1  826 131 CHARACTERIZATION OF K562 CELLS: UNCOVERING NOVEL CHROMOSOMES, ASSESSING TRANSFERRIN RECEPTOR EXPRESSION, AND PROBING PHARMACOLOGICAL THERAPIES. HUMAN ERYTHROLEUKEMIC K562 CELLS REPRESENT THE PROTOTYPICAL CELL CULTURE MODEL OF CHRONIC MYELOID LEUKEMIA (CML). THE CELLS ARE PSEUDO-TRIPLOID AND POSITIVE FOR THE PHILADELPHIA CHROMOSOME. THEREFORE, K562 CELLS HAVE BEEN WIDELY USED FOR INVESTIGATING THE BCR/ABL1 ONCOGENE AND THE TYROSINE KINASE INHIBITOR, IMATINIB-MESYLATE. FURTHER, K562 CELLS OVEREXPRESS TRANSFERRIN RECEPTORS (TFR) AND HAVE BEEN USED AS A MODEL FOR TARGETING CYTOTOXIC THERAPIES, VIA RECEPTOR-MEDIATED ENDOCYTOSIS. HERE, WE HAVE CHARACTERIZED K562 CELLS FOCUSING ON THE KARYOTYPE OF CELLS IN PROLONGED CULTURE, REGULATION OF EXPRESSION OF TFR IN WILDTYPE (WT) AND DOXORUBICIN-RESISTANT CELLS, AND RESPONSES TO HISTONE DEACETYLASE INHIBITION (HDACI). KARYOTYPE ANALYSIS INDICATES NOVEL CHROMOSOMES AND GENE EXPRESSION ANALYSIS SUGGESTS A SHIFT OF CULTURED K562 CELLS AWAY FROM PATIENT-DERIVED LEUKEMIC CELLS. WE CONFIRM THE HIGH EXPRESSION OF TFR ON K562 CELLS USING IMMUNOFLUORESCENCE AND CELL-SURFACE RECEPTOR BINDING RADIOASSAYS. IMPORTANTLY, HIGH TFR EXPRESSION IS OBSERVED IN PATIENT-DERIVED CELLS, AND WE HIGHLIGHT THE PERSISTENT EXPRESSION OF TFR FOLLOWING DOXORUBICIN ACQUIRED RESISTANCE. EPIGENETIC ANALYSIS INDICATES THAT PERMISSIVE HISTONE ACETYLATION AND METHYLATION AT THE PROMOTER REGION REGULATES THE TRANSCRIPTION OF TFR IN K562 CELLS. FINALLY, WE SHOW RELATIVELY HIGH EXPRESSION OF HDAC ENZYMES IN K562 CELLS AND DEMONSTRATE THE CHEMOTOXIC EFFECTS OF HDACI, USING THE FDA-APPROVED HYDROXAMIC ACID, VORINOSTAT. TOGETHER WITH A DESCRIPTION OF MORPHOLOGY, INFRARED SPECTRAL ANALYSIS, AND EXAMINATION OF METABOLIC PROPERTIES, WE PROVIDE A COMPREHENSIVE CHARACTERIZATION OF K562 CELLS. OVERALL, K562 CELL CULTURE SYSTEMS REMAIN WIDELY USED FOR THE INVESTIGATION OF NOVEL THERAPEUTICS FOR CML, WHICH IS PARTICULARLY IMPORTANT IN CASES OF IMATINIB-MESYLATE RESISTANCE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                   
2 1669  35 DOWNREGULATION OF THE HISTONE METHYLTRANSFERASE SETD2 PROMOTES IMATINIB RESISTANCE IN CHRONIC MYELOID LEUKAEMIA CELLS. OBJECTIVES: EPIGENETIC MODIFIERS WERE IMPORTANT PLAYERS IN THE DEVELOPMENT OF HAEMATOLOGICAL MALIGNANCIES AND SENSITIVITY TO THERAPY. MUTATIONS OF SET DOMAIN-CONTAINING 2 (SETD2), A METHYLTRANSFERASE THAT CATALYSES THE TRIMETHYLATION OF HISTONE 3 ON LYSINE 36 (H3K36ME3), WERE FOUND IN VARIOUS MYELOID MALIGNANCIES. HOWEVER, THE DETAILED MECHANISMS THROUGH WHICH SETD2 CONFERS CHRONIC MYELOID LEUKAEMIA PROGRESSION AND RESISTANCE TO THERAPY TARGETING ON BCR-ABL REMAIN UNCLEAR. MATERIALS AND METHODS: THE LEVEL OF SETD2 IN IMATINIB-SENSITIVE AND IMATINIB-RESISTANT CHRONIC MYELOID LEUKAEMIA (CML) CELLS WAS EXAMINED BY IMMUNOBLOTTING AND QUANTITATIVE REAL-TIME PCR. WE ANALYSED CD34(+) CD38(-) LEUKAEMIC STEM CELLS BY FLOW CYTOMETRY AND COLONY FORMATION ASSAYS UPON SETD2 KNOCKDOWN OR OVEREXPRESSION. THE IMPACT OF SETD2 EXPRESSION ALTERATIONS OR SMALL-MOLECULE INHIBITOR JIB-04 TARGETING H3K36ME3 LOSS ON IMATINIB SENSITIVITY WAS ASSESSED BY IC50, CELL APOPTOSIS AND PROLIFERATION ASSAYS. FINALLY, RNA SEQUENCING AND CHIP-QUANTITATIVE PCR WERE PERFORMED TO VERIFY PUTATIVE DOWNSTREAM TARGETS. RESULTS: SETD2 WAS FOUND TO ACT AS A TUMOUR SUPPRESSOR IN CML. THE NOVEL ONCOGENIC TARGETS MYCN AND ERG WERE SHOWN TO BE THE DIRECT DOWNSTREAM TARGETS OF SETD2, WHERE THEIR OVEREXPRESSION INDUCED BY SETD2 KNOCKDOWN CAUSED IMATINIB INSENSITIVITY AND LEUKAEMIC STEM CELL ENRICHMENT IN CML CELL LINES. TREATMENT WITH JIB-04, AN INHIBITOR THAT RESTORES H3K36ME3 LEVELS THROUGH BLOCKADE OF ITS DEMETHYLATION, SUCCESSFULLY IMPROVED THE CELL IMATINIB SENSITIVITY AND ENHANCED THE CHEMOTHERAPEUTIC EFFECT. CONCLUSIONS: OUR STUDY NOT ONLY EMPHASIZES THE REGULATORY MECHANISM OF SETD2 IN CML, BUT ALSO PROVIDES PROMISING THERAPEUTIC STRATEGIES FOR OVERCOMING THE IMATINIB RESISTANCE IN PATIENTS WITH CML.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3  390  37 AN INTEGRATIVE MODEL OF PATHWAY CONVERGENCE IN GENETICALLY HETEROGENEOUS BLAST CRISIS CHRONIC MYELOID LEUKEMIA. TARGETED THERAPIES AGAINST THE BCR-ABL1 KINASE HAVE REVOLUTIONIZED TREATMENT OF CHRONIC PHASE (CP) CHRONIC MYELOID LEUKEMIA (CML). IN CONTRAST, MANAGEMENT OF BLAST CRISIS (BC) CML REMAINS CHALLENGING BECAUSE BC CELLS ACQUIRE COMPLEX MOLECULAR ALTERATIONS THAT CONFER STEMNESS FEATURES TO PROGENITOR POPULATIONS AND RESISTANCE TO BCR-ABL1 TYROSINE KINASE INHIBITORS. COMPREHENSIVE MODELS OF BC TRANSFORMATION HAVE PROVED ELUSIVE BECAUSE OF THE RARITY AND GENETIC HETEROGENEITY OF BC, BUT ARE IMPORTANT FOR DEVELOPING BIOMARKERS PREDICTING BC PROGRESSION AND EFFECTIVE THERAPIES. TO BETTER UNDERSTAND BC, WE PERFORMED AN INTEGRATED MULTIOMICS ANALYSIS OF 74 CP AND BC SAMPLES USING WHOLE-GENOME AND EXOME SEQUENCING, TRANSCRIPTOME AND METHYLOME PROFILING, AND CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY HIGH-THROUGHPUT SEQUENCING. EMPLOYING PATHWAY-BASED ANALYSIS, WE FOUND THE BC GENOME WAS SIGNIFICANTLY ENRICHED FOR MUTATIONS AFFECTING COMPONENTS OF THE POLYCOMB REPRESSIVE COMPLEX (PRC) PATHWAY. WHILE TRANSCRIPTOMICALLY, BC PROGENITORS WERE ENRICHED AND DEPLETED FOR PRC1- AND PRC2-RELATED GENE SETS RESPECTIVELY. BY INTEGRATING OUR DATA SETS, WE DETERMINED THAT BC PROGENITORS UNDERGO PRC-DRIVEN EPIGENETIC REPROGRAMMING TOWARD A CONVERGENT TRANSCRIPTOMIC STATE. SPECIFICALLY, PRC2 DIRECTS BC DNA HYPERMETHYLATION, WHICH IN TURN SILENCES KEY GENES INVOLVED IN MYELOID DIFFERENTIATION AND TUMOR SUPPRESSOR FUNCTION VIA SO-CALLED EPIGENETIC SWITCHING, WHEREAS PRC1 REPRESSES AN OVERLAPPING AND DISTINCT SET OF GENES, INCLUDING NOVEL BC TUMOR SUPPRESSORS. ON THE BASIS OF THESE OBSERVATIONS, WE DEVELOPED AN INTEGRATED MODEL OF BC THAT FACILITATED THE IDENTIFICATION OF COMBINATORIAL THERAPIES CAPABLE OF REVERSING BC REPROGRAMMING (DECITABINE+PRC1 INHIBITORS), NOVEL PRC-SILENCED TUMOR SUPPRESSOR GENES (NR4A2), AND GENE EXPRESSION SIGNATURES PREDICTIVE OF DISEASE PROGRESSION AND DRUG RESISTANCE IN CP.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                             
4 3087  37 GENOME?WIDE EXPRESSION AND METHYLATION ANALYSES REVEAL ABERRANT CELL ADHESION SIGNALING IN TYROSINE KINASE INHIBITOR?RESISTANT CML CELLS. ALTHOUGH CHRONIC MYELOID LEUKEMIA (CML) CAN BE EFFECTIVELY TREATED USING BCR?ABL1 KINASE INHIBITORS, RESISTANCE DUE TO KINASE ALTERATIONS OR TO BCR?ABL1 INDEPENDENT MECHANISMS REMAIN A THERAPEUTIC CHALLENGE. FOR THE LATTER, THE UNDERLYING MECHANISMS ARE WIDELY DISCUSSED; FOR INSTANCE, GENE EXPRESSION CHANGES, EPIGENETIC FACTORS AND ALTERNATIVE SIGNALING PATHWAY ACTIVATION. IN THE PRESENT STUDY, IN VITRO?CML CELL MODELS OF RESISTANCE AGAINST THE TYROSINE KINASE INHIBITORS (TKIS) IMATINIB (0.5 AND 2 MICROM) AND NILOTINIB (0.1 MICROM) WITH BIOLOGICAL REPLICATES WERE GENERATED TO IDENTIFY NOVEL MECHANISMS OF RESISTANCE. SUBSEQUENTLY, GENOME?WIDE MRNA EXPRESSION AND DNA METHYLATION WERE ANALYZED. WHILE MRNA EXPRESSION PATTERNS DIFFERED LARGELY BETWEEN BIOLOGICAL REPLICATES, THERE WAS AN OVERLAP OF 71 GENES DIFFERENTIALLY EXPRESSED BETWEEN CELLS RESISTANT AGAINST IMATINIB OR NILOTINIB. MOREOVER, ALL TKI RESISTANT CELL LINES DEMONSTRATED A SLIGHT HYPERMETHYLATION COMPARED WITH NATIVE CELLS. IN A COMBINED ANALYSIS OF 151 GENES DIFFERENTIALLY EXPRESSED IN THE BIOLOGICAL REPLICATES OF IMATINIB RESISTANCE, CELL ADHESION SIGNALING, IN PARTICULAR THE CELLULAR MATRIX PROTEIN FIBRONECTIN 1 (FN1), WAS SIGNIFICANTLY DYSREGULATED. THIS GENE WAS ALSO DOWNREGULATED IN NILOTINIB RESISTANCE. FURTHER ANALYSES SHOWED SIGNIFICANT FN1?DOWNREGULATION IN IMATINIB RESISTANCE ON MRNA (P<0.001) AND PROTEIN LEVEL (P<0.001). SIRNA?MEDIATED FN1?KNOCKDOWN IN NATIVE CELLS REDUCED CELL ADHESION (P=0.02), DECREASED IMATINIB SUSCEPTIBILITY VISIBLE BY HIGHER KI?67 EXPRESSION (1.5?FOLD, P=0.04) AND INCREASED CELL NUMBER (1.5?FOLD, P=0.03). VICE VERSA, RECOVERY OF FN1?EXPRESSION IN IMATINIB RESISTANT CELLS WAS SUFFICIENT TO PARTIALLY RESTORE THE RESPONSE TO IMATINIB. OVERALL, THESE RESULTS SUGGESTED A ROLE OF CELL ADHESION SIGNALING AND FIBRONECTIN 1 IN TKI RESISTANT CML AND A POTENTIAL TARGET FOR NOVEL STRATEGIES IN TREATMENT OF RESISTANT CML.	2022	
                                                                                                                                                                                                                                                                                                                                                                   
5  171  38 ABROGATION OF HISTONE DEACETYLASES (HDACS) DECREASES SURVIVAL OF CHRONIC MYELOID LEUKEMIA CELLS: NEW INSIGHT INTO ATTENUATING EFFECTS OF THE PI3K/C-MYC AXIS ON PANOBINOSTAT CYTOTOXICITY. ALTHOUGH THE IDENTIFICATION OF TYROSINE KINASE INHIBITORS (TKIS) HAS CHANGED THE TREATMENT PARADIGM OF MANY CANCER TYPES INCLUDING CHRONIC MYELOID LEUKEMIA (CML), STILL ADJUSTMENT OF NEOPLASTIC CELLS TO CYTOTOXIC EFFECTS OF ANTICANCER DRUGS IS A SERIOUS CHALLENGE. IN THE AREA OF DRUG RESISTANCE, EPIGENETIC ALTERATIONS ARE AT THE CENTER OF ATTENTION AND THE PRESENT STUDY AIMED TO EVALUATE WHETHER BLOCKAGE OF EPIGENETICS MECHANISMS USING A PAN-HISTONE DEACETYLASE (HDAC) INHIBITOR INDUCES CELL DEATH IN CML-DERIVED K562 CELLS. WE FOUND THAT THE ABROGATION OF HDACS USING PANOBINOSTAT RESULTED IN A REDUCTION IN SURVIVAL OF THE K562 CELL LINE THROUGH P27-MEDIATED CELL CYCLE ARREST. NOTEWORTHY, THE RESULTS OF THE SYNERGISTIC EXPERIMENTS REVEALED THAT HDAC SUPPRESSION COULD BE RECRUITED AS A WAY TO POTENTIATE CYTOTOXICITY OF IMATINIB AND TO ENHANCE THE THERAPEUTIC EFFICACY OF CML. HERE, WE PROPOSED FOR THE FIRST TIME THAT THE INHIBITORY EFFECT OF PANOBINOSTAT WAS OVERSHADOWED, AT LEAST PARTIALLY, THROUGH THE ABERRANT ACTIVATION OF THE PHOSPHOINOSITIDE 3-KINASE (PI3K)/C-MYC AXIS. MEANWHILE, WE FOUND THAT UPON BLOCKAGE OF AUTOPHAGY AND THE PROTEASOME PATHWAY, AS THE MAIN AXIS INVOLVED IN THE ACTIVATION OF AUTOPHAGY, THE ANTI-LEUKEMIC PROPERTY OF THE HDAC INHIBITOR WAS POTENTIATED. TAKEN TOGETHER, OUR STUDY SUGGESTS THE BENEFICIAL APPLICATION OF HDAC INHIBITION IN THE TREATMENT STRATEGIES OF CML; HOWEVER, FURTHER IN VIVO STUDIES ARE NEEDED TO DETERMINE THE EFFICACY OF THIS INHIBITOR, EITHER AS A SINGLE AGENT OR IN COMBINATION WITH SMALL MOLECULE INHIBITORS OF PI3K AND/OR C-MYC IN THIS MALIGNANCY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
6 5405  39 REGULATED EXPRESSION OF P210 BCR-ABL DURING EMBRYONIC STEM CELL DIFFERENTIATION STIMULATES MULTIPOTENTIAL PROGENITOR EXPANSION AND MYELOID CELL FATE. P210 BCR-ABL IS AN ACTIVATED TYROSINE KINASE ONCOGENE ENCODED BY THE PHILADELPHIA CHROMOSOME ASSOCIATED WITH HUMAN CHRONIC MYELOGENOUS LEUKEMIA (CML). THE DISEASE REPRESENTS A CLONAL DISORDER ARISING IN THE PLURIPOTENT HEMATOPOIETIC STEM CELL. DURING THE CHRONIC PHASE, PATIENTS PRESENT WITH A DRAMATIC EXPANSION OF MYELOID CELLS AND A MILD ANEMIA. RETROVIRAL GENE TRANSFER AND TRANSGENIC EXPRESSION IN RODENTS HAVE DEMONSTRATED THE ABILITY OF BCR-ABL TO INDUCE VARIOUS TYPES OF LEUKEMIA. HOWEVER, STUDY OF HUMAN CML OR RODENT MODELS HAS NOT DETERMINED THE DIRECT AND IMMEDIATE EFFECTS OF BCR-ABL ON HEMATOPOIETIC CELLS FROM THOSE REQUIRING SECONDARY GENETIC OR EPIGENETIC CHANGES SELECTED DURING THE PATHOGENIC PROCESS. WE UTILIZED TETRACYCLINE-REGULATED EXPRESSION OF BCR-ABL FROM A PROMOTER ENGINEERED FOR ROBUST EXPRESSION IN PRIMITIVE STEM CELLS THROUGH MULTILINEAGE BLOOD CELL DEVELOPMENT IN COMBINATION WITH THE IN VITRO DIFFERENTIATION OF EMBRYONAL STEM CELLS INTO HEMATOPOIETIC ELEMENTS. OUR RESULTS DEMONSTRATE THAT BCR-ABL EXPRESSION ALONE IS SUFFICIENT TO INCREASE THE NUMBER OF MULTIPOTENT AND MYELOID LINEAGE COMMITTED PROGENITORS IN A DOSE-DEPENDENT MANNER WHILE SUPPRESSING THE DEVELOPMENT OF COMMITTED ERYTHROID PROGENITORS. THESE EFFECTS ARE REVERSIBLE UPON EXTINGUISHING BCR-ABL EXPRESSION. THESE FINDINGS ARE CONSISTENT WITH BCR-ABL BEING THE SOLE GENETIC CHANGE NEEDED FOR THE ESTABLISHMENT OF THE CHRONIC PHASE OF CML AND PROVIDE A POWERFUL SYSTEM FOR THE ANALYSIS OF ANY GENETIC CHANGE THAT ALTERS CELL GROWTH AND LINEAGE CHOICES OF THE HEMATOPOIETIC STEM CELL.	2000	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7 2189  37 EPIGENETIC MECHANISMS UNDERLYING THE THERAPEUTIC EFFECTS OF HDAC INHIBITORS IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A HEMATOLOGICAL DISORDER CAUSED BY THE ONCOGENIC BCR-ABL FUSION PROTEIN IN MORE THAN 90% OF PATIENTS. DESPITE THE STRIKING IMPROVEMENTS IN THE MANAGEMENT OF CML PATIENTS SINCE THE INTRODUCTION OF TYROSINE KINASE INHIBITORS (TKIS), THE APPEARANCE OF TKI RESISTANCE AND SIDE EFFECTS LEAD TO TREATMENT FAILURE, JUSTIFYING THE NEED OF NOVEL THERAPEUTIC APPROACHES. HISTONE DEACETYLASE INHIBITORS (HDACIS), ABLE TO MODULATE GENE EXPRESSION PATTERNS AND IMPORTANT CELLULAR SIGNALING PATHWAYS THROUGH THE REGULATION OF THE ACETYLATION STATUS OF BOTH HISTONE AND NON-HISTONE PROTEIN TARGETS, HAVE BEEN REPORTED TO DISPLAY PROMISING ANTI-LEUKEMIC PROPERTIES ALONE OR IN COMBINATION WITH TKIS. THIS REVIEW SUMMARIZES PRE-CLINICAL AND CLINICAL STUDIES THAT INVESTIGATED THE MECHANISMS UNDERLYING THE ANTICANCER POTENTIAL OF HDACIS AND DISCUSSES THE RATIONALE FOR A COMBINATION OF HDACIS WITH TKIS AS A THERAPEUTIC OPTION IN CML.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
8 1465  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9 3362  37 HISTONE LYSINE DEMETHYLASE KDM5B MAINTAINS CHRONIC MYELOID LEUKEMIA VIA MULTIPLE EPIGENETIC ACTIONS. THE HISTONE LYSINE DEMETHYLASE KDM5 FAMILY IS IMPLICATED IN NORMAL DEVELOPMENT AND STEM CELL MAINTENANCE BY EPIGENETIC MODULATION OF HISTONE METHYLATION STATUS. DEREGULATION OF THE KDM5 FAMILY HAS BEEN REPORTED IN VARIOUS TYPES OF CANCERS, INCLUDING HEMATOLOGICAL MALIGNANCIES. HOWEVER, THEIR TRANSCRIPTIONAL REGULATORY ROLES IN THE CONTEXT OF LEUKEMIA REMAIN UNCLEAR. HERE, WE FIND THAT KDM5B IS STRONGLY EXPRESSED IN NORMAL CD34(+) HEMATOPOIETIC STEM/PROGENITOR CELLS AND CHRONIC MYELOID LEUKEMIA (CML) CELLS. KNOCKDOWN OF KDM5B IN K562 CML CELLS REDUCED LEUKEMIA COLONY-FORMING POTENTIAL. TRANSCRIPTOME PROFILING OF KDM5B KNOCKDOWN K562 CELLS REVEALED THE DEREGULATION OF GENES INVOLVED IN MYELOID DIFFERENTIATION AND TOLL-LIKE RECEPTOR SIGNALING. THROUGH THE INTEGRATION OF TRANSCRIPTOME AND CHIP-SEQ PROFILING DATA, WE SHOW THAT KDM5B IS ENRICHED AT THE BINDING SITES OF THE GATA AND AP-1 TRANSCRIPTION FACTOR FAMILIES, SUGGESTING THEIR COLLABORATIONS IN THE REGULATION OF TRANSCRIPTION. EVEN THOUGH THE BINDING OF KDM5B SUBSTANTIALLY OVERLAPPED WITH H3K4ME1 OR H3K4ME3 MARK AT GENE PROMOTERS, ONLY A SMALL SUBSET OF THE KDM5B TARGETS SHOWED DIFFERENTIAL EXPRESSION IN ASSOCIATION WITH THE HISTONE DEMETHYLATION ACTIVITY. BY CHARACTERIZING THE INTERACTING PROTEINS IN K562 CELLS, WE DISCOVERED THAT KDM5B RECRUITS PROTEIN COMPLEXES INVOLVED IN THE MRNA PROCESSING MACHINERY, IMPLYING AN ALTERNATIVE EPIGENETIC ACTION MEDIATED BY KDM5B IN GENE REGULATION. OUR STUDY HIGHLIGHTS THE ONCOGENIC FUNCTIONS OF KDM5B IN CML CELLS AND SUGGESTS THAT KDM5B IS VITAL TO THE TRANSCRIPTIONAL REGULATION VIA MULTIPLE EPIGENETIC MECHANISMS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  709  40 C-MYC ONCOPROTEIN DICTATES TRANSCRIPTIONAL PROFILES OF ATP-BINDING CASSETTE TRANSPORTER GENES IN CHRONIC MYELOGENOUS LEUKEMIA CD34+ HEMATOPOIETIC PROGENITOR CELLS. RESISTANCE TO CHEMOTHERAPEUTIC AGENTS REMAINS ONE OF THE MAJOR IMPEDIMENTS TO A SUCCESSFUL TREATMENT OF CHRONIC MYELOID LEUKEMIA (CML). MISREGULATION OF THE ACTIVITY OF A SPECIFIC GROUP OF ATP-BINDING CASSETTE TRANSPORTERS (ABC) IS RESPONSIBLE FOR REDUCING THE INTRACELLULAR CONCENTRATION OF DRUGS IN LEUKEMIC CELLS. MOREOVER, A CONSISTENT BODY OF EVIDENCE ALSO SUGGESTS THAT ABC TRANSPORTERS PLAY A ROLE IN CANCER PROGRESSION BEYOND THE EFFLUX OF CYTOTOXIC DRUGS. DESPITE A LARGE NUMBER OF STUDIES THAT INVESTIGATED THE FUNCTION OF THE ABC TRANSPORTERS, LITTLE IS KNOWN ABOUT THE TRANSCRIPTIONAL REGULATION OF THE ABC GENES. HERE, WE PRESENT DATA SHOWING THAT THE ONCOPROTEIN C-MYC IS A DIRECT TRANSCRIPTIONAL REGULATOR OF A LARGE SET OF ABC TRANSPORTERS IN CML. FURTHERMORE, MOLECULAR ANALYSIS CARRIED OUT IN CD34+ HEMATOPOIETIC CELL PRECURSORS OF 21 CML PATIENTS REVEALS THAT THE OVEREXPRESSION OF ABC TRANSPORTERS DRIVEN BY C-MYC IS A PECULIAR CHARACTERISTIC OF THE CD34+ POPULATION IN CML AND WAS NOT FOUND EITHER IN THE POPULATION OF MONONUCLEAR CELLS FROM WHICH THEY HAD BEEN PURIFIED NOR IN CD34+ CELLS ISOLATED FROM HEALTHY DONORS. FINALLY, WE DESCRIBE HOW THE METHYLATION STATE OF CPG ISLANDS MAY REGULATE THE ACCESS OF C-MYC TO ABCG2 GENE PROMOTER, A WELL-STUDIED GENE ASSOCIATED WITH MULTIDRUG RESISTANCE IN CML, HENCE, AFFECTING ITS EXPRESSION. TAKEN TOGETHER, OUR FINDINGS SUPPORT A MODEL IN WHICH C-MYC-DRIVEN TRANSCRIPTIONAL EVENTS, COMBINED WITH EPIGENETIC MECHANISMS, DIRECT AND REGULATE THE EXPRESSION OF ABC GENES WITH POSSIBLE IMPLICATIONS IN TUMOR MALIGNANCY AND DRUG EFFLUX IN CML.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11 6198  43 THE IMPLICATION OF CANCER PROGENITOR CELLS AND THE ROLE OF EPIGENETICS IN THE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES FOR CHRONIC MYELOID LEUKEMIA. SIGNIFICANCE: CHRONIC MYELOID LEUKEMIA (CML) INVOLVES THE MALIGNANT TRANSFORMATION OF HEMATOPOIETIC STEM CELLS, DEFINED LARGELY BY THE PHILADELPHIA CHROMOSOME AND EXPRESSION OF THE BREAKPOINT CLUSTER REGION-ABELSON (BCR-ABL) ONCOPROTEIN. PHARMACOLOGICAL TYROSINE KINASE INHIBITORS (TKIS), INCLUDING IMATINIB MESYLATE, HAVE OVERCOME LIMITATIONS IN CONVENTIONAL TREATMENT FOR THE IMPROVED CLINICAL MANAGEMENT OF CML. RECENT ADVANCES: ACCUMULATED EVIDENCE HAS LED TO THE IDENTIFICATION OF A SUBPOPULATION OF QUIESCENT LEUKEMIA PROGENITOR CELLS WITH STEM-LIKE SELF RENEWAL PROPERTIES THAT MAY INITIATE LEUKEMOGENESIS, WHICH ARE ALSO SHOWN TO BE PRESENT IN RESIDUAL DISEASE DUE TO THEIR INSENSITIVITY TO TYROSINE KINASE INHIBITION. CRITICAL ISSUES: THE CHARACTERIZATION OF QUIESCENT LEUKEMIA PROGENITOR CELLS AS A UNIQUE CELL POPULATION IN CML PATHOGENESIS HAS BECOME CRITICAL WITH THE COMPLETE ELUCIDATION OF MECHANISMS INVOLVED IN THEIR SURVIVAL INDEPENDENT OF BCR-ABL THAT IS IMPORTANT IN THE DEVELOPMENT OF NOVEL ANTICANCER STRATEGIES. UNDERSTANDING OF THESE FUNCTIONAL PATHWAYS IN CML PROGENITOR CELLS WILL ALLOW FOR THEIR SELECTIVE THERAPEUTIC TARGETING. IN ADDITION, DISEASE PATHOGENESIS AND DRUG RESPONSIVENESS IS ALSO THOUGHT TO BE MODULATED BY EPIGENETIC REGULATORY MECHANISMS SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION, WITH A CAPACITY TO CONTROL CML-ASSOCIATED GENE TRANSCRIPTION. FUTURE DIRECTIONS: A NUMBER OF COMPOUNDS IN COMBINATION WITH TKIS ARE UNDER PRECLINICAL AND CLINICAL INVESTIGATION TO ASSESS THEIR SYNERGISTIC POTENTIAL IN TARGETING LEUKEMIC PROGENITOR CELLS AND/OR THE EPIGENOME IN CML. DESPITE THE COLLECTIVE PROMISE, FURTHER RESEARCH IS REQUIRED IN ORDER TO REFINE UNDERSTANDING, AND, ULTIMATELY, ADVANCE ANTILEUKEMIC THERAPEUTIC STRATEGIES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
12  825  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13  149  35 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	

14 6773  25 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
15 2781  36 EZH2 IN MYELOID MALIGNANCIES. OUR UNDERSTANDING OF THE SIGNIFICANCE OF EPIGENETIC DYSREGULATION IN THE PATHOGENESIS OF MYELOID MALIGNANCIES HAS GREATLY ADVANCED IN THE PAST DECADE. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS THE CATALYTIC CORE COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), WHICH IS RESPONSIBLE FOR GENE SILENCING THROUGH TRIMETHYLATION OF H3K27. EZH2 DYSREGULATION IS HIGHLY TUMORIGENIC AND HAS BEEN OBSERVED IN VARIOUS CANCERS, WITH EZH2 ACTING AS AN ONCOGENE OR A TUMOR-SUPPRESSOR DEPENDING ON CELLULAR CONTEXT. WHILE LOSS-OF-FUNCTION MUTATIONS OF EZH2 FREQUENTLY AFFECT PATIENTS WITH MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS, MYELODYSPLASTIC SYNDROME AND MYELOFIBROSIS, CASES OF CHRONIC MYELOID LEUKEMIA (CML) SEEM TO BE LARGELY CHARACTERIZED BY EZH2 OVEREXPRESSION. A VARIETY OF OTHER FACTORS FREQUENTLY ABERRANT IN MYELOID LEUKEMIA CAN AFFECT PRC2 FUNCTION AND DISEASE PATHOGENESIS, INCLUDING ADDITIONAL SEX COMBS LIKE 1 (ASXL1) AND SPLICING GENE MUTATIONS. AS THE GENETIC BACKGROUND OF MYELOID MALIGNANCIES IS LARGELY HETEROGENEOUS, IT IS NOT SURPRISING THAT EZH2 MUTATIONS ACT IN CONJUNCTION WITH OTHER ABERRATIONS. SINCE EZH2 MUTATIONS ARE CONSIDERED TO BE EARLY EVENTS IN DISEASE PATHOGENESIS, THEY ARE OF THERAPEUTIC INTEREST TO RESEARCHERS, THOUGH TARGETING OF EZH2 LOSS-OF-FUNCTION DOES PRESENT UNIQUE CHALLENGES. PRELIMINARY RESEARCH INDICATES THAT COMBINED TYROSINE KINASE INHIBITOR (TKI) AND EZH2 INHIBITOR THERAPY MAY PROVIDE A STRATEGY TO ELIMINATE THE RESIDUAL DISEASE BURDEN IN CML TO ALLOW PATIENTS TO REMAIN IN TREATMENT-FREE REMISSION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16 1660  34 DOWN-REGULATION OF HEMATOPOIESIS MASTER REGULATOR PU.1 VIA ABERRANT METHYLATION IN CHRONIC MYELOID LEUKEMIA. THE PU.1 TRANSCRIPTION FACTOR IS A CRUCIAL REGULATOR OF HEMATOPOIESIS, AND ITS EXPRESSION IS ALTERED IN VARIOUS LEUKEMIC PROCESSES. IT HAS BEEN SHOWN THAT EXPRESSION OF PU.1 IS SEVERELY IMPAIRED IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML), BUT THE MECHANISM UNDERLYING THIS EFFECT REMAINS UNKNOWN. THROUGH BISULFITE SEQUENCING, SEMI-QUANTITATIVE PCR, AND INDIRECT IMMUNOFLUORESCENCE AND WESTERN BLOT TECHNIQUES, WE FOUND ABERRANT METHYLATION IN THE PROMOTER REGION OF TRANSCRIPTION FACTOR PU.1 IN CML PATIENTS BOTH IN THE CHRONIC AND BLAST CRISIS PHASES, AS WELL AS IN THE CML BLAST K562 CELL LINE. OF THESE, SEVERAL CPG SITES WERE MORE HIGHLY METHYLATED IN BLAST CRISIS THAN CHRONIC PHASE, WHILE NO METHYLATION OF THESE SITES WAS OBSERVED IN HEALTHY INDIVIDUALS. INTERESTINGLY, CML PATIENTS ACHIEVED COMPLETE CYTOGENETIC REMISSION UNDER IMATINIB MESYLATE TREATMENT, BUT THE ABERRANT METHYLATION STATUS OF PU.1 WAS NOT REVERSED. DOWN-REGULATION OF PU.1 EXPRESSION AT THE MRNA AND PROTEIN LEVELS WAS ALSO OBSERVED IN ASSOCIATION WITH ABERRANT METHYLATION. THUS, FOR THE FIRST TIME, WE HAVE REVEALED A POTENTIAL EPIGENETIC MODIFICATION OF PU.1 IN CML, WHICH MAY BE RESPONSIBLE FOR THE DOWN-REGULATION OF PU.1. THESE DATA SUGGEST THAT ABERRANT METHYLATION OF PU.1 MAY PLAY A ROLE IN CML PATHOGENESIS, AND MAY THEREFORE SERVE AS A USEFUL BIOMARKER AND POTENTIAL TARGET FOR DEMETHYLATING DRUGS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
17 2928  33 GENERATION OF IPSCS FROM CULTURED HUMAN MALIGNANT CELLS. INDUCED PLURIPOTENT STEM CELLS (IPSCS) CAN BE GENERATED FROM VARIOUS DIFFERENTIATED CELL TYPES BY THE EXPRESSION OF A SET OF DEFINED TRANSCRIPTION FACTORS. SO FAR, IPSCS HAVE BEEN GENERATED FROM PRIMARY CELLS, BUT IT IS UNCLEAR WHETHER HUMAN CANCER CELL LINES CAN BE REPROGRAMMED. HERE WE DESCRIBE THE GENERATION AND CHARACTERIZATION OF IPSCS DERIVED FROM HUMAN CHRONIC MYELOID LEUKEMIA CELLS. WE SHOW THAT, DESPITE THE PRESENCE OF ONCOGENIC MUTATIONS, THESE CELLS ACQUIRED PLURIPOTENCY BY THE EXPRESSION OF 4 TRANSCRIPTION FACTORS AND UNDERWENT DIFFERENTIATION INTO CELL TYPES DERIVED OF ALL 3 GERM LAYERS DURING TERATOMA FORMATION. INTERESTINGLY, ALTHOUGH THE PARENTAL CELL LINE WAS STRICTLY DEPENDENT ON CONTINUOUS SIGNALING OF THE BCR-ABL ONCOGENE, ALSO TERMED ONCOGENE ADDICTION, REPROGRAMMED CELLS LOST THIS DEPENDENCY AND BECAME RESISTANT TO THE BCR-ABL INHIBITOR IMATINIB. THIS FINDING INDICATES THAT THE THERAPEUTIC AGENT IMATINIB TARGETS CELLS IN A SPECIFIC EPIGENETIC DIFFERENTIATED CELL STATE, AND THIS MAY CONTRIBUTE TO ITS INABILITY TO FULLY ERADICATE DISEASE IN CHRONIC MYELOID LEUKEMIA PATIENTS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 1542  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19  851  27 CHIP-SEQ ANALYSIS OF HUMAN CHRONIC MYELOID LEUKEMIA CELLS. MANY TRANSCRIPTION FACTORS, CHROMATIN-ASSOCIATED PROTEINS AND REGULATORY DNA ELEMENTS ARE GENETICALLY AND/OR EPIGENETICALLY ALTERED IN CANCER, INCLUDING CHRONIC MYELOID LEUKEMIA (CML). THIS LEADS TO DEREGULATION OF TRANSCRIPTION THAT IS OFTEN CAUSALLY LINKED TO THE TUMORIGENIC STATE. CHROMATIN-IMMUNOPRECIPITATION COUPLED WITH MASSIVELY PARALLEL DNA SEQUENCING (CHIP-SEQ) IS THE KEY TECHNOLOGY TO STUDY TRANSCRIPTION AS IT ALLOWS IN VIVO WHOLE-GENOME MAPPING OF EPIGENETIC MODIFICATIONS AND INTERACTIONS OF PROTEINS WITH DNA OR CHROMATIN. HOWEVER, NUMEROUS DNA/CHROMATIN-BINDING PROTEINS, INCLUDING EZH2, REMAIN DIFFICULT TO "CHIP," THUS YIELDING GENOME-WIDE BINDING MAPS OF ONLY SUBOPTIMAL QUALITY. HERE, WE DESCRIBE A CHIP-SEQ PROTOCOL OPTIMIZED FOR HIGH-QUALITY PROTEIN-GENOME BINDING MAPS THAT HAVE PROVEN ESPECIALLY USEFUL FOR STUDYING DIFFICULT TO 'CHIP' TRANSCRIPTION REGULATORY FACTORS IN CHRONIC MYELOID LEUKEMIA (CML) AND RELATED MALIGNANCIES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  109  34 A REVIEW ON THE THERAPEUTIC ROLE OF TKIS IN CASE OF CML IN COMBINATION WITH EPIGENETIC DRUGS. CHRONIC MYELOID LEUKEMIA IS A MALIGNANCY OF BONE MARROW THAT AFFECTS WHITE BLOOD CELLS. THERE IS STRONG EVIDENCE THAT DISEASE PROGRESSION, TREATMENT RESPONSES, AND OVERALL CLINICAL OUTCOMES OF CML PATIENTS ARE INFLUENCED BY THE ACCUMULATION OF OTHER GENETIC AND EPIGENETIC ABNORMALITIES, RATHER THAN ONLY THE BCR/ABL1 ONCOPROTEIN. BOTH GENETIC AND EPIGENETIC FACTORS INFLUENCE THE EFFICACY OF CML TREATMENT STRATEGIES. TARGETED MEDICINES KNOWN AS TYROSINE-KINASE INHIBITORS HAVE DRAMATICALLY IMPROVED LONG-TERM SURVIVAL RATES IN CML PATIENTS DURING THE PREVIOUS 2 DECADES. WHEN COMPARED TO EARLIER CHEMOTHERAPY TREATMENTS, THESE DRUGS HAVE REVOLUTIONIZED CML TREATMENT AND ALLOWED MOST PEOPLE TO LIVE LONGER LIVES. ALTHOUGH EPIGENETIC INHIBITORS' ACTIVITY IS DISRUPTED IN MANY CANCERS, INCLUDING CML, BUT WHEN COMBINED WITH TKI, THEY MAY OFFER POTENTIAL THERAPEUTIC STRATEGIES FOR THE TREATMENT OF CML CELLS. THE EPIGENETICS OF TYROSINE KINASE INHIBITORS AND RESISTANCE TO THEM IS BEING STUDIED, WITH A PARTICULAR FOCUS ON IMATINIB, WHICH IS USED TO TREAT CML. IN ADDITION, THE USE OF EPIGENETIC DRUGS IN CONJUNCTION WITH TKIS HAS BEEN DISCUSSED. RESISTANCE TO TKIS IS STILL A PROBLEM IN CURING THE DISEASE, NECESSITATING THE DEVELOPMENT OF NEW THERAPIES. THIS STUDY FOCUSED ON EPIGENETIC PATHWAYS INVOLVED IN CML PATHOGENESIS AND TUMOR CELL RESISTANCE TO TKIS, BOTH OF WHICH CONTRIBUTE TO LEUKEMIC CLONE BREAKOUT AND PROLIFERATION.	2021