1 3113 167 GERMINAL EPIMUTATION OF FRAGILE HISTIDINE TRIAD (FHIT) GENE IS ASSOCIATED WITH PROGRESSION TO ACUTE AND CHRONIC ADULT T-CELL LEUKEMIA DISEASES. BACKGROUND: HUMAN T CELL LEUKEMIA VIRUS TYPE 1 (HTLV-I) IS ETIOLOGICALLY LINKED TO ADULT T CELL LEUKEMIA/LYMPHOMA (ATL) AND AN INFLAMMATORY NEURODEGENERATIVE DISEASE CALLED HTLV-I-ASSOCIATED MYELOPATHY OR TROPICAL SPASTIC PARAPARESIS (HAM/TSP). THE EXACT GENETIC OR EPIGENETIC EVENTS AND/OR ENVIRONMENTAL FACTORS THAT INFLUENCE THE DEVELOPMENT OF ATL, OR HAM/TSP DISEASES ARE LARGELY UNKNOWN. THE TUMOR SUPPRESSOR GENE, FRAGILE HISTIDINE TRIAD DIADENOSINE TRIPHOSPHATASE (FHIT), IS FREQUENTLY LOST IN CANCER THROUGH EPIGENETIC MODIFICATIONS AND/OR DELETION. FHIT IS A TUMOR SUPPRESSOR ACTING AS GENOME CARETAKER BY REGULATING CELLULAR DNA REPAIR. INDEED, FHIT LOSS LEADS TO REPLICATIVE STRESS AND ACCUMULATION OF DOUBLE DNA STRAND BREAKS. THEREFORE, LOSS OF FHIT EXPRESSION PLAYS A KEY ROLE IN CELLULAR TRANSFORMATION. METHODS: HERE, WE STUDIED OVER 400 SAMPLES FROM HTLV-I-INFECTED INDIVIDUALS WITH ATL, TSP/HAM, OR ASYMPTOMATIC CARRIERS (AC) FOR FHIT LOSS AND EXPRESSION. WE EXAMINED THE EPIGENETIC STATUS OF FHIT THROUGH METHYLATION SPECIFIC PCR AND BISULFITE SEQUENCING; AND CORRELATED THESE RESULTS TO FHIT EXPRESSION IN PATIENT SAMPLES. RESULTS: WE FOUND THAT EPIGENETIC ALTERATION OF FHIT IS SPECIFICALLY FOUND IN CHRONIC AND ACUTE ATL BUT IS ABSENT IN ASYMPTOMATIC HTLV-I CARRIERS AND TSP/HAM PATIENTS' SAMPLES. FURTHERMORE, THE EXTENT OF FHIT METHYLATION IN ATL PATIENTS WAS QUANTITATIVELY COMPARABLE IN VIRUS-INFECTED AND VIRUS NON-INFECTED CELLS. WE ALSO FOUND THAT LONGITUDINAL HTLV-I CARRIERS THAT PROGRESSED TO SMOLDERING ATL AND DESCENDANTS OF ATL PATIENTS HARBOR FHIT METHYLATION. CONCLUSIONS: THESE RESULTS SUGGEST THAT GERMINAL EPIGENETIC MUTATION OF FHIT REPRESENTS A PREEXISTING MARK PREDISPOSING TO THE DEVELOPMENT OF ATL DISEASES. THESE FINDINGS HAVE IMPORTANT CLINICAL IMPLICATIONS AS PATIENTS WITH ACUTE ATL ARE RARELY CURED. OUR STUDY SUGGESTS AN ALTERNATIVE STRATEGY TO THE CURRENT "WAIT AND SEE APPROACH" IN THAT EARLY SCREENING OF HTLV-I-INFECTED INDIVIDUALS FOR GERMINAL EPIMUTATION OF FHIT AND EARLY TREATMENT MAY OFFER SIGNIFICANT CLINICAL BENEFITS.	2021	
                                                                                                                                                                                                             
2 4760  42 NOVEL TREATMENTS OF ADULT T CELL LEUKEMIA LYMPHOMA. ADULT T CELL LEUKEMIA-LYMPHOMA (ATL) IS AN AGGRESSIVE MALIGNANCY SECONDARY TO CHRONIC INFECTION WITH THE HUMAN T CELL LEUKEMIA VIRUS TYPE I (HTLV-I) RETROVIRUS. ATL CARRIES A DISMAL PROGNOSIS. ATL CLASSIFIES INTO FOUR SUBTYPES (ACUTE, LYMPHOMA, CHRONIC, AND SMOLDERING) WHICH DISPLAY DIFFERENT CLINICAL FEATURES, PROGNOSIS AND RESPONSE TO THERAPY, HENCE REQUIRING DIFFERENT CLINICAL MANAGEMENT. SMOLDERING AND CHRONIC SUBTYPES RESPOND WELL TO ANTIRETROVIRAL THERAPY USING THE COMBINATION OF ZIDOVUDINE (AZT) AND INTERFERON-ALPHA (IFN) WITH A SIGNIFICANT PROLONGATION OF SURVIVAL. CONVERSELY, THE WATCH AND WAIT STRATEGY OR CHEMOTHERAPY FOR THESE INDOLENT SUBTYPES ALLIES WITH A POOR LONG-TERM OUTCOME. ACUTE ATL IS ASSOCIATED WITH CHEMO-RESISTANCE AND DISMAL PROGNOSIS. LYMPHOMA SUBTYPES RESPOND BETTER TO INTENSIVE CHEMOTHERAPY BUT SURVIVAL REMAINS POOR. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) RESULTS IN LONG-TERM SURVIVAL IN ROUGHLY ONE THIRD OF TRANSPLANTED PATIENTS BUT ONLY A SMALL PERCENTAGE OF PATIENTS CAN MAKE IT TO TRANSPLANT. OVERALL, CURRENT TREATMENTS OF AGGRESSIVE ATL ARE NOT SATISFACTORY. PROGNOSIS OF REFRACTORY OR RELAPSED PATIENTS IS DISMAL WITH SOME ENCOURAGING RESULTS WHEN USING LENALIDOMIDE OR MOGAMULIZUMAB. TO OVERCOME RESISTANCE AND PREVENT RELAPSE, PRECLINICAL OR PILOT CLINICAL STUDIES USING TARGETED THERAPIES SUCH AS ARSENIC/IFN, MONOCLONAL ANTIBODIES, EPIGENETIC THERAPIES ARE PROMISING BUT WARRANT FURTHER CLINICAL INVESTIGATION. ANTI-ATL VACCINES INCLUDING TAX PEPTIDE-PULSED DENDRITIC CELLS, INDUCED TAX-SPECIFIC CTL RESPONSES IN ATL PATIENTS. FINALLY, BASED ON THE PROGRESS IN UNDERSTANDING THE PATHOPHYSIOLOGY OF ATL, AND THE RISK-ADAPTED TREATMENT APPROACHES TO DIFFERENT ATL SUBTYPES, TREATMENT STRATEGIES OF ATL SHOULD TAKE INTO ACCOUNT THE HOST IMMUNE RESPONSES AND THE HOST MICROENVIRONMENT INCLUDING HTLV-1 INFECTED NON-MALIGNANT CELLS. HEREIN, WE WILL PROVIDE A SUMMARY OF NOVEL TREATMENTS OF ATL IN VITRO, IN VIVO, AND IN EARLY CLINICAL TRIALS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                 
3 6590  45 TUMOR SUPPRESSOR INACTIVATION IN THE PATHOGENESIS OF ADULT T-CELL LEUKEMIA. TUMOR SUPPRESSOR FUNCTIONS ARE ESSENTIAL TO CONTROL CELLULAR PROLIFERATION, TO ACTIVATE THE APOPTOSIS OR SENESCENCE PATHWAY TO ELIMINATE UNWANTED CELLS, TO LINK DNA DAMAGE SIGNALS TO CELL CYCLE ARREST CHECKPOINTS, TO ACTIVATE APPROPRIATE DNA REPAIR PATHWAYS, AND TO PREVENT THE LOSS OF ADHESION TO INHIBIT INITIATION OF METASTASES. THEREFORE, TUMOR SUPPRESSOR GENES ARE INDISPENSABLE TO MAINTAINING GENETIC AND GENOMIC INTEGRITY. CONSEQUENTLY, INACTIVATION OF TUMOR SUPPRESSORS BY SOMATIC MUTATIONS OR EPIGENETIC MECHANISMS IS FREQUENTLY ASSOCIATED WITH TUMOR INITIATION AND DEVELOPMENT. IN CONTRAST, REACTIVATION OF TUMOR SUPPRESSOR FUNCTIONS CAN EFFECTIVELY REVERSE THE TRANSFORMED PHENOTYPE AND LEAD TO CELL CYCLE ARREST OR DEATH OF CANCEROUS CELLS AND BE USED AS A THERAPEUTIC STRATEGY. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL) IS AN AGGRESSIVE LYMPHOPROLIFERATIVE DISEASE ASSOCIATED WITH INFECTION OF CD4 T CELLS BY THE HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-I). HTLV-I-ASSOCIATED T-CELL TRANSFORMATION IS THE RESULT OF A MULTISTEP ONCOGENIC PROCESS IN WHICH THE VIRUS INITIALLY INDUCES CHRONIC T-CELL PROLIFERATION AND ALTERS CELLULAR PATHWAYS RESULTING IN THE ACCUMULATION OF GENETIC DEFECTS AND THE DEREGULATED GROWTH OF VIRALLY INFECTED CELLS. THIS REVIEW WILL FOCUS ON THE CURRENT KNOWLEDGE OF THE GENETIC AND EPIGENETIC MECHANISMS REGULATING THE INACTIVATION OF TUMOR SUPPRESSORS IN THE PATHOGENESIS OF HTLV-I.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4 6789  36 [CURRENT STATUS OF ATL RESEARCH: EFFORTS FOR PREVENTION AND PRECISION MEDICINE FOR ATL]. THE INTRODUCTION OF NEW AGENTS AND HEMATOPOIETIC STEM CELL TRANSPLANTATION INTO THE TREATMENT OF ATL HAS ACTIVATED ITS CLINICAL RESEARCH. HOWEVER, THE PROGNOSIS OF ATL REMAINS POOR COMPARED WITH THOSE OF OTHER LEUKEMIAS AND LYMPHOMAS. THUS, SEEMINGLY WE HAVE TO RECONSIDER A NEW STRATEGY OF ATL THERAPY BASED ON ITS UNIQUE CHARACTERISTICS. HTLV-1 INFECTION OF T CELLS RESULTS IN CLONAL PROLIFERATION OF INFECTED CELLS THAT ACCUMULATE GENETIC AND EPIGENETIC ABNORMALITIES BEFORE THE ONSET OF ATL. THEREFORE, THE TREATMENT STRATEGY SHOULD INCLUDE THE PREVENTION OF HTLV-1 INFECTION AND ATL DEVELOPMENT IN ADDITION TO PRECISION MEDICINE BASED ON THE STRATIFICATION OF ATL CASES BY BIOMARKERS THAT DISCRIMINATE CLINICAL STAGES OF ATL. I SUMMARIZE HERE THE RECENT PROGRESS IN ATL RESEARCH FOCUSING ON THE BIOMOLECULAR ABNORMALITIES THAT LEAD TO CLONAL EXPANSION AND MALIGNANT TRANSFORMATION OF HTLV-1-INFECTED T CELLS. APPARENTLY, ONE OF THE BASES FOR THE PREVENTION OF ATL IS TO ESTABLISH A DISEASE ENTITY OF "CHRONIC ACTIVE HTLV-1 INFECTION" THAT DEFINES HIGH-RISK CARRIERS FOR ATL DEVELOPMENT AND ENABLES PREVENTIVE INTERVENTION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5 2494  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6 5245  39 PROGNOSTIC RELEVANCE OF INTEGRATED GENETIC PROFILING IN ADULT T-CELL LEUKEMIA/LYMPHOMA. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATL) IS A HETEROGENEOUS GROUP OF PERIPHERAL T-CELL MALIGNANCIES CHARACTERIZED BY HUMAN T-CELL LEUKEMIA VIRUS TYPE-1 INFECTION, WHOSE GENETIC PROFILE HAS RECENTLY BEEN FULLY INVESTIGATED. HOWEVER, IT IS STILL POORLY UNDERSTOOD HOW THESE ALTERATIONS AFFECT CLINICAL FEATURES AND PROGNOSIS. WE INVESTIGATED THE EFFECTS OF GENETIC ALTERATIONS COMMONLY FOUND IN ATL ON DISEASE PHENOTYPES AND CLINICAL OUTCOMES, BASED ON GENOTYPING DATA OBTAINED FROM 414 AND 463 ATL PATIENTS USING TARGETED-CAPTURE SEQUENCING AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAY KARYOTYPING, RESPECTIVELY. AGGRESSIVE (ACUTE/LYMPHOMA) SUBTYPES WERE ASSOCIATED WITH AN INCREASED BURDEN OF GENETIC AND EPIGENETIC ALTERATIONS, HIGHER FREQUENCIES OF TP53 AND IRF4 MUTATIONS, AND MANY COPY NUMBER ALTERATIONS (CNAS), INCLUDING PD-L1 AMPLIFICATIONS AND CDKN2A DELETIONS, COMPARED WITH INDOLENT (CHRONIC/SMOLDERING) SUBTYPES. BY CONTRAST, STAT3 MUTATIONS WERE MORE CHARACTERISTIC OF INDOLENT ATL. HIGHER NUMBERS OF SOMATIC MUTATIONS AND CNAS SIGNIFICANTLY CORRELATED WITH WORSE SURVIVAL. IN A MULTIVARIATE ANALYSIS INCORPORATING BOTH CLINICAL FACTORS AND GENETIC ALTERATIONS, THE JAPAN CLINICAL ONCOLOGY GROUP PROGNOSTIC INDEX HIGH-RISK, OLDER AGE, PRKCB MUTATIONS, AND PD-L1 AMPLIFICATIONS WERE INDEPENDENT POOR PROGNOSTIC FACTORS IN AGGRESSIVE ATL. IN INDOLENT ATL, IRF4 MUTATIONS, PD-L1 AMPLIFICATIONS, AND CDKN2A DELETIONS WERE SIGNIFICANTLY ASSOCIATED WITH SHORTER SURVIVAL, ALTHOUGH THE CHRONIC SUBTYPE WITH UNFAVORABLE CLINICAL FACTORS WAS ONLY MARGINALLY SIGNIFICANT. THUS, SOMATIC ALTERATIONS CHARACTERIZING AGGRESSIVE DISEASES PREDICT WORSE PROGNOSIS IN INDOLENT ATL, AMONG WHICH PD-L1 AMPLIFICATIONS ARE A STRONG GENETIC PREDICTOR IN BOTH AGGRESSIVE AND INDOLENT ATL. ATL SUBTYPES ARE FURTHER CLASSIFIED INTO MOLECULARLY DISTINCT SUBSETS WITH DIFFERENT PROGNOSIS. GENETIC PROFILING MIGHT CONTRIBUTE TO IMPROVED PROGNOSTICATION AND MANAGEMENT OF ATL PATIENTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                              
7   59  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8 3340  45 HISTONE DEACETYLASE MEDIATED TRANSCRIPTIONAL ACTIVATION REDUCES PROVIRAL LOADS IN HTLV-1 ASSOCIATED MYELOPATHY/TROPICAL SPASTIC PARAPARESIS PATIENTS. EPIGENETIC MODIFICATIONS OF CHROMATIN MAY PLAY A ROLE IN MAINTAINING VIRAL LATENCY AND THUS PERSISTENCE OF THE HUMAN T-LYMPHOTROPIC VIRUS TYPE 1 (HTLV-1), WHICH IS RESPONSIBLE FOR HTLV-ASSOCIATED MYELOPATHY/TROPICAL SPASTIC PARAPARESIS (HAM/TSP). A MAJOR DETERMINANT OF DISEASE PROGRESSION IS INCREASED PERIPHERAL BLOOD PROVIRAL LOAD (PVL), POSSIBLY VIA THE ACCUMULATION OF INFECTED CELLS IN THE CENTRAL NERVOUS SYSTEM (CNS) CREATING A DAMAGING INFLAMMATORY RESPONSE. CURRENT THERAPEUTIC APPROACHES THAT FOCUS ON REDUCING EITHER CELL PROLIFERATION, VIRAL REPLICATION, OR TISSUE INVASION ARE STILL UNSATISFACTORY. CONTRASTING WITH THESE INHIBITORY STRATEGIES, WE EVALUATED THE EFFICACY OF A NOVEL APPROACH AIMED, PARADOXICALLY, AT ACTIVATING VIRAL GENE EXPRESSION TO EXPOSE VIRUS-POSITIVE CELLS TO THE HOST IMMUNE RESPONSE. WE USED VALPROATE (VPA), A HISTONE DEACETYLASE INHIBITOR THAT HAS BEEN USED FOR DECADES AS A CHRONIC, SAFE TREATMENT FOR EPILEPTIC DISORDERS. BASED ON IN VITRO AND IN VIVO DATA, WE PROVIDE EVIDENCE THAT TRANSIENT ACTIVATION OF THE LATENT VIRAL RESERVOIR CAUSES ITS COLLAPSE, A PROCESS THAT MAY ALLEVIATE THE CONDITION OF HAM/TSP. THIS REPRESENTS THE FIRST SUCH APPROACH TO TREATING HAM/TSP, USING GENE ACTIVATION THERAPY TO TILT THE HOST-PATHOGEN BALANCE IN FAVOR OF AN EXISTING ANTIVIRAL RESPONSE. THIS TRIAL IS REGISTERED AT HTTP://CLINICALTRIALS.GOV/AS NO. NCT00519181.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9 5687  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10  160  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 6773  29 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12  149  47 ABERRANT HYDROXYMETHYLATION IN PROMOTER CPG REGIONS OF GENES RELATED TO THE CELL CYCLE AND APOPTOSIS CHARACTERIZES ADVANCED CHRONIC MYELOID LEUKEMIA DISEASE, POOR IMATINIB RESPONDENTS AND POOR SURVIVAL. BACKGROUND: THERE IS STRONG EVIDENCE THAT DISEASE PROGRESSION, DRUG RESPONSE AND OVERALL CLINICAL OUTCOMES OF CML DISEASE ARE NOT ONLY DECIDED BY BCR/ABL1 ONCOPROTEIN BUT DEPEND ON ACCUMULATION OF ADDITIONAL GENETIC AND EPIGENETIC ABERRATIONS. DNA HYDROXYMETHYLATION IS IMPLICATED IN THE DEVELOPMENT OF VARIETY OF DISEASES. DNA HYDROXYMETHYLATION IN GENE PROMOTERS PLAYS IMPORTANT ROLES IN DISEASE PROGRESSION, DRUG RESPONSE AND CLINICAL OUTCOME OF VARIOUS DISEASES. THEREFORE IN THIS STUDY, WE AIMED TO EXPLORE THE ROLE OF ABERRANT HYDROXYMETHYLATION IN PROMOTER REGIONS OF DIFFERENT TUMOR SUPPRESSOR GENES IN RELATION TO CML DISEASE PROGRESSION, RESPONSE TO IMATINIB THERAPY AND CLINICAL OUTCOME. METHODS: WE RECRUITED 150 CML PATIENTS AT DIFFERENT CLINICAL STAGES OF THE DISEASE. PATIENTS WERE FOLLOWED UP FOR 48 MONTHS AND HAEMATOLOGICAL/MOLECULAR RESPONSES WERE ANALYSED. HAEMATOLOGICAL RESPONSE WAS ANALYSED BY PERIPHERAL BLOOD SMEAR. BCR/ABL1 SPECIFIC TAQMAN PROBE BASED QRT-PCR WAS USED FOR ASSESSING THE MOLECULAR RESPONSE OF CML PATIENTS ON IMATINIB THERAPY. PROMOTER HYDROXYMETHYLATION OF THE GENES WAS CHARACTERIZED USING MS-PCR. RESULTS: WE OBSERVED THAT PROMOTER HYDROXYMETHYLATION OF DAPK1, RIZ1, P16INK4A, RASSF1A AND P14ARF(ARF) GENES CHARACTERIZE ADVANCED CML DISEASE AND POOR IMATINIB RESPONDENTS. ALTHOUGH, CYTOKINE SIGNALLING (SOCS1) GENE WAS HYPERMETHYLATED IN ADVANCED STAGES OF CML AND ACCUMULATED IN PATIENTS WITH POOR IMATINIB RESPONSE, BUT THE DIFFERENCES WERE NOT STATISTICALLY SIGNIFICANT. MOREOVER, WE FOUND HYPERMETHYLATION OF P14(ARF), RASSF1 AND P16(INK4A) GENES AND CYTOKINE SIGNALLING GENE (SOCS1) SIGNIFICANTLY ASSOCIATED WITH POOR OVERALL SURVIVAL OF CML PATIENTS ON IMATINIB THERAPY. THE RESULTS OF THIS STUDY ARE IN AGREEMENT OF THE ROLE OF ABERRANT DNA METHYLATION OF DIFFERENT TUMOR SUPPRESSOR GENES AS POTENTIAL BIOMARKERS OF CML DISEASE PROGRESSION, POOR IMATINIB RESPONSE AND OVERALL CLINICAL OUTCOME. CONCLUSION: IN THIS STUDY, WE REPORT THAT PROMOTER HYDROXYMETHYLATION OF DAPK1, RIZ1, P16INK4A, RASSF1A AND P14ARF(ARF) GENES IS A CHARACTERISTIC FEATURE OF CML DISEASE PROGRESSIONS, DEFINES POOR IMATINIB RESPONDENTS AND POOR OVERALL SURVIVAL OF CML PATIENTS TO IMATINIB THERAPY.	2022	

13 3822  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
14 1577  36 DNA METHYLATION PROFILE IN CHRONIC MYELOMONOCYTIC LEUKEMIA ASSOCIATES WITH DISTINCT CLINICAL, BIOLOGICAL AND GENETIC FEATURES. CHROMOSOMAL ABNORMALITIES ARE DETECTED IN 20-30% OF PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND CORRELATE WITH PROGNOSIS. ON THE MUTATION LEVEL, DISRUPTIVE ALTERATIONS ARE PARTICULARLY FREQUENT IN CHROMATIN REGULATORY GENES. HOWEVER, LITTLE IS KNOWN ABOUT THE CONSEQUENTIAL ALTERATIONS IN THE EPIGENETIC MARKING OF THE GENOME. HERE, WE REPORT THE ANALYSIS OF GENOMIC DNA METHYLATION PATTERNS OF 64 CMML PATIENTS AND 10 HEALTHY CONTROLS, USING A DNA METHYLATION MICROARRAY FOCUSED ON PROMOTER REGIONS. DIFFERENTIAL METHYLATION ANALYSIS BETWEEN PATIENTS AND CONTROLS ALLOWED US TO IDENTIFY ABNORMALITIES IN DNA METHYLATION, INCLUDING HYPERMETHYLATION OF SPECIFIC GENES AND LARGE GENOME REGIONS WITH ABERRANT DNA METHYLATION. UNSUPERVISED HIERARCHICAL CLUSTER ANALYSIS IDENTIFIED TWO MAIN CLUSTERS THAT ASSOCIATED WITH THE CLINICAL, BIOLOGICAL, AND GENETIC FEATURES OF PATIENTS. GROUP 1 WAS ENRICHED IN PATIENTS WITH ADVERSE CLINICAL AND BIOLOGICAL CHARACTERISTICS AND POORER OVERALL AND PROGRESSION-FREE SURVIVAL. IN ADDITION, SIGNIFICANT DIFFERENCES IN DNA METHYLATION WERE OBSERVED BETWEEN PATIENTS WITH LOW RISK AND INTERMEDIATE/HIGH RISK KARYOTYPES AND BETWEEN TET2 MUTANT AND WILD TYPE PATIENTS. TAKEN TOGETHER, OUR RESULTS DEMONSTRATE THAT ALTERED DNA METHYLATION PATTERNS REFLECT THE CMML DISEASE STATE AND ALLOW TO IDENTIFY PATIENT GROUPS WITH DISTINCT CLINICAL FEATURES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15 3686  33 INFLAMMATION-RELATED ABERRANT PATTERNS OF DNA METHYLATION: DETECTION AND ROLE IN EPIGENETIC DEREGULATION OF CANCER CELL TRANSCRIPTOME. IT IS NOW APPARENT THAT EPIGENETIC ABNORMALITIES, IN PARTICULAR ALTERED DNA METHYLATION, PLAY A CRUCIAL ROLE IN THE DEVELOPMENT AND PROGRESSION OF HUMAN CANCERS. DNA HYPERMETHYLATION AT PROMOTER CPG ISLANDS IS NOW RECOGNIZED AS A THIRD MECHANISM BY WHICH INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS. ABERRANT CPG ISLAND HYPERMETHYLATION IS ALSO FREQUENTLY OBSERVED IN CHRONIC INFLAMMATION AND PRECANCEROUS LESIONS, WHICH SUGGESTS THAT IT IS AN EARLY EVENT IN TUMORIGENESIS THAT COULD SERVE AS A USEFUL TUMOR MARKER. A VARIETY OF SCREENING TECHNIQUES HAVE BEEN DEVELOPED FOR GENOME-WIDE SCREENING OF METHYLATION STATUS. OF THOSE, TRANSCRIPTOME ANALYSIS COUPLED WITH PHARMACOLOGICAL UNMASKING HAS EMERGED AS A POWERFUL TOOL FOR REVEALING DNA METHYLATION PATTERNS IN CANCER CELLS AND IDENTIFYING NEW TUMOR MARKER CANDIDATES.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16 1542  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17  606  45 BEYOND GENETICS--THE EMERGING ROLE OF EPIGENETIC CHANGES IN HEMATOPOIETIC MALIGNANCIES. THE TERM EPIGENETIC REFERS TO A HERITABLE CHANGE IN GENE EXPRESSION THAT IS MEDIATED BY MECHANISMS OTHER THAN ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. DNA METHYLATION AT CYTOSINE BASES THAT ARE LOCATED 5' TO GUANOSINE WITHIN A CPG DINUCLEOTIDE IS THE MAIN EPIGENETIC MODIFICATION IN HUMANS. PATTERNS OF DNA METHYLATION ARE PROFOUNDLY DERANGED IN HUMAN CANCER AND COMPRISE GENOME-WIDE LOSSES AS WELL AS REGIONAL GAINS IN DNA METHYLATION. HYPERMETHYLATION OF CPG ISLANDS WITHIN GENE PROMOTER REGIONS IS ASSOCIATED WITH TRANSCRIPTIONAL INACTIVATION AND REPRESENTS, IN ADDITION TO GENETIC ABERRATIONS, AN IMPORTANT MECHANISM OF GENE SILENCING IN THE PATHOGENESIS OF HEMATOPOIETIC MALIGNANCIES. THIS EPIGENETIC PHENOMENON ACTS AS AN ALTERNATIVE TO MUTATIONS AND DELETIONS TO DISRUPT TUMOR SUPPRESSOR GENE FUNCTION. A LARGE NUMBER OF GENES INVOLVING FUNDAMENTAL CELLULAR PATHWAYS MAY BE AFFECTED IN VIRTUALLY ALL TYPES OF HUMAN CANCER BY ABERRANT CPG ISLAND METHYLATION IN ASSOCIATION WITH TRANSCRIPTIONAL SILENCING. ALTERED METHYLATION PATTERNS CAN BE USED AS BIOMARKERS FOR CANCER DETECTION, ASSESSMENT OF PROGNOSIS, AND PREDICTION OF RESPONSE TO ANTITUMOR TREATMENT. FURTHERMORE, CLINICAL TRIALS USING EPIGENETICALLY TARGETED THERAPIES HAVE YIELDED PROMISING RESULTS FOR ACUTE AND CHRONIC LEUKEMIAS AS WELL AS FOR MYELODYSPLASTIC SYNDROMES. THE EXPLORATION OF OUR GROWING KNOWLEDGE ABOUT EPIGENETIC ABERRATIONS MAY HELP DEVELOP NOVEL STRATEGIES FOR THE DIAGNOSIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES IN THE FUTURE.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18 6523  42 TRANSCRIPTIONAL AND EPIGENETIC REGULATORY MECHANISMS AFFECTING HTLV-1 PROVIRUS. HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-1) IS A RETROVIRUS ASSOCIATED WITH HUMAN DISEASES, SUCH AS ADULT T-CELL LEUKEMIA (ATL) AND HTLV-1-ASSOCIATED MYELOPATHY/TROPIC SPASTIC PARAPARESIS (HAM/TSP). AS A RETROVIRUS, ITS LIFE CYCLE INCLUDES A STEP WHERE HTLV-1 IS INTEGRATED INTO THE HOST GENOMIC DNA AND FORMS PROVIRAL DNA. IN THE CHRONIC PHASE OF THE INFECTION, HTLV?1 IS KNOWN TO PROLIFERATE AS A PROVIRUS VIA THE MITOTIC DIVISION OF THE INFECTED HOST CELLS. THERE ARE GENERALLY TENS OF THOUSANDS OF INFECTED CLONES WITHIN AN INFECTED INDIVIDUAL. THEY EXIST NOT ONLY IN PERIPHERAL BLOOD, BUT ALSO IN VARIOUS LYMPHOID ORGANS. VIRAL PROTEINS ENCODED IN HTLV-1 GENOME PLAY A ROLE IN THE PROLIFERATION AND SURVIVAL OF THE INFECTED CELLS. AS IS THE CASE WITH OTHER CHRONIC VIRAL INFECTIONS, HTLV-1 GENE EXPRESSION INDUCES THE ACTIVATION OF THE HOST IMMUNITY AGAINST THE VIRUS. THUS, THE TRANSCRIPTION FROM HTLV-1 PROVIRUS NEEDS TO BE CONTROLLED IN ORDER TO EVADE THE HOST IMMUNE SURVEILLANCE. THERE SHOULD BE A DYNAMIC AND COMPLEX REGULATION IN VIVO, WHERE AN EQUILIBRIUM BETWEEN VIRAL ANTIGEN EXPRESSION AND HOST IMMUNE SURVEILLANCE IS ACHIEVED. THE MECHANISMS REGULATING VIRAL GENE EXPRESSION FROM THE PROVIRUS ARE A KEY TO UNDERSTANDING THE PERSISTENT/LATENT INFECTION WITH HTLV-1 AND ITS PATHOGENESIS. IN THIS ARTICLE, WE WOULD LIKE TO REVIEW OUR CURRENT UNDERSTANDING ON THIS TOPIC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19 2747  44 EXPRESSION ANALYSIS OF THE EPIGENETIC METHYLTRANSFERASES AND METHYL-CPG BINDING PROTEIN FAMILIES IN THE NORMAL B-CELL AND B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN CARCINOGENESIS HAS BEEN A SOURCE OF CONTROVERSY FOR SOME TIME. THERE IS LITTLE DOUBT THAT CHANGES IN GENOMIC HYPERMETHYLATION CONTRIBUTE TO THE SILENCING OF TUMOR SUPPRESSOR GENES. FURTHERMORE, RECENT STUDIES HAVE ALSO IDENTIFIED THE SIGNIFICANCE OF GENOMIC HYPOMETHYLATION ASSOCIATED WITH CHROMOSOMAL INSTABILITY AND TUMORIGENESIS. ONE OF THE MOST PERPLEXING QUESTIONS REGARDING EPIGENETIC MODIFICATIONS AND LEUKEMOGENESIS IS THE RELATIONSHIP WITH DNA METHYLTRANSFERASES (DNMT'S). THE PRIMARY FUNCTION OF THE DNMT ENZYMES IS TO METHYLATE GENOMIC DNA, WHEREAS THE METHYL-CPG BINDING DOMAIN PROTEINS (MBD) INTERPRET THIS METHYLATION SIGNAL AND REGULATE GENE EXPRESSION AND CHROMATIN BEHAVIOR. IN THIS STUDY WE ANALYSE THESE GENE FAMILIES BY QUANTITATIVE REAL-TIME PCR TO INVESTIGATE WHETHER EXPRESSION LEVELS AND THE B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) PHENOTYPE ARE ASSOCIATED. FURTHERMORE, GIVEN THE EPIGENETIC CROSSTALK BETWEEN GENOME STABILITY AND THE HISTONE CHROMATIN CODE WE HAVE ANALYSED EUKARYOTIC HISTONE METHYLTRANSFERASE (EU-HMTASEI). SURPRISINGLY, WE DID NOT OBSERVE SIGNIFICANT CHANGES IN DNMT1 EXPRESSION IN B-CLL CASES WHEN COMPARED TO NORMAL LYMPHOCYTES, REGARDLESS OF WHETHER WE NORMALISE AGAINST GAPDH OR PCNA AS REFERENCE STANDARDS. INDEED, EXPRESSION OF THE MAINTENANCE AND DE NOVO METHYLASES WERE INDEPENDENTLY REGULATED. OF PARTICULAR NOTE WAS THE SIGNIFICANT DOWN REGULATION OF DNMT3B. FURTHERMORE, WE OBSERVED A POSITIVE CORRELATION BETWEEN HMTASEI EXPRESSION LEVELS AND STAGE OF LEUKEMIA SUGGESTING THAT CHANGES IN THE METHYLATION PATTERNS IN B-CLL MAY REPRESENT DEREGULATION OF THE EPIGENETIC REPERTOIRE THAT ALSO INCLUDE THE METHYLATION DEPENDENT BINDING PROTEINS, MBD2 AND MECP2. WE ENVISAGE CHANGES IN THE EPIGENETIC PROGRAM ARE MULTIFACTORIAL IN NATURE AND POSTULATE THAT THE PREVALENT GENOMIC METHYLASES JUST ONE COMPONENT OF A LARGER EPIGENETIC REPERTOIRE.	2004	
                                                                                                                                                                                                                                                                                                                                 
20 6684  27 VALIDATION OF AN LC-MS BASED APPROACH FOR PROFILING HISTONES IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE IN VITRO EVALUATION OF HISTONES AND THEIR PTMS HAS DRAWN SUBSTANTIAL INTEREST IN THE DEVELOPMENT OF EPIGENETIC THERAPIES. THE DIFFERENTIAL EXPRESSION OF HISTONE ISOFORMS MAY SERVE AS A POTENTIAL MARKER IN THE CLASSIFICATION OF DISEASES AFFECTED BY CHROMATIN ABNORMALITIES. IN THIS STUDY, PROTEIN PROFILING BY LC AND MS WAS USED TO EXPLORE DIFFERENCES IN HISTONE COMPOSITION IN PRIMARY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS. EXTENSIVE METHOD VALIDATIONS WERE PERFORMED TO DETERMINE THE EXPERIMENTAL VARIANCES THAT WOULD IMPACT HISTONE RELATIVE ABUNDANCE. THE RESULTING DATA DEMONSTRATED THAT THE PROPOSED METHODOLOGY WAS SUITABLE FOR THE ANALYSIS OF HISTONE PROFILES. IN 4 NORMAL INDIVIDUALS AND 40 CLL PATIENTS, A SIGNIFICANT DECREASE IN THE RELATIVE ABUNDANCE OF HISTONE H2A VARIANTS (H2AFL AND H2AFA/M*) WAS OBSERVED IN PRIMARY CLL CELLS AS COMPARED TO NORMAL B CELLS. PROTEIN IDENTITIES WERE DETERMINED USING HIGH MASS ACCURACY MS AND SHOTGUN PROTEOMICS.	2009