1 1616 110 DNA METHYLTRANSFERASE AND HISTONE DEACETYLASE INHIBITORS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROMES. THE RECENTLY APPROVED DRUGS 5-AZACITIDINE (5AC) AND 5-AZA-2'-DEOXYAZACYTIDINE (DAC) ARE IN WIDE CLINICAL USE FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME (MDS) OF ALL TYPES AND CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). THESE AGENTS WERE DEVELOPED BASED UPON AN UNDERSTANDING OF THE IMPORTANCE OF EPIGENETIC CHANGES IN MALIGNANCY, AND THEY HAVE BEEN EVALUATED IN RANDOMIZED CLINICAL TRIALS, WHICH DEMONSTRATE RESPONSE RATES BETWEEN 20% AND 40% IN PATIENTS FOR WHOM NO PREVIOUS STANDARD OF CARE WAS AVAILABLE. AS UNDERSTANDING OF THE EPIGENETIC CHANGES CHARACTERISTIC OF THE MALIGNANT PHENOTYPE IMPROVES, WE ARE ABLE TO TARGET OTHER REGULATORS OF CHROMATIN CONFORMATION THAT CONTRIBUTE TO ABERRANT GENE TRANSCRIPTION AND DYSREGULATED CELL GROWTH. THE HISTONE DEACETYLASE (HDAC) INHIBITORS BELONG TO ONE CLASS OF THERAPEUTICS DEVELOPED USING THIS PARADIGM. ALTHOUGH RESPONSES USING HDAC INHIBITORS ALONE IN MDS HAVE BEEN MODEST, ROBUST PRECLINICAL DATA DRIVE CLINICAL TRIALS IN WHICH THEY ARE UTILIZED IN COMBINATION WITH DNA METHYLTRANSFERASE (DNMT) INHIBITORS. COMBINATION THERAPY OFFERS THE POSSIBILITY OF HEMATOLOGIC IMPROVEMENT AND REMISSION TO MYELODYSPLASTIC PATIENTS WITH PREVIOUSLY UNTREATABLE DISEASE.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2 5499  42 REVIEW: RECENT CLINICAL TRIALS IN EPIGENETIC THERAPY. EPIGENETIC FACTORS SUCH AS DNA METHYLATION AND HISTONE DEACETYLATION ARE KNOWN TO CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF CELLS BY SILENCING CRITICAL GENES. DRUGS THAT INHIBIT DNA METHYLTRANSFERASES OR HISTONE DEACETYLASES WERE SHOWN TO HAVE THE POTENTIAL TO REACTIVATE SILENCED GENES AND INDUCE DIFFERENTIATION OR APOPTOSIS OF MALIGNANT CELLS. THE MOST INTENSIVELY STUDIED CLASS OF SUCH AGENTS IS DNA METHYLTRANSFERASE INHIBITORS, INCLUDING 5-AZACYTIDINE (AZACITIDINE) AND 5-AZA-2'-DEOXYCYTIDINE (DECITABINE). IN 2004, AZACITIDINE WAS APPROVED FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME ON THE BASIS OF PHASE II AND III STUDIES THAT SHOWED A RESPONSE RATE (COMPLETE AND PARTIAL RESPONSES) OF 15%. AZACITIDINE IS ALSO BEING EVALUATED IN CLINICAL TRIALS FOR OTHER MALIGNANT DISEASES. DECITABINE HAS RESPONSE RATES OF 17-49% IN MYELODYSPLASTIC SYNDROME IN MULTIPLE PHASE II AND III STUDIES AND ALSO ACTIVITY IN ACUTE AND CHRONIC MYELOGENOUS LEUKEMIA. HISTONE DEACETYLASE INHIBITORS BELONG TO ANOTHER CLASS OF EPIGENETIC MODIFYING AGENTS THAT INCLUDE DEPSIPEPTIDE, BUTYRATE DERIVATIVES, SUBEROYLANILIDE HYDROXAMIC ACID AND VALPROIC ACID. NO AGENT IN THIS CLASS HAS BEEN STUDIED IN A PHASE III TRIAL, BUT SEVERAL AGENTS HAVE BEEN OR ARE BEING STUDIED IN PHASE II TRIALS. FURTHER RESEARCH IS NEEDED TO DETERMINE THE APPROPRIATE PATIENT SELECTION AND DOSING SCHEDULES.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3 1046  39 CLINICAL DEVELOPMENT OF DECITABINE AS A PROTOTYPE FOR AN EPIGENETIC DRUG PROGRAM. THIS REVIEW HIGHLIGHTS DECITABINE AS A PROTOTYPE EPIGENETIC MODIFYING DRUG TO SHOW HOW THE CLINICAL DEVELOPMENT OF EPIGENETIC AGENTS DIFFERS FROM THAT OF TRADITIONAL CYTOTOXIC CHEMOTHERAPIES. DECITABINE, A CYTOSINE ANALOGUE, IS CYTOTOXIC AT HIGH DOSES BUT HAS SELECTIVE DNA DEMETHYLATING ACTIVITY AT LOW DOSES. THE FOCUS OF CURRENT DECITABINE INVESTIGATIONS IS TWOFOLD: TO ELUCIDATE ALL OF THE MECHANISMS OF ACTION AND TO DETERMINE THE OPTIMAL DOSE, SCHEDULE, AND CONCOMITANT THERAPIES. NEW PHASE I TRIALS HAVE IDENTIFIED A "BIOLOGICALLY EFFECTIVE DOSE," WHICH IS 1 TO 2 LOGS LOWER THAN THE CYTOTOXIC DOSE. A CLINICAL DEVELOPMENT PROGRAM WITH LOW-DOSE DECITABINE IN MALIGNANT DISEASES IS FOCUSED ON MYELODYSPLASTIC SYNDROME (MDS), ACUTE MYELOGENOUS LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). A PHASE III TRIAL IN MDS SHOWED OBJECTIVE RESPONSES (COMPLETE [CR] PLUS PARTIAL [PR] REMISSION) AND LONGER MEDIAN TIME TO PROGRESSION TO AML OR DEATH WITH DECITABINE THAN WITH SUPPORTIVE CARE ALONE. THE OPTIMAL USE OF DECITABINE MAY BE IN COMBINATION WITH OTHER AGENTS THAT PROMOTE GENE EXPRESSION, NAMELY, HISTONE DEACETYLASE (HDAC) INHIBITORS. OPTIMIZED DECITABINE DOSES AND COMBINATIONS WITH OTHER EPIGENETIC THERAPIES THAT CAN BE USED AT MINIMALLY TOXIC DOSES PROVIDE POTENTIALLY SAFER THERAPEUTIC OPTIONS AND INTRODUCE NOVEL COMBINATION THERAPIES.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4 2494  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5 2237  42 EPIGENETIC MODIFIERS IN MYELOID MALIGNANCIES: THE ROLE OF HISTONE DEACETYLASE INHIBITORS. MYELOID HEMATOLOGICAL MALIGNANCIES ARE CLONAL BONE MARROW NEOPLASMS, COMPRISING OF ACUTE MYELOID LEUKEMIA (AML), THE MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), THE MYELOPROLIFERATIVE NEOPLASMS (MPN) AND SYSTEMIC MASTOCYTOSIS (SM). THE FIELD OF EPIGENETIC REGULATION OF NORMAL AND MALIGNANT HEMATOPOIESIS IS RAPIDLY GROWING. IN RECENT YEARS, HETEROZYGOUS SOMATIC MUTATIONS IN GENES ENCODING EPIGENETIC REGULATORS HAVE BEEN FOUND IN ALL SUBTYPES OF MYELOID MALIGNANCIES, SUPPORTING THE RATIONALE FOR TREATMENT WITH EPIGENETIC MODIFIERS. HISTONE DEACETYLASE INHIBITORS (HDACI) ARE EPIGENETIC MODIFIERS THAT, IN VITRO, HAVE BEEN SHOWN TO INDUCE GROWTH ARREST, APOPTOTIC OR AUTOPHAGIC CELL DEATH, AND TERMINAL DIFFERENTIATION OF MYELOID TUMOR CELLS. THESE EFFECTS WERE OBSERVED BOTH AT THE BULK TUMOR LEVEL AND IN THE MOST IMMATURE CD34(+)38(-) CELL COMPARTMENTS CONTAINING THE LEUKEMIC STEM CELLS. THUS, THERE IS A STRONG RATIONALE SUPPORTING HDACI THERAPY IN MYELOID MALIGNANCIES. HOWEVER, DESPITE INITIAL PROMISING RESULTS IN PHASE I TRIALS, HDACI IN MONOTHERAPY AS WELL AS IN COMBINATION WITH OTHER DRUGS, HAVE FAILED TO IMPROVE RESPONSES OR SURVIVAL. THIS REVIEW PROVIDES AN OVERVIEW OF THE RATIONALE FOR HDACI IN MYELOID MALIGNANCIES, CLINICAL RESULTS AND SPECULATIONS ON WHY CLINICAL TRIALS HAVE THUS FAR NOT MET THE EXPECTATIONS, AND HOW THIS MAY BE IMPROVED IN THE FUTURE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6 6773  31 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7 4487  34 MOLECULARLY TARGETED DRUG COMBINATIONS DEMONSTRATE SELECTIVE EFFECTIVENESS FOR MYELOID- AND LYMPHOID-DERIVED HEMATOLOGIC MALIGNANCIES. TRANSLATING THE GENETIC AND EPIGENETIC HETEROGENEITY UNDERLYING HUMAN CANCERS INTO THERAPEUTIC STRATEGIES IS AN ONGOING CHALLENGE. LARGE-SCALE SEQUENCING EFFORTS HAVE UNCOVERED A SPECTRUM OF MUTATIONS IN MANY HEMATOLOGIC MALIGNANCIES, INCLUDING ACUTE MYELOID LEUKEMIA (AML), SUGGESTING THAT COMBINATIONS OF AGENTS WILL BE REQUIRED TO TREAT THESE DISEASES EFFECTIVELY. COMBINATORIAL APPROACHES WILL ALSO BE CRITICAL FOR COMBATING THE EMERGENCE OF GENETICALLY HETEROGENEOUS SUBCLONES, RESCUE SIGNALS IN THE MICROENVIRONMENT, AND TUMOR-INTRINSIC FEEDBACK PATHWAYS THAT ALL CONTRIBUTE TO DISEASE RELAPSE. TO IDENTIFY NOVEL AND EFFECTIVE DRUG COMBINATIONS, WE PERFORMED EX VIVO SENSITIVITY PROFILING OF 122 PRIMARY PATIENT SAMPLES FROM A VARIETY OF HEMATOLOGIC MALIGNANCIES AGAINST A PANEL OF 48 DRUG COMBINATIONS. THE COMBINATIONS WERE DESIGNED AS DRUG PAIRS THAT TARGET NONOVERLAPPING BIOLOGICAL PATHWAYS AND COMPRISE DRUGS FROM DIFFERENT CLASSES, PREFERABLY WITH FOOD AND DRUG ADMINISTRATION APPROVAL. A COMBINATION RATIO (CR) WAS DERIVED FOR EACH DRUG PAIR, AND CRS WERE EVALUATED WITH RESPECT TO DIAGNOSTIC CATEGORIES AS WELL AS AGAINST GENETIC, CYTOGENETIC, AND CELLULAR PHENOTYPES OF SPECIMENS FROM THE TWO LARGEST DISEASE CATEGORIES: AML AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). NEARLY ALL TESTED COMBINATIONS INVOLVING A BCL2 INHIBITOR SHOWED ADDITIONAL BENEFIT IN PATIENTS WITH MYELOID MALIGNANCIES, WHEREAS SELECT COMBINATIONS INVOLVING PI3K, CSF1R, OR BROMODOMAIN INHIBITORS SHOWED PREFERENTIAL BENEFIT IN LYMPHOID MALIGNANCIES. EXPANDED ANALYSES OF PATIENTS WITH AML AND CLL REVEALED SPECIFIC PATTERNS OF EX VIVO DRUG COMBINATION EFFICACY THAT WERE ASSOCIATED WITH SELECT GENETIC, CYTOGENETIC, AND PHENOTYPIC DISEASE SUBSETS, WARRANTING FURTHER EVALUATION. THESE FINDINGS HIGHLIGHT THE HEURISTIC VALUE OF AN INTEGRATED FUNCTIONAL GENOMIC APPROACH TO THE IDENTIFICATION OF NOVEL TREATMENT STRATEGIES FOR HEMATOLOGIC MALIGNANCIES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  160  30 ABERRANT PROMOTER HYPOMETHYLATION IN CLL: DOES IT MATTER FOR DISEASE DEVELOPMENT? OVER THE LAST 30 YEARS, STUDIES OF ABERRANT DNA METHYLATION IN HEMATOLOGIC MALIGNANCIES HAVE BEEN DOMINATED BY THE PRIMARY FOCUS OF UNDERSTANDING PROMOTER HYPERMETHYLATION. THESE EFFORTS NOT ONLY RESULTED IN A BETTER UNDERSTANDING OF THE BASIS OF EPIGENETIC SILENCING OF TUMOR SUPPRESSOR GENES BUT ALSO RESULTED IN APPROVAL OF HYPOMETHYLATING AGENTS FOR THE TREATMENT OF SEVERAL MALIGNANCIES, SUCH AS MYELODYSPLASTIC SYNDROME AND ACUTE MYELOID LEUKEMIA. RECENT ADVANCES IN GLOBAL METHYLATION PROFILING COUPLED WITH THE USE OF MOUSE MODELS SUGGEST THAT ABERRANT PROMOTER HYPOMETHYLATION IS ALSO A FREQUENT EVENT IN HEMATOLOGIC MALIGNANCIES, PARTICULARLY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). PROMOTER HYPOMETHYLATION AFFECTS GENE EXPRESSION AND, THEREFORE, MAY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. HERE, WE REVIEW RECENT FINDINGS AND DISCUSS THE POTENTIAL INVOLVEMENT OF ABERRANT PROMOTER HYPOMETHYLATION IN CLL.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9 1542  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10 1288  33 DECITABINE. PURPOSE OF REVIEW: DECITABINE IS A CYTOSINE ANALOGUE SYNTHESIZED IN THE 1960S THAT IS CURRENTLY ENJOYING A REVIVAL OF INTEREST PROMPTED BY THE ELUCIDATION OF DNA METHYLATION INHIBITION AS ITS MAJOR MECHANISM OF ACTION, ALONG WITH INCREASED UNDERSTANDING OF THE ROLE OF DNA METHYLATION IN EPIGENETIC DYSREGULATION IN CANCER. THESE ADVANCES HAVE TURNED THIS AGENT FROM JUST ANOTHER CYTOSINE ANALOGUE INTO A TARGETED DRUG AIMED AT REVERSING EPIGENETIC SILENCING IN CANCER CELLS. HERE, RECENT CLINICAL AND TRANSLATIONAL STUDIES WITH DECITABINE ARE REVIEWED. RECENT FINDINGS: SCIENTISTS ARE NOW TAKING A CLOSER LOOK AT THIS DRUG AS A TARGETED AGENT, WITH PARTICULAR ATTENTION TO SCHEDULES OF ADMINISTRATION AND MECHANISMS OF IN VIVO EFFICACY. TWO PHASE II TRIALS HAVE REPORTED SUBSTANTIAL CLINICAL ACTIVITY OF DECITABINE IN THE MYELODYSPLASTIC SYNDROME AND IN CHRONIC MYELOGENOUS LEUKEMIA. THERE IS CONSIDERABLE INTEREST IN COMBINING DECITABINE WITH HISTONE DEACETYLASE INHIBITORS AND IN USING IT TO SENSITIZE CELLS TO CHEMOTHERAPY OR TO BIOLOGIC THERAPY. FINALLY, ONGOING EFFORTS ARE DECIPHERING THE IN VIVO MECHANISMS OF RESPONSES SEEN AFTER DECITABINE ADMINISTRATION. SUMMARY: DECITABINE, AN OLD DRUG, HAS NOW MADE A COMEBACK AS A TARGETED AGENT AND A PROTOTYPE FOR EPIGENETIC THERAPY IN CANCER. DOSES, SCHEDULES OF ADMINISTRATION, AND THE DEVELOPMENT OF RATIONAL COMBINATIONS INCLUDING THIS AGENT MUST ALL TAKE THIS CRITICAL MECHANISM OF ACTION INTO ACCOUNT.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
11  358  43 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12 4660  41 NEW APPROACHES TO THE TREATMENT OF MYELODYSPLASIA. THE THERAPEUTIC DILEMMA THAT CONFRONTS THE MANAGEMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) IS ILLUSTRATED BY THE ABSENCE OF A FOOD AND DRUG ADMINISTRATION-APPROVED AGENT WITH AN INDICATION FOR THIS DISEASE. CLINICAL HETEROGENEITY AND INADEQUATE UNDERSTANDING OF THE DISEASE PATHOBIOLOGY HAVE LIMITED PROGRESS IN THE DEVELOPMENT OF NOVEL THERAPEUTICS. PRECLINICAL INVESTIGATIONS INDICATE THAT RECIPROCAL INTERACTION BETWEEN THE MALIGNANT CLONE AND THE MICROENVIRONMENT SERVE TO CREATE A HOSTILE MILIEU THAT REINFORCES INEFFECTIVE BLOOD CELL PRODUCTION. INEFFECTIVE HEMATOPOIESIS, THE HALLMARK OF MDS, ARISES FROM IMPAIRED PROGENITOR RESPONSIVENESS TO NORMAL TROPHIC SIGNALS AND EXCESS LOCAL GENERATION OF INHIBITORY CYTOKINES, WHICH PROMOTE ACCELERATED APOPTOTIC LOSS OF PROGENITORS AND THEIR PROGENY. EVIDENCE TO SUPPORT THIS MODEL DERIVES FROM CYTOKINE NEUTRALIZATION STUDIES AND THE DIRECT RELATIONSHIP BETWEEN PLASMA TUMOR NECROSIS FACTOR-ALPHA CONCENTRATION AND DNA OXIDATION AND GLUTATHIONE DEPLETION IN MALIGNANT CD34+ PROGENITORS. RECENT INVESTIGATIONS INDICATE THAT ANGIOGENIC MOLECULES GENERATED BY MALIGNANT MYELOMONOCYTIC PRECURSORS REPRESENT INTEGRAL DIFFUSABLE SIGNALS THAT REINFORCE LEUKEMIA PROGENITOR SELF-RENEWAL WHILE PROMOTING THE GENERATION OF PROAPOPTOTIC CYTOKINES AND MEDULLARY ANGIOGENIC RESPONSE. THE POTENTIAL FOR LEUKEMIA EVOLUTION IS COMPOUNDED BY EPIGENETIC EVENTS INCLUDING METHYLATION SILENCING OF THE P15 PROTO-ONCOGENE OR ACTIVATING RAS POINT MUTATIONS. DELINEATION OF SUCH BIOLOGIC FEATURES THAT ARE CENTRAL TO THE PATHOBIOLOGY OF MDS PROVIDES A RELIABLE FRAMEWORK FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. ANTIANGIOGENIC AGENTS IN CLINICAL TESTING INCLUDE VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) RECEPTOR TYROSINE KINASE INHIBITORS, THALIDOMIDE AND RELATED ANALOGUES, AND THE RECOMBINANT VEGF NEUTRALIZING ANTIBODY, BEVACIZUMAB. AGENTS WHOSE ACTIONS MAY RESTORE DIFFERENTIATION PROGRAMS, SUCH AS THE DNA METHYLTRANSFERASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS, OFFER THE PROSPECT TO PROMOTE EFFECTIVE HEMATOPOIESIS WHILE IMPACTING THE POTENTIAL FOR LEUKEMIA EVOLUTION. RAS FARNESYL TRANSFERASE INHIBITORS HAVE SHOWN ENCOURAGING PRELIMINARY RESULTS IN ACUTE MYELOID LEUKEMIA AND ARE CURRENTLY UNDER INVESTIGATION IN ADVANCED MDS AND CHRONIC MYELOMONOCYTIC LEUKEMIA. ARSENIC TRIOXIDE (ATO) INTERACTS WITH A SPECTRUM OF BIOLOGIC TARGETS THAT MAY BE UNIQUELY SUITED TO MDS. ATO IS A POTENT INDUCER OF APOPTOSIS IN THIOL-DEPLETED MALIGNANT PROGENITORS AND NEOVASCULAR ENDOTHELIUM, WHILE PROMOTING DIFFERENTIATION THROUGH HISTONE ACETYLATION AND INACTIVATION OF TRANSCRIPTIONAL COREPRESSORS. THE IDENTIFICATION OF RELEVANT BIOLOGIC TARGETS IN MDS HAS RAISED EXPECTATIONS FOR THE DEVELOPMENT OF DISEASE-SPECIFIC THERAPIES FOR MDS IN THE YEARS THAT FOLLOW.	2002	

13 1882  24 EMERGING TREATMENTS IN ACUTE MYELOID LEUKAEMIA. ACUTE MYELOID LEUKAEMIA (AML) IS THE MOST COMMON FORM OF LEUKAEMIA IN YOUNG ADULTS. ALTHOUGH 75-85% OF PATIENTS WILL ACHIEVE COMPLETE REMISSION AFTER INDUCTION CHEMOTHERAPY, THE LONG-TERM SURVIVAL IS STILL < 50% AT 5 YEARS. CHEMOTHERAPY HAS INCREASED IN INTENSITY IN RECENT YEARS AND IS PERCEIVED TO HAVE REACHED THE LIMIT OF TOXICITY. ALLOGENEIC BONE MARROW TRANSPLANTATION, WHICH IS UNDOUBTEDLY THE MOST EFFECTIVE WAY TO PREVENT RELAPSE, MAY NOT ADD SUBSTANTIAL SURVIVAL BENEFITS. SEVERAL NEW PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF AML ARE NOW BECOMING AVAILABLE, WITH VARIOUS MOLECULAR TARGETS IDENTIFIED, INCLUDING THE FARNESYLATION OF RAS FAMILY PROTEINS AND TYROSINE KINASES INVOLVED IN SIGNAL TRANSDUCTION AND EPIGENETIC METHYLATION. MORE SELECTIVE DELIVERY OF CHEMOTHERAPEUTIC AGENTS IS ALSO FEASIBLE USING HUMANISED MONOCLONAL ANTIBODIES, WITH THE INTRIGUING POSSIBILITY OF INCREASING TREATMENT DELIVERY WITHOUT INCREASING THE TOXICITY. HOWEVER, DESPITE THE PROGRESS IN THE RATIONAL DESIGN OF DRUGS IN DISORDERS SUCH AS CHRONIC MYELOID LEUKAEMIA, AML LACKS A SINGLE SPECIFIC PATHOGNOMIC GENETIC EVENT TO ACT AS A DRUG TARGET. THIS REVIEW DISCUSSES THE DRUGS PRESENTLY UNDER INVESTIGATION IN PHASE II OR PHASE III TRIALS IN AML.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
14  606  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15 1242  38 CURRENT AND NOVEL THERAPEUTIC APPROACHES IN MYELODYSPLASTIC SYNDROMES. MYELODYSPLASTIC SYNDROMES (MDS) ARE A HETEROGENEOUS GROUP OF HEMATOLOGIC NEOPLASMS WITH AN ANNUAL INCIDENCE OF 4.1 CASES PER 100,000 AMERICANS. PATIENTS WITH MDS SUFFER FROM CHRONIC CYTOPENIAS THAT MAY LEAD TO RECURRENT TRANSFUSIONS, INFECTIONS, AND INCREASED RISK FOR BLEEDING. THEY ARE ALSO AT RISK FOR PROGRESSION TO ACUTE MYELOID LEUKEMIA. ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IS THE ONLY POTENTIALLY CURATIVE TREATMENT FOR MDS, ALTHOUGH 3 DRUGS HAVE BEEN APPROVED BY THE US FOOD AND DRUG ADMINISTRATION FOR ITS TREATMENT: LENALIDOMIDE, 5-AZACITIDINE, AND DECITABINE. THESE THERAPIES CAN BE EFFECTIVE IN THE RELIEF OF CYTOPENIAS, ACHIEVEMENT OF CYTOGENETIC REMISSIONS, AND REDUCTION IN BONE MARROW BLASTS. 5-AZACITIDINE HAS ALSO BEEN SHOWN TO IMPROVE OVERALL SURVIVAL. HOWEVER, THERE REMAIN MANY UNMET NEEDS IN THE TREATMENT OF MDS. BREAKTHROUGHS IN OUR UNDERSTANDING OF THE COMPLEX PATHOGENESIS OF MDS THROUGH EPIGENETIC, GENETIC, IMMUNOLOGIC, AND OTHER BIOLOGICAL MECHANISMS HAVE ALLOWED US TO DEVELOP NEW THERAPEUTIC STRATEGIES THAT CAN LEAD TO IMPROVEMENTS IN OUTCOMES IN MDS. IN THIS REVIEW, WE AIM TO PROVIDE AN OVERVIEW OF THE EVOLUTION IN CLASSIFCATION AND RISK STRATIFCATION IN MDS AND TO ILLUSTRATE HOW WE CAN USE THIS TO GUIDE US IN TAILORING THERAPEUTIC CHOICES IN THIS DISEASE. RESPONSES AND OUTCOMES RELATED TO COM MONLY USED MDS THERAPIES WILL BE DISCUSSED TOGETHER WITH NOVEL THERAPIES THAT HAVE EVOLVED WITH THE IMPROVED UNDERSTANDING OF MDS PATHOPHYSIOLOGY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16 2652  28 EPIGENOMICS OF LEUKEMIA: FROM MECHANISMS TO THERAPEUTIC APPLICATIONS. LEUKEMOGENESIS IS A MULTISTEP PROCESS IN WHICH SUCCESSIVE TRANSFORMATIONAL EVENTS ENHANCE THE ABILITY OF A CLONAL POPULATION ARISING FROM HEMATOPOIETIC PROGENITOR CELLS TO PROLIFERATE, DIFFERENTIATE AND SURVIVE. CLINICALLY AND PATHOLOGICALLY, LEUKEMIA IS SUBDIVIDED INTO FOUR MAIN CATEGORIES: CHRONIC LYMPHOCYTIC LEUKEMIA, CHRONIC MYELOID LEUKEMIA, ACUTE LYMPHOCYTIC LEUKEMIA AND ACUTE MYELOID LEUKEMIA. LEUKEMIA HAS BEEN PREVIOUSLY CONSIDERED ONLY AS A GENETIC DISEASE. HOWEVER, IN RECENT YEARS, SIGNIFICANT ADVANCES HAVE BEEN MADE IN THE ELUCIDATION OF THE LEUKEMOGENESIS-ASSOCIATED PROCESSES. THUS, WE HAVE COME TO UNDERSTAND THAT EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNA ARE INVOLVED IN THE PERMANENT CHANGES OF GENE EXPRESSION CONTROLLING THE LEUKEMIA PHENOTYPE. IN THIS ARTICLE, WE WILL FOCUS ON THE EPIGENETIC DEFECTS ASSOCIATED WITH LEUKEMIA AND THEIR IMPLICATIONS AS BIOMARKERS FOR DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC APPLICATIONS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17 3565  34 IMPACT OF GENETIC POLYMORPHISMS AND BIOMARKERS ON THE EFFECTIVENESS AND TOXICITY OF TREATMENT OF CHRONIC MYELOID LEUKEMIA AND ACUTE MYELOID LEUKEMIA. MOST MALIGNANT HEMATOLOGICAL DISEASES ARE GENERALLY A CONSEQUENCE OF ACQUIRED MUTATIONS OR REARRANGEMENTS IN CELL REPLICATION PROCESSES. ACUTE MYELOID LEUKEMIA (AML) IS A CLINICALLY AND MOLECULARLY HETEROGENEOUS DISEASE THAT RESULTS FROM ACQUIRED GENETIC AND EPIGENETIC ALTERATIONS IN HEMATOPOIETIC PROGENITOR CELLS. DESPITE THE ADVANCES MADE IN UNDERSTANDING THE PATHOGENESIS OF THIS DISEASE, THE OVERALL SURVIVAL OF PATIENTS REMAINS VERY LOW DUE TO THE HIGH RELAPSE RATE. PHARMACOGENETICS AND MASSIVE SEQUENCING STUDIES HAVE ALLOWED THE IDENTIFICATION OF NEW RECURRENT MUTATIONS WITH SIGNIFICANT PROGNOSTIC IMPACT IN AML; FURTHERMORE, IT SEEMS LIKELY THAT WHOLE GENOME SEQUENCING WILL SOON BECOME A STANDARD DIAGNOSTIC TEST, WHICH WILL ALLOW THE MOLECULAR DIAGNOSIS OF PATIENTS. THEREFORE, IT IS NECESSARY TO DEVELOP MOLECULAR TARGETS THAT OPEN NEW THERAPEUTIC PERSPECTIVES AND ALLOW INDIVIDUALIZED TREATMENT OF PATIENTS WITH THIS AGGRESSIVE DISEASE. CHRONIC MYELOID LEUKEMIA (CML) IS THE FIRST NEOPLASTIC DISEASE FOR WHICH A CHARACTERISTIC GENETIC ALTERATION WAS DESCRIBED. IT HAS, BY DEFINITION, A GENETIC MARKER, THE BCR::ABL1 REARRANGEMENT, AS A CONSEQUENCE OF THE T9;22(Q34;Q11) TRANSLOCATION. ITS STUDY IS ESSENTIAL FOR THE DIAGNOSIS OF THIS ENTITY AND ALSO FOR MONITORING THE RESPONSE TO TREATMENT. DRUGS KNOWN AS TYROSINE KINASE INHIBITORS (TKIS) THAT TARGET THE BCR::ABL1 PROTEIN (ORAL TARGETED THERAPY) ARE THE CONVENTIONAL TREATMENT OF CML, REPRESENTING A CHANGE OF PARADIGM IN THE MANAGEMENT OF ONCOHEMATOLOGICAL PATIENTS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18 4681  28 NEW OPTIONS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROME. MYELODYSPLASTIC SYNDROME (MDS) IS A HETEROGENEOUS GROUP OF PROGRESSIVE CHRONIC HEMATOPOIETIC DISORDERS, USUALLY PRESENTING AS REFRACTORY ANEMIA OR CYTOPENIA, WITH AN APPROXIMATELY 25% RISK OF PROGRESSION TOWARD ACUTE MYELOID LEUKAEIMA (AML), AND NO PROVEN CURATIVE TREATMENT. NOVEL BIOLOGICAL TREATMENT STRATEGIES TARGETING BOTH THE MALIGNANT BLOOD CELL AND ITS MICROENVIRONMENT CAN OVERCOME RESISTANCE TO CURRENT THERAPIES, AND REPRESENT A PROMISING TREATMENT PARADIGM FOR IMPROVING PATIENT OUTCOME. MANY OF THESE AGENTS HAVE MULTIPLE BIOLOGIC ACTIVITIES. THE OBJECTIVE OF THIS ARTICLE IS TO PRESENT A COMPARATIVE REVIEW OF CLASSIFICATION SYSTEMS IN MDS AND TO DISCUSS THE EVOLVING TRENDS IN THE TREATMENT OF MDS (IMMUNOSUPPRESIVE THERAPY, IMMUNOMODULATORY DRUGS, ARSENIC TRIOXIDE, PROTEASOME INHIBITORS, EPIGENETIC THERAPY).	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  109  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20 5687  28 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