IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), THE MICROENVIRONMENT INFLUENCES GENE EXPRESSION PATTERNS; HOWEVER, KNOWLEDGE IS LIMITED REGARDING THE EXTENT TO WHICH METHYLATION CHANGES WITH TIME AND EXPOSURE TO SPECIFIC MICROENVIRONMENTS. USING HIGH-RESOLUTION 450K ARRAYS, WE PROVIDE THE MOST COMPREHENSIVE DNA METHYLATION STUDY OF CLL TO DATE, ANALYZING PAIRED DIAGNOSTIC/FOLLOW-UP SAMPLES FROM IGHV-MUTATED/UNTREATED AND IGHV-UNMUTATED/TREATED PATIENTS (N=36) AND PATIENT-MATCHED PERIPHERAL BLOOD AND LYMPH NODE SAMPLES (N=20). ON AN UNPRECEDENTED SCALE, WE REVEALED 2239 DIFFERENTIALLY METHYLATED CPG SITES BETWEEN IGHV-MUTATED AND UNMUTATED PATIENTS, WITH THE MAJORITY OF SITES POSITIONED OUTSIDE ANNOTATED CPG ISLANDS. INTRIGUINGLY, CLL PROGNOSTIC GENES (FOR EXAMPLE, CLLU1, LPL, ZAP70 AND NOTCH1), EPIGENETIC REGULATOR (FOR EXAMPLE, HDAC9, HDAC4 AND DNMT3B), B-CELL SIGNALING (FOR EXAMPLE, IBTK) AND NUMEROUS TGF-BETA AND NF-KAPPAB/TNF PATHWAY GENES WERE ALTERNATIVELY METHYLATED BETWEEN SUBGROUPS. CONTRARY, DNA METHYLATION OVER TIME WAS DEEMED RATHER STABLE WITH FEW RECURRENT CHANGES NOTED WITHIN SUBGROUPS. ALTHOUGH A LARGER NUMBER OF NON-RECURRENT CHANGES WERE IDENTIFIED AMONG IGHV-UNMUTATED RELATIVE TO MUTATED CASES OVER TIME, THESE EQUATED TO A LOW GLOBAL CHANGE. SIMILARLY, FEW CHANGES WERE IDENTIFIED BETWEEN COMPARTMENT CASES. ALTOGETHER, WE REVEAL CLL SUBGROUPS TO DISPLAY UNIQUE METHYLATION PROFILES AND UNVEIL METHYLATION AS RELATIVELY STABLE OVER TIME AND SIMILAR WITHIN DIFFERENT CLL COMPARTMENTS, IMPLYING ABERRANT METHYLATION AS AN EARLY LEUKEMOGENIC EVENT. 2013 18 5111 25 POLYSOME-CAGE OF TCL1-DRIVEN CHRONIC LYMPHOCYTIC LEUKEMIA REVEALED MULTIPLE N-TERMINALLY ALTERED EPIGENETIC REGULATORS AND A TRANSLATION STRESS SIGNATURE. THE TRANSFORMATION OF NORMAL TO MALIGNANT CELLS IS ACCOMPANIED BY SUBSTANTIAL CHANGES IN GENE EXPRESSION PROGRAMS THROUGH DIVERSE MECHANISMS. HERE, WE EXAMINED THE CHANGES IN THE LANDSCAPE OF TRANSCRIPTION START SITES AND ALTERNATIVE PROMOTER (AP) USAGE AND THEIR IMPACT ON THE TRANSLATOME IN TCL1-DRIVEN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). OUR FINDINGS REVEALED A MARKED ELEVATION OF APS IN CLL B CELLS FROM EMICRO-TCL1 TRANSGENIC MICE, WHICH ARE PARTICULARLY ENRICHED WITH INTRA-GENIC PROMOTERS THAT GENERATE N-TERMINALLY TRUNCATED OR MODIFIED PROTEINS. INTRA-GENIC PROMOTER ACTIVATION IS MEDIATED BY (1) LOSS OF FUNCTION OF 'CLOSED CHROMATIN' EPIGENETIC REGULATORS DUE TO THE GENERATION OF INACTIVE N-TERMINALLY MODIFIED ISOFORMS OR REDUCED EXPRESSION; (2) UPREGULATION OF TRANSCRIPTION FACTORS, INCLUDING C-MYC, TARGETING THE INTRA-GENIC PROMOTERS AND THEIR ASSOCIATED ENHANCERS. EXOGENOUS EXPRESSION OF TCL1 IN MEFS IS SUFFICIENT TO INDUCE INTRA-GENIC PROMOTERS OF EPIGENETIC REGULATORS AND PROMOTE C-MYC EXPRESSION. WE FURTHER FOUND A DRAMATIC TRANSLATION DOWNREGULATION OF TRANSCRIPTS BEARING CNY CAP-PROXIMAL TRINUCLEOTIDES, REMINISCENT OF CELLS UNDERGOING METABOLIC STRESS. THESE FINDINGS UNCOVERED THE ROLE OF TCL1 ONCOGENIC FUNCTION IN ALTERING PROMOTER USAGE AND MRNA TRANSLATION IN LEUKEMOGENESIS. 2022 19 954 18 CHRONIC MYELOID LEUKEMIA: CURRENT PERSPECTIVES. CHRONIC MYELOID LEUKEMIA (CML), CHARACTERIZED BY THE T(9;22) AND BCR/ABL1 FUSION, IS A DISEASE MODEL FOR STUDYING THE MECHANISMS OF GENETIC ABNORMALITIES IN LEUKEMOGENESIS. THE DETECTION OF THE T(9;22), CHARACTERIZATION OF THE BCR/ABL FUSION, AND THE DISCOVERY OF IMATINIB HAVE ELEGANTLY REFLECTED THE SUCCESS OF OUR RESEARCH EFFORTS IN CML. HOWEVER, GENOMIC INSTABILITIES THAT LEAD TO THE FORMATION OF THE BCR/ ABL1 FUSION ARE NOT FULLY UNDERSTOOD. IT IS IMPORTANT TO UNDERSTAND HOW VARIOUS GENES THAT ARE INVOLVED IN REGULATING THE SIGNALING PATHWAY AND EPIGENETIC DEREGULATION COOPERATE WITH THE BCR/ABL1 FUSION IN THE INITIATION AND PROGRESSION OF CML. 2011 20 3158 31 GLYCOGEN SYNTHASE KINASE 3BETA MISSPLICING CONTRIBUTES TO LEUKEMIA STEM CELL GENERATION. RECENT EVIDENCE SUGGESTS THAT A RARE POPULATION OF SELF-RENEWING CANCER STEM CELLS (CSC) IS RESPONSIBLE FOR CANCER PROGRESSION AND THERAPEUTIC RESISTANCE. CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS AN IMPORTANT PARADIGM FOR UNDERSTANDING THE GENETIC AND EPIGENETIC EVENTS INVOLVED IN CSC PRODUCTION. CML PROGRESSES FROM A CHRONIC PHASE (CP) IN HEMATOPOIETIC STEM CELLS (HSC) THAT HARBOR THE BCR-ABL TRANSLOCATION, TO BLAST CRISIS (BC), CHARACTERIZED BY ABERRANT ACTIVATION OF BETA-CATENIN WITHIN GRANULOCYTE-MACROPHAGE PROGENITORS (GMP). A MAJOR BARRIER TO PREDICTING AND INHIBITING BLAST CRISIS TRANSFORMATION HAS BEEN THE IDENTIFICATION OF MECHANISMS DRIVING BETA-CATENIN ACTIVATION. HERE WE SHOW THAT BC CML MYELOID PROGENITORS, IN PARTICULAR GMP, SERIALLY TRANSPLANT LEUKEMIA IN IMMUNOCOMPROMISED MICE AND THUS ARE ENRICHED FOR LEUKEMIA STEM CELLS (LSC). NOTABLY, CDNA SEQUENCING OF WNT/BETA-CATENIN PATHWAY REGULATORY GENES, INCLUDING ADENOMATOUS POLYPOSIS COLI, GSK3BETA, AXIN 1, BETA-CATENIN, LYMPHOID ENHANCER FACTOR-1, CYCLIN D1, AND C-MYC, REVEALED A NOVEL IN-FRAME SPLICE DELETION OF THE GSK3BETA KINASE DOMAIN IN THE GMP OF BC SAMPLES THAT WAS NOT DETECTABLE BY SEQUENCING IN BLASTS OR NORMAL PROGENITORS. MOREOVER, BC CML PROGENITORS WITH MISSPLICED GSK3BETA HAVE ENHANCED BETA-CATENIN EXPRESSION AS WELL AS SERIAL ENGRAFTMENT POTENTIAL WHILE REINTRODUCTION OF FULL-LENGTH GSK3BETA REDUCES BOTH IN VITRO REPLATING AND LEUKEMIC ENGRAFTMENT. WE PROPOSE THAT CP CML IS INITIATED BY BCR-ABL EXPRESSION IN AN HSC CLONE BUT THAT PROGRESSION TO BC MAY INCLUDE MISSPLICING OF GSK3BETA IN GMP LSC, ENABLING UNPHOSPHORYLATED BETA-CATENIN TO PARTICIPATE IN LSC SELF-RENEWAL. MISSPLICING OF GSK3BETA REPRESENTS A UNIQUE MECHANISM FOR THE EMERGENCE OF BC CML LSC AND MIGHT PROVIDE A NOVEL DIAGNOSTIC AND THERAPEUTIC TARGET. 2009