1 1093 51 COHESIN RAD21 GENE PROMOTER METHYLATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON TYPE OF LEUKEMIA IN ADULTS AND IS CHARACTERIZED BY THE PRESENCE OF SPECIFIC CYTOGENETIC ABNORMALITIES. CLL RESEARCH HAS BEEN FOCUSED ON EPIGENETIC PROCESSES LIKE GENE PROMOTER METHYLATION OF CPG ISLANDS. IN THE PRESENT STUDY, THE METHYLATION STATUS OF THE RAD21 GENE IS STUDIED AND ASSOCIATED WITH CYTOGENETIC FINDINGS IN CLL PATIENTS IN ORDER TO INVESTIGATE ITS POSSIBLE IMPLICATION IN CLL PATHOGENESIS AND THE FORMATION OF CLL CHROMOSOMAL ABNORMALITIES. 2018 2 5687 19 SIGNIFICANCE OF INACTIVATED GENES IN LEUKEMIA: PATHOGENESIS AND PROGNOSIS. EPIGENETIC AND GENETIC ALTERATIONS ARE TWO MECHANISMS PARTICIPATING IN LEUKEMIA, WHICH CAN INACTIVATE GENES INVOLVED IN LEUKEMIA PATHOGENESIS OR PROGRESSION. THE PURPOSE OF THIS REVIEW WAS TO INTRODUCE VARIOUS INACTIVATED GENES AND EVALUATE THEIR POSSIBLE ROLE IN LEUKEMIA PATHOGENESIS AND PROGNOSIS. BY SEARCHING THE MESH WORDS "GENE, SILENCING AND LEUKEMIA" IN PUBMED WEBSITE, RELEVANT ENGLISH ARTICLES DEALT WITH HUMAN SUBJECTS AS OF 2000 WERE INCLUDED IN THIS STUDY. GENE INACTIVATION IN LEUKEMIA IS LARGELY MEDIATED BY PROMOTER'S HYPERMETHYLATION OF GENE INVOLVING IN CELLULAR FUNCTIONS SUCH AS CELL CYCLE, APOPTOSIS, AND GENE TRANSCRIPTION. INACTIVATED GENES, SUCH AS ASPP1, TP53, IKZF1 AND P15, MAY CORRELATE WITH POOR PROGNOSIS IN ACUTE LYMPHOID LEUKEMIA (ALL), CHRONIC LYMPHOID LEUKEMIA (CLL), CHRONIC MYELOGENOUS LEUKEMIA (CML) AND ACUTE MYELOID LEUKEMIA (AML), RESPECTIVELY. GENE INACTIVATION MAY PLAY A CONSIDERABLE ROLE IN LEUKEMIA PATHOGENESIS AND PROGNOSIS, WHICH CAN BE CONSIDERED AS COMPLEMENTARY DIAGNOSTIC TESTS TO DIFFERENTIATE DIFFERENT LEUKEMIA TYPES, DETERMINE LEUKEMIA PROGNOSIS, AND ALSO DETECT RESPONSE TO THERAPY. IN GENERAL, THIS REVIEW SHOWED SOME GENES INACTIVATED ONLY IN LEUKEMIA (WITH DIFFERENCES BETWEEN B-ALL, T-ALL, CLL, AML AND CML). THESE DIFFERENCES COULD BE OF INTEREST AS AN ADDITIONAL TOOL TO BETTER CATEGORIZE LEUKEMIA TYPES. FURTHERMORE; BASED ON INACTIVATED GENES, A DIVERSE CLASSIFICATION OF LEUKEMIAS COULD REPRESENT A POWERFUL METHOD TO ADDRESS A TARGETED THERAPY OF THE PATIENTS, IN ORDER TO MINIMIZE SIDE EFFECTS OF CONVENTIONAL THERAPIES AND TO ENHANCE NEW DRUG STRATEGIES. 2017 3 160 18 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 4 2966 17 GENETIC AND EPIGENETIC PROFILING OF CLL DISEASE PROGRESSION REVEALS LIMITED SOMATIC EVOLUTION AND SUGGESTS A RELATIONSHIP TO MEMORY-CELL DEVELOPMENT. WE EXAMINED GENETIC AND EPIGENETIC CHANGES THAT OCCUR DURING DISEASE PROGRESSION FROM INDOLENT TO AGGRESSIVE FORMS OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) USING SERIAL SAMPLES FROM 27 PATIENTS. ANALYSIS OF DNA MUTATIONS GROUPED THE LEUKEMIA CASES INTO THREE CATEGORIES: EVOLVING (26%), EXPANDING (26%) AND STATIC (47%). THUS, APPROXIMATELY THREE-QUARTERS OF THE CLL CASES HAD LITTLE TO NO GENETIC SUBCLONAL EVOLUTION. HOWEVER, WE IDENTIFIED SIGNIFICANT RECURRENT DNA METHYLATION CHANGES DURING PROGRESSION AT 4752 CPGS ENRICHED FOR REGIONS NEAR POLYCOMB 2 REPRESSIVE COMPLEX (PRC2) TARGETS. PROGRESSION-ASSOCIATED CPGS NEAR THE PRC2 TARGETS UNDERGO METHYLATION CHANGES IN THE SAME DIRECTION DURING DISEASE PROGRESSION AS DURING NORMAL DEVELOPMENT FROM NAIVE TO MEMORY B CELLS. OUR STUDY SHOWS THAT CLL PROGRESSION DOES NOT TYPICALLY OCCUR VIA SUBCLONAL EVOLUTION, BUT THAT CERTAIN CPG SITES UNDERGO RECURRENT METHYLATION CHANGES. OUR RESULTS SUGGEST CLL PROGRESSION MAY INVOLVE DEVELOPMENTAL PROCESSES SHARED IN COMMON WITH THE GENERATION OF NORMAL MEMORY B CELLS. 2015 5 4426 29 MOLECULAR BASIS OF CHRONIC LYMPHOCYTIC LEUKEMIA DIAGNOSIS AND PROGNOSIS. BACKGROUNDS: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON TYPE OF LEUKEMIA IN ADULTS AND IS CHARACTERIZED BY A CLONAL ACCUMULATION OF MATURE APOPTOSIS-RESISTANT NEOPLASTIC CELLS. IT IS ALSO A HETEROGENEOUS DISEASE WITH A VARIABLE CLINICAL OUTCOME. HERE, WE PRESENT A REVIEW OF CURRENTLY KNOWN (EPI)GENETIC ALTERATIONS THAT ARE RELATED TO THE ETIOLOGY, PROGRESSION AND CHEMO-REFRACTORINESS OF CLL. RELEVANT LITERATURE WAS IDENTIFIED THROUGH A PUBMED SEARCH (1994-2014) OF ENGLISH-LANGUAGE PAPERS USING THE TERMS CLL, SIGNALING PATHWAY, CYTOGENETIC ABNORMALITY, SOMATIC MUTATION, EPIGENETIC ALTERATION AND MICRO-RNA. RESULTS: CLL IS CHARACTERIZED BY THE PRESENCE OF GROSS CHROMOSOMAL ABNORMALITIES, EPIGENETIC ALTERATIONS, MICRO-RNA EXPRESSION ALTERATIONS, IMMUNOGLOBULIN HEAVY CHAIN GENE MUTATIONS AND OTHER GENETIC LESIONS. THE EXPRESSION OF UNMUTATED IMMUNOGLOBULIN HEAVY CHAIN VARIABLE REGION (IGHV) GENES, ZAP-70 AND CD38 PROTEINS, THE OCCURRENCE OF CHROMOSOMAL ABNORMALITIES SUCH AS 17P AND 11Q DELETIONS AND MUTATIONS OF THE NOTCH1, SF3B1 AND BIRC3 GENES HAVE BEEN ASSOCIATED WITH A POOR PROGNOSIS. IN ADDITION, MUTATIONS IN TUMOR SUPPRESSOR GENES, SUCH AS TP53 AND ATM, HAVE BEEN ASSOCIATED WITH REFRACTORINESS TO CONVENTIONAL CHEMOTHERAPEUTIC AGENTS. MICRO-RNA EXPRESSION ALTERATIONS AND ABERRANT METHYLATION PATTERNS IN GENES THAT ARE SPECIFICALLY DEREGULATED IN CLL, INCLUDING THE BCL-2, TCL1 AND ZAP-70 GENES, HAVE ALSO BEEN ENCOUNTERED AND LINKED TO DISTINCT CLINICAL PARAMETERS. CONCLUSIONS: SPECIFIC CHROMOSOMAL ABNORMALITIES AND GENE MUTATIONS MAY SERVE AS DIAGNOSTIC AND PROGNOSTIC INDICATORS FOR DISEASE PROGRESSION AND SURVIVAL. THE IDENTIFICATION OF THESE ANOMALIES BY STATE-OF-THE-ART MOLECULAR (CYTO)GENETIC TECHNIQUES SUCH AS FLUORESCENCE IN SITU HYBRIDIZATION (FISH), COMPARATIVE GENOMIC HYBRIDIZATION (CGH), SINGLE NUCLEOTIDE POLYMORPHISM (SNP) MICROARRAY-BASED GENOMIC PROFILING AND NEXT-GENERATION SEQUENCING (NGS) CAN BE OF PARAMOUNT HELP FOR THE CLINICAL MANAGEMENT OF THESE PATIENTS, INCLUDING OPTIMAL TREATMENT DESIGN. THE EFFICACY OF NOVEL THERAPEUTICS SHOULD TO BE TESTED ACCORDING TO THE PRESENCE OF THESE MOLECULAR LESIONS IN CLL PATIENTS. 2015 6 349 22 ALTERED DNA METHYLATION PROFILES IN SF3B1 MUTATED CLL PATIENTS. MUTATIONS IN SPLICING FACTOR GENES HAVE A SEVERE IMPACT ON THE SURVIVAL OF CANCER PATIENTS. SPLICING FACTOR 3B SUBUNIT 1 (SF3B1) IS ONE OF THE MOST FREQUENTLY MUTATED GENES IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL); PATIENTS CARRYING THESE MUTATIONS HAVE A POOR PROGNOSIS. SINCE THE SPLICING MACHINERY AND THE EPIGENOME ARE CLOSELY INTERCONNECTED, WE INVESTIGATED WHETHER THESE ALTERATIONS MAY AFFECT THE EPIGENOMES OF CLL PATIENTS. WHILE AN OVERALL HYPOMETHYLATION DURING CLL CARCINOGENESIS HAS BEEN OBSERVED, THE INTERPLAY BETWEEN THE EPIGENETIC STAGE OF THE ORIGINATING B CELLS AND SF3B1 MUTATIONS, AND THE SUBSEQUENT EFFECT OF THE MUTATIONS ON METHYLATION ALTERATIONS IN CLL, HAVE NOT BEEN INVESTIGATED. WE PROFILED THE GENOME-WIDE DNA METHYLATION PATTERNS OF 27 CLL PATIENTS WITH AND WITHOUT SF3B1 MUTATIONS AND IDENTIFIED LOCAL DECREASES IN METHYLATION LEVELS IN SF3B1(MUT) CLL PATIENTS AT 67 GENOMIC REGIONS, MOSTLY IN PROXIMITY TO TELOMERIC REGIONS. THESE DIFFERENTIALLY METHYLATED REGIONS (DMRS) WERE ENRICHED IN GENE BODIES OF CANCER-RELATED SIGNALING GENES, E.G., NOTCH1, HTRA3, AND BCL9L. IN OUR STUDY, SF3B1 MUTATIONS EXCLUSIVELY EMERGED IN TWO OUT OF THREE EPIGENETIC STAGES OF THE ORIGINATING B CELLS. HOWEVER, NOT ALL THE DMRS COULD BE ASSOCIATED WITH THE METHYLATION PROGRAMMING OF B CELLS DURING DEVELOPMENT, SUGGESTING THAT MUTATIONS IN SF3B1 CAUSE ADDITIONAL EPIGENETIC ABERRATIONS DURING CARCINOGENESIS. 2021 7 2689 14 EVOLUTION OF DNA METHYLATION IS LINKED TO GENETIC ABERRATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA. ALTHOUGH CLONAL SELECTION BY GENETIC DRIVER ABERRATIONS IN CANCER IS WELL DOCUMENTED, THE ABILITY OF EPIGENETIC ALTERATIONS TO PROMOTE TUMOR EVOLUTION IS UNDEFINED. WE USED 450K ARRAYS AND NEXT-GENERATION SEQUENCING TO EVALUATE INTRATUMOR HETEROGENEITY AND EVOLUTION OF DNA METHYLATION AND GENETIC ABERRATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). CLL CASES EXHIBIT VAST INTERPATIENT DIFFERENCES IN INTRATUMOR METHYLATION HETEROGENEITY, WITH GENETICALLY CLONAL CASES MAINTAINING LOW METHYLATION HETEROGENEITY AND UP TO 10% OF TOTAL CPGS IN A MONOALLELICALLY METHYLATED STATE. INCREASING METHYLATION HETEROGENEITY CORRELATES WITH ADVANCED GENETIC SUBCLONAL COMPLEXITY. SELECTION OF NOVEL DNA METHYLATION PATTERNS IS OBSERVED ONLY IN CASES THAT UNDERGO GENETIC EVOLUTION, AND INDEPENDENT GENETIC EVOLUTION IS UNCOMMON AND IS RESTRICTED TO LOW-RISK ALTERATIONS. THESE RESULTS REVEAL THAT ALTHOUGH EVOLUTION OF DNA METHYLATION OCCURS IN HIGH-RISK, CLINICALLY PROGRESSIVE CASES, POSITIVE SELECTION OF NOVEL METHYLATION PATTERNS ENTAILS COEVOLUTION OF GENETIC ALTERATION(S) IN CLL. 2014 8 1976 17 EPIGENETIC ALTERATIONS IN A MURINE MODEL FOR CHRONIC LYMPHOCYTIC LEUKEMIA. EARLY STAGES IN THE DEVELOPMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAVE NOT BEEN EXPLORED MAINLY DUE TO THE INABILITY TO STUDY NORMAL B-CELLS EN ROUTE TO TRANSFORMATION. IN ORDER TO DETERMINE SUCH EARLY EVENTS OF LEUKEMOGENESIS, WE HAVE USED A WELL ESTABLISHED MOUSE MODEL FOR CLL. OVER-EXPRESSION OF HUMAN TCL1, A KNOWN CLL ONCOGENE IN MURINE B-CELLS LEADS TO THE DEVELOPMENT OF MATURE CD19+/CD5+/IGM+ CLONAL LEUKEMIA WITH A DISEASE PHENOTYPE SIMILAR TO THAT SEEN IN HUMAN CLL. HEREIN, WE REVIEW OUR RECENT STUDY USING THIS TCL1-DRIVEN MOUSE MODEL FOR CLL AND CORRESPONDING HUMAN CLL SAMPLES IN A CROSS-SPECIES EPIGENOMICS APPROACH TO ADDRESS THE TIMING AND RELEVANCE OF EPIGENETIC EVENTS OCCURRING DURING LEUKEMOGENESIS. WE DEMONSTRATED THAT THE MOUSE MODEL RECAPITULATES THE EPIGENETIC EVENTS THAT HAVE BEEN REPORTED FOR HUMAN CLL, AFFIRMING THE POWER AND VALIDITY OF THIS MOUSE MODEL TO STUDY EARLY EPIGENETIC EVENTS IN CANCER PROGRESSION. EPIGENETIC ALTERATIONS ARE DETECTED AS EARLY AS THREE MONTHS AFTER BIRTH, FAR BEFORE DISEASE MANIFESTS AT ABOUT 11 MONTHS OF AGE. THESE MICE UNDERGO NFKAPPAB REPRESSOR COMPLEX MEDIATED INACTIVATION OF THE TRANSCRIPTION FACTOR FOXD3, WHOSE TARGETS BECOME ABERRANTLY METHYLATED AND SILENCED IN MOUSE AND HUMAN CLL. OVERALL, OUR DATA SUGGEST THE ACCUMULATED EPIGENETIC ALTERATIONS DURING CLL PATHOGENESIS AS A CONSEQUENCE OF GENE SILENCING THROUGH TCL1 AND NFKAPPAB REPRESSOR COMPLEX, SUGGESTING THE RELEVANCE FOR NFKAPPAB AS A THERAPEUTIC TARGET IN CLL. 2009 9 2494 17 EPIGENETICS AND CHRONIC LYMPHOCYTIC LEUKEMIA. THE DNA METHYLATION LEVEL IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IS GENERALLY LOWER THAN HEALTHY INDIVIDUALS. ALTHOUGH DNA METHYLATION IS GLOBALLY DECREASED, REGIONAL HYPERMETHYLATION OF GENE PROMOTERS LEADS TO GENE SILENCING. MANY OF THESE GENES HAVE TUMOR SUPPRESSOR PHENOTYPES. UNLIKE MUTATIONS OR DELETIONS, HYPERMETHYLATION IS POTENTIALLY REVERSIBLE AFTER INHIBITION WITH DNA METHYLATION MODULATORS. MYELODYSPLASTIC SYNDROME HAS BEEN A MODEL DISEASE IN WHICH TREATMENT OF PATIENTS RESULTS IN DEMETHYLATION OF SPECIFIC GENES. THE STORY IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IS SLOWLY UNRAVELING AS EPIGENETIC MODIFICATIONS LIKELY ALSO PLAY AN IMPORTANT ROLE. ONGOING CLINICAL TRIALS CORRELATING CLINICAL RESPONSE TO GENE EXPRESSION AFTER TREATMENT WITH DNA METHYLATION INHIBITORS WILL ULTIMATELY ALLOW US TO BETTER RISK STRATIFY AND PREDICT THE SUBGROUP OF PATIENTS WHO WILL BENEFIT FROM TREATMENT WITH THIS CLASS OF DRUGS. 2006 10 59 17 A GENOME-WIDE SCREEN IDENTIFIES FREQUENTLY METHYLATED GENES IN HAEMATOLOGICAL AND EPITHELIAL CANCERS. BACKGROUND: GENETIC AS WELL AS EPIGENETIC ALTERATIONS ARE A HALLMARK OF BOTH EPITHELIAL AND HAEMATOLOGICAL MALIGNANCIES. HIGH THROUGHPUT SCREENS ARE REQUIRED TO IDENTIFY EPIGENETIC MARKERS THAT CAN BE USEFUL FOR DIAGNOSTIC AND PROGNOSTIC PURPOSES ACROSS MALIGNANCIES. RESULTS: HERE WE REPORT FOR THE FIRST TIME THE USE OF THE MIRA ASSAY (METHYLATED CPG ISLAND RECOVERY ASSAY) IN COMBINATION WITH GENOME-WIDE CPG ISLAND ARRAYS TO IDENTIFY EPIGENETIC MOLECULAR MARKERS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) ON A GENOME-WIDE SCALE. WE IDENTIFIED 30 GENES DEMONSTRATING METHYLATION FREQUENCIES OF > OR =25% IN CHILDHOOD ALL, NINE GENES SHOWED SIGNIFICANTLY DIFFERENT METHYLATION FREQUENCIES IN B VS T-ALL. FOR MAJORITY OF THE GENES EXPRESSION COULD BE RESTORED IN METHYLATED LEUKEMIA LINES AFTER TREATMENT WITH 5-AZADC. FORTY-FOUR PERCENT OF THE GENES REPRESENT TARGETS OF THE POLYCOMB COMPLEX. IN CHRONIC MYELOID LEUKEMIA (CML) TWO OF THE GENES, (TFAP2A AND EBF2), DEMONSTRATED INCREASED METHYLATION IN BLAST CRISIS COMPARED TO CHRONIC PHASE (P < 0.05). FURTHERMORE HYPERMETHYLATION OF AN AUTOPHAGY RELATED GENE ATG16L2 WAS ASSOCIATED WITH POORER PROGNOSIS IN TERMS OF MOLECULAR RESPONSE TO IMATINIB TREATMENT. LASTLY WE DEMONSTRATED THAT TEN OF THESE GENES WERE ALSO FREQUENTLY METHYLATED IN COMMON EPITHELIAL CANCERS. CONCLUSION: IN SUMMARY WE HAVE IDENTIFIED A LARGE NUMBER OF GENES SHOWING FREQUENT METHYLATION IN CHILDHOOD ALL, METHYLATION STATUS OF TWO OF THESE GENES IS ASSOCIATED WITH ADVANCED DISEASE IN CML AND METHYLATION STATUS OF ANOTHER GENE IS ASSOCIATED WITH PROGNOSIS. IN ADDITION A SUBSET OF THESE GENES MAY ACT AS EPIGENETIC MARKERS ACROSS HEMATOLOGICAL MALIGNANCIES AS WELL AS COMMON EPITHELIAL CANCERS. 2010 11 3896 20 LARGE-SCALE ANALYSIS OF DNA METHYLATION IN CHRONIC LYMPHOCYTIC LEUKEMIA. AIMS: B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A HETEROGENEOUS MALIGNANCY THAT CLINICALLY RANGES FROM INDOLENT TO RAPIDLY PROGRESSIVE. CLL, LIKE OTHER CANCERS, CAN BE AFFECTED BY EPIGENETIC ALTERATIONS. MATERIALS & METHODS: A MICROARRAY DISCOVERY-BASED STUDY WAS INITIATED TO DETERMINE DNA METHYLATION IN CLL CASES WITH A RANGE OF CD38 EXPRESSION (1-92%). RESULTS: MANY LOCI WERE EITHER METHYLATED OR UNMETHYLATED ACROSS ALL CD38 LEVELS, BUT DIFFERENTIAL METHYLATION WAS ALSO OBSERVED FOR SOME GENES. GENOMIC SEQUENCING OF DLEU7 CONFIRMED EXTENSIVE CYTOSINE METHYLATION PREFERENTIALLY IN PATIENT SAMPLES WITH LOW CD38 EXPRESSION, WHEREAS NRP2, SFRP2 AND ADAM12 WERE MORE COMMONLY METHYLATED IN THOSE WITH HIGH CD38 EXPRESSION. CONCLUSION: THIS STUDY DEMONSTRATES THAT CLL IS AFFECTED BY CPG ISLAND METHYLATION IN SOME GENES THAT SEGREGATE WITH CD38 EXPRESSION LEVELS, WHILE MOST OTHERS SHOW SIMILAR METHYLATION PATTERNS ACROSS ALL LEVELS. THE CPG ISLAND METHYLATION IN CERTAIN FUNCTIONAL GENE GROUPS AND PATHWAY-ASSOCIATED GENES THAT ARE KNOWN TO BE DEREGULATED IN CLL PROVIDES ADDITIONAL INSIGHTS INTO THE CLL METHYLOME AND EPIGENETIC CONTRIBUTION TO CELLULAR DYSFUNCTION. IT WILL NOW BE USEFUL TO INVESTIGATE THE EFFECTIVENESS OF EPIGENETIC THERAPEUTIC REVERSAL OF THESE ALTERATIONS TO DEVELOP EFFECTIVE TREATMENTS FOR THE DISEASE. 2009 12 5210 19 PRENEOPLASTIC ALTERATIONS DEFINE CLL DNA METHYLOME AND PERSIST THROUGH DISEASE PROGRESSION AND THERAPY. MOST HUMAN CANCERS CONVERGE TO A DEREGULATED METHYLOME WITH REDUCED GLOBAL LEVELS AND ELEVATED METHYLATION AT SELECT CPG ISLANDS. TO INVESTIGATE THE EMERGENCE AND DYNAMICS OF THE CANCER METHYLOME, WE CHARACTERIZED GENOME-WIDE DNA METHYLATION IN PRE-NEOPLASTIC MONOCLONAL B CELL LYMPHOCYTOSIS (MBL) AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), INCLUDING SERIAL SAMPLES COLLECTED ACROSS DISEASE COURSE. WE DETECTED THE ABERRANT TUMOR-ASSOCIATED METHYLATION LANDSCAPE AT CLL DIAGNOSIS AND FOUND NO SIGNIFICANTLY DIFFERENTIALLY METHYLATED REGIONS IN THE HIGH-COUNT MBL-TO-CLL TRANSITION. PATIENT METHYLOMES SHOWED REMARKABLE STABILITY WITH NATURAL DISEASE AND POST-THERAPY PROGRESSION. SINGLE CLL CELLS WERE CONSISTENTLY ABERRANTLY METHYLATED, INDICATING A HOMOGENEOUS TRANSITION TO THE ALTERED EPIGENETIC STATE, AND A DISTINCT EXPRESSION PROFILE TOGETHER WITH MBL CELLS COMPARED TO NORMAL B CELLS. OUR LONGITUDINAL ANALYSIS REVEALS THE CANCER METHYLOME TO EMERGE EARLY, WHICH MAY PROVIDE A PLATFORM FOR SUBSEQUENT GENETICALLY-DRIVEN GROWTH DYNAMICS AND TOGETHER WITH ITS PERSISTENT PRESENCE SUGGESTS A CENTRAL ROLE IN THE NORMAL-TO-CANCER TRANSITION. 2021 13 1561 23 DNA METHYLATION OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH DIFFERENTIAL RESPONSE TO CHEMOTHERAPY. ACQUIRED RESISTANCE TO CHEMOTHERAPY IS AN IMPORTANT CLINICAL PROBLEM AND CAN ALSO OCCUR WITHOUT DETECTABLE CYTOGENETIC ABERRATIONS OR GENE MUTATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS MOLECULARLY WELL CHARACTERIZED AND HAS BEEN ELEMENTAL FOR ESTABLISHING CENTRAL PARADIGMS IN ONCOLOGY. THIS PROMPTED US TO CHECK WHETHER SPECIFIC EPIGENETIC CHANGES AT THE LEVEL OF DNA METHYLATION MIGHT UNDERLIE DEVELOPMENT OF TREATMENT RESISTANCE. WE USED ILLUMINA INFINIUM HUMANMETHYLATION450 BEADCHIPS TO OBTAIN DNA METHYLATION PROFILES OF 71 CLL PATIENTS WITH DIFFERENTIAL RESPONSES. THIRTY-SIX PATIENTS WERE CATEGORIZED AS RELAPSED/REFRACTORY AFTER TREATMENT WITH FLUDARABINE OR BENDAMUSTINE AND 21 OF THEM HAD GENETIC ABERRATIONS OF TP53. THE OTHER 35 PATIENTS WERE UNTREATED AT THE TIME OF SAMPLING AND 15 OF THEM HAD GENETIC ABERRATION OF TP53. ALTHOUGH WE COULD NOT CORRELATE CHEMORESISTANCE WITH EPIGENETIC CHANGES, THE PATIENTS WERE COMPREHENSIVELY CHARACTERIZED REGARDING RELEVANT PROGNOSTIC AND MOLECULAR MARKERS (E.G. IGHV MUTATION STATUS, CHROMOSOME ABERRATIONS, TP53 MUTATION STATUS, CLINICAL PARAMETERS), WHICH MAKES OUR DATASET A UNIQUE AND VALUABLE RESOURCE THAT CAN BE USED BY RESEARCHERS TO TEST ALTERNATIVE HYPOTHESES. 2020 14 2652 19 EPIGENOMICS OF LEUKEMIA: FROM MECHANISMS TO THERAPEUTIC APPLICATIONS. LEUKEMOGENESIS IS A MULTISTEP PROCESS IN WHICH SUCCESSIVE TRANSFORMATIONAL EVENTS ENHANCE THE ABILITY OF A CLONAL POPULATION ARISING FROM HEMATOPOIETIC PROGENITOR CELLS TO PROLIFERATE, DIFFERENTIATE AND SURVIVE. CLINICALLY AND PATHOLOGICALLY, LEUKEMIA IS SUBDIVIDED INTO FOUR MAIN CATEGORIES: CHRONIC LYMPHOCYTIC LEUKEMIA, CHRONIC MYELOID LEUKEMIA, ACUTE LYMPHOCYTIC LEUKEMIA AND ACUTE MYELOID LEUKEMIA. LEUKEMIA HAS BEEN PREVIOUSLY CONSIDERED ONLY AS A GENETIC DISEASE. HOWEVER, IN RECENT YEARS, SIGNIFICANT ADVANCES HAVE BEEN MADE IN THE ELUCIDATION OF THE LEUKEMOGENESIS-ASSOCIATED PROCESSES. THUS, WE HAVE COME TO UNDERSTAND THAT EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNA ARE INVOLVED IN THE PERMANENT CHANGES OF GENE EXPRESSION CONTROLLING THE LEUKEMIA PHENOTYPE. IN THIS ARTICLE, WE WILL FOCUS ON THE EPIGENETIC DEFECTS ASSOCIATED WITH LEUKEMIA AND THEIR IMPLICATIONS AS BIOMARKERS FOR DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC APPLICATIONS. 2011 15 2639 19 EPIGENOMIC ANALYSIS DETECTS WIDESPREAD GENE-BODY DNA HYPOMETHYLATION IN CHRONIC LYMPHOCYTIC LEUKEMIA. WE HAVE EXTENSIVELY CHARACTERIZED THE DNA METHYLOMES OF 139 PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WITH MUTATED OR UNMUTATED IGHV AND OF SEVERAL MATURE B-CELL SUBPOPULATIONS THROUGH THE USE OF WHOLE-GENOME BISULFITE SEQUENCING AND HIGH-DENSITY MICROARRAYS. THE TWO MOLECULAR SUBTYPES OF CLL HAVE DIFFERING DNA METHYLOMES THAT SEEM TO REPRESENT EPIGENETIC IMPRINTS FROM DISTINCT NORMAL B-CELL SUBPOPULATIONS. DNA HYPOMETHYLATION IN THE GENE BODY, TARGETING MOSTLY ENHANCER SITES, WAS THE MOST FREQUENT DIFFERENCE BETWEEN NAIVE AND MEMORY B CELLS AND BETWEEN THE TWO MOLECULAR SUBTYPES OF CLL AND NORMAL B CELLS. ALTHOUGH DNA METHYLATION AND GENE EXPRESSION WERE POORLY CORRELATED, WE IDENTIFIED GENE-BODY CPG DINUCLEOTIDES WHOSE METHYLATION WAS POSITIVELY OR NEGATIVELY ASSOCIATED WITH EXPRESSION. WE HAVE ALSO RECOGNIZED A DNA METHYLATION SIGNATURE THAT DISTINGUISHES NEW CLINICO-BIOLOGICAL SUBTYPES OF CLL. WE PROPOSE AN EPIGENOMIC SCENARIO IN WHICH DIFFERENTIAL METHYLATION IN THE GENE BODY MAY HAVE FUNCTIONAL AND CLINICAL IMPLICATIONS IN LEUKEMOGENESIS. 2012 16 6773 16 [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 17 3740 16 INSIGHT INTO GENETIC PREDISPOSITION TO CHRONIC LYMPHOCYTIC LEUKEMIA FROM INTEGRATIVE EPIGENOMICS. GENOME-WIDE ASSOCIATION STUDIES HAVE PROVIDED EVIDENCE FOR INHERITED GENETIC PREDISPOSITION TO CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). TO GAIN INSIGHT INTO THE MECHANISMS UNDERLYING CLL RISK WE ANALYZE CHROMATIN ACCESSIBILITY, ACTIVE REGULATORY ELEMENTS MARKED BY H3K27AC, AND DNA METHYLATION AT 42 RISK LOCI IN UP TO 486 PRIMARY CLLS. WE IDENTIFY THAT RISK LOCI ARE SIGNIFICANTLY ENRICHED FOR ACTIVE CHROMATIN IN CLL WITH EVIDENCE OF BEING CLL-SPECIFIC OR DIFFERENTIALLY REGULATED IN NORMAL B-CELL DEVELOPMENT. WE THEN USE IN SITU PROMOTER CAPTURE HI-C, IN CONJUNCTION WITH GENE EXPRESSION DATA TO REVEAL LIKELY TARGET GENES OF THE RISK LOCI. CANDIDATE TARGET GENES ARE ENRICHED FOR PATHWAYS RELATED TO B-CELL DEVELOPMENT SUCH AS MYC AND BCL2 SIGNALLING. AT 14 LOCI THE ANALYSIS HIGHLIGHTS 63 VARIANTS AS THE PROBABLE FUNCTIONAL BASIS OF CLL RISK. BY INTEGRATING GENETIC AND EPIGENETIC INFORMATION OUR ANALYSIS REVEALS NOVEL INSIGHTS INTO THE RELATIONSHIP BETWEEN INHERITED PREDISPOSITION AND THE REGULATORY CHROMATIN LANDSCAPE OF CLL. 2019 18 3098 17 GENOMIC DISRUPTION OF THE HISTONE METHYLTRANSFERASE SETD2 IN CHRONIC LYMPHOCYTIC LEUKAEMIA. HISTONE METHYLTRANSFERASES (HMTS) ARE IMPORTANT EPIGENETIC REGULATORS OF GENE TRANSCRIPTION AND ARE DISRUPTED AT THE GENOMIC LEVEL IN A SPECTRUM OF HUMAN TUMOURS INCLUDING HAEMATOLOGICAL MALIGNANCIES. USING HIGH-RESOLUTION SINGLE NUCLEOTIDE POLYMORPHISM (SNP) ARRAYS, WE IDENTIFIED RECURRENT DELETIONS OF THE SETD2 LOCUS IN 3% (8/261) OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) PATIENTS. FURTHER VALIDATION IN TWO INDEPENDENT COHORTS SHOWED THAT SETD2 DELETIONS WERE ASSOCIATED WITH LOSS OF TP53, GENOMIC COMPLEXITY AND CHROMOTHRIPSIS. WITH NEXT-GENERATION SEQUENCING WE DETECTED MUTATIONS OF SETD2 IN AN ADDITIONAL 3.8% OF PATIENTS (23/602). IN MOST CASES, SETD2 DELETIONS OR MUTATIONS WERE OFTEN OBSERVED AS A CLONAL EVENT AND ALWAYS AS A MONO-ALLELIC LESION, LEADING TO REDUCED MRNA EXPRESSION IN SETD2-DISRUPTED CASES. PATIENTS WITH SETD2 ABNORMALITIES AND WILD-TYPE TP53 AND ATM FROM FIVE CLINICAL TRIALS EMPLOYING CHEMOTHERAPY OR CHEMO-IMMUNOTHERAPY HAD REDUCED PROGRESSION-FREE AND OVERALL SURVIVAL COMPARED WITH CASES WILD TYPE FOR ALL THREE GENES. CONSISTENT WITH ITS POSTULATED ROLE AS A TUMOUR SUPPRESSOR, OUR DATA HIGHLIGHT SETD2 ABERRATION AS A RECURRENT, EARLY LOSS-OF-FUNCTION EVENT IN CLL PATHOBIOLOGY LINKED TO AGGRESSIVE DISEASE. 2016 19 3822 20 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 20 825 13 CHARACTERIZATION OF FUNCTIONAL TRANSPOSABLE ELEMENT ENHANCERS IN ACUTE MYELOID LEUKEMIA. TRANSPOSABLE ELEMENTS (TES) HAVE BEEN SHOWN TO HAVE IMPORTANT GENE REGULATORY FUNCTIONS AND THEIR ALTERATION COULD LEAD TO DISEASE PHENOTYPES. ACUTE MYELOID LEUKEMIA (AML) DEVELOPS AS A CONSEQUENCE OF A SERIES OF GENETIC CHANGES IN HEMATOPOIETIC PRECURSOR CELLS, INCLUDING MUTATIONS IN EPIGENETIC FACTORS. HERE, WE SET OUT TO STUDY THE GENE REGULATORY ROLE OF TES IN AML. WE FIRST EXPLORED THE EPIGENETIC LANDSCAPE OF TES IN AML PATIENTS USING ATAC-SEQ DATA. WE SHOW THAT A LARGE NUMBER OF TES IN GENERAL, AND MORE SPECIFICALLY MAMMALIAN-WIDE INTERSPERSED REPEATS (MIRS), ARE MORE ENRICHED IN AML CELLS THAN IN NORMAL BLOOD CELLS. WE OBTAINED A SIMILAR FINDING WHEN ANALYZING HISTONE MODIFICATION DATA IN AML PATIENTS. GENE ONTOLOGY ENRICHMENT ANALYSIS SHOWED THAT GENES NEAR MIRS IN OPEN CHROMATIN REGIONS ARE INVOLVED IN LEUKEMOGENESIS. TO FUNCTIONALLY VALIDATE THEIR REGULATORY ROLE, WE SELECTED 19 MIR REGIONS IN AML CELLS, AND TESTED THEM FOR ENHANCER ACTIVITY IN AN AML CELL LINE (KASUMI-1) AND A CHRONIC MYELOID LEUKEMIA (CML) CELL LINE (K562); THE RESULTS REVEALED SEVERAL MIRS TO BE FUNCTIONAL ENHANCERS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT TES ARE POTENTIALLY INVOLVED IN MYELOID LEUKEMOGENESIS AND HIGHLIGHT THESE SEQUENCES AS POTENTIAL CANDIDATES HARBORING AML-ASSOCIATED VARIATION. 2020