1 1621 212 DNA METHYLTRANSFERASES AS TARGETS FOR CANCER THERAPY. METHYLATION OF DNA AT 5-POSITION OF CYTOSINE, CATALYZED BY DNA METHYLTRANSFERASES, IS THE PREDOMINANT EPIGENETIC MODIFICATION IN MAMMALS. ABERRATIONS IN METHYLATION PLAY A CAUSAL ROLE IN A VARIETY OF DISEASES, INCLUDING CANCER. RECENT STUDIES HAVE ESTABLISHED THAT LIKE MUTATION, METHYLATION-MEDIATED GENE SILENCING OFTEN LEADS TO TUMORIGENESIS. PARADOXICALLY, GENOME-WIDE DNA HYPOMETHYLATION MAY ALSO PLAY A CAUSAL ROLE IN CARCINOGENESIS BY INDUCING CHROMOSOMAL INSTABILITY AND SPURIOUS GENE EXPRESSION. SINCE METHYLATION DOES NOT ALTER DNA BASE SEQUENCE, MUCH ATTENTION HAS BEEN FOCUSED RECENTLY ON DEVELOPING SMALL MOLECULE INHIBITORS OF DNA METHYLTRANSFERASES THAT CAN POTENTIALLY BE USED AS ANTICANCER AGENTS. VIDAZA (5-AZACYTIDINE), MARKETED BY PHARMION (BOULDER, CO, USA), WAS THE FIRST DNA METHYLTRANSFERASE INHIBITOR APPROVED BY THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) FOR CHEMOTHERAPY AGAINST MYELODYSPLASTIC SYNDROME (MDS), A HETEROGENEOUS BONE MARROW DISORDER. RECENTLY MGI PHARMA INC. (BLOOMINGTON, MN, USA) GOT FDA APPROVAL TO MARKET DACOGEN (5-AZA-2'-DEOXYCYTIDINE, OR DECITABINE) FOR TREATING MDS PATIENTS. THESE DRUGS WERE USED EARLIER AGAINST CERTAIN ANEMIAS TO INDUCE EXPRESSION OF FETAL GLOBIN GENES. INTEREST IN CLINICAL TRIALS OF THESE DRUGS AS ANTICANCER AGENTS HAS BEEN RENEWED ONLY RECENTLY BECAUSE OF REVERSAL OF METHYLATION-MEDIATED SILENCING OF CRITICAL GENES IN CANCER. CLINICAL TRIALS HAVE SHOWN THAT BOTH DRUGS HAVE THERAPEUTIC POTENTIAL AGAINST LEUKEMIA SUCH AS MDS, ACUTE MYELOID LEUKEMIA, CHRONIC MYELOGENOUS LEUKEMIA AND CHRONIC MYELOMONOCYTIC LEUKEMIA. IN CONTRAST, THEIR EFFECTIVENESS WITH SOLID TUMORS APPEARS TO BE LESS PROMISING, WHICH CHALLENGES RESEARCHERS TO DEVELOP INHIBITORS WITH MORE EFFICACY AND LESS TOXICITY. THE MAJOR HINDRANCE OF THEIR USAGE AS ANTICANCER AGENTS IS THEIR INSTABILITY IN VIVO AS WELL AS THE TOXICITY SECONDARY TO THEIR EXCESSIVE INCORPORATION INTO DNA, WHICH CAUSES CELL CYCLE ARREST. GENE EXPRESSION PROFILING IN CANCER CELLS REVEALED THAT ANTINEOPLASTIC PROPERTY OF THESE DRUGS IS MEDIATED THROUGH BOTH METHYLATION-DEPENDENT AND -INDEPENDENT PATHWAYS. RECENTLY, WE HAVE SHOWN THAT TREATMENT OF CANCER CELLS WITH THESE CYTIDINE ANALOGUES ALSO INDUCES PROTEASOMAL DEGRADATION OF DNA METHYLTRANSFERASE 1, THE UBIQUITOUSLY EXPRESSED ENZYME UPREGULATED IN ALMOST ALL CANCER CELLS. DEVELOPMENT OF RELATED STABLE DRUGS THAT CAN FACILITATE GENE ACTIVATION IN CANCER CELLS BY ENHANCING DEGRADATION OF DNA METHYLTRANSFERASES WITHOUT BEING INCORPORATED INTO DNA WOULD BE IDEAL FOR CHEMOTHERAPY. IN THIS MONOGRAPH WE REVIEW HISTORICAL PERSPECTIVE AND RECENT ADVANCES ON THE MOLECULAR MECHANISMS OF ACTION AND CLINICAL APPLICATIONS OF THESE DNA HYPOMETHYLATING AGENTS. 2007 2 1542 61 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 3 1288 55 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 4 6896 42 [TARGETED EPIGENETIC THERAPY OF CANCER. ACHIEVEMENTS AND PERSPECTIVES]. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL EPIGENETIC CHANGES OF NORMAL CELLS AND CANCER CELLS, AND EMPHASIZE THE ACHIEVEMENTS AND THE PERSPECTIVES OF CANCER EPIGENETIC THERAPY. CANCER EPIGENETIC ALTERATIONS CORRESPOND FOREMOST TO HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES PROMOTORS, GLOBAL DNA HYPOMETHYLATION, AND OVEREXPRESSION AND ACTIVITY OF HISTONE DEACETYLASES. THE PURPOSE OF EPIGENETIC THERAPY IS TO REVERT THE EPIGENETIC ALTERATIONS IN CANCER CELLS AND OBTAIN THE "NORMAL EPIGENOME" RESTORATION. EPIGENETIC TARGETS IN CANCER THERAPY HAVE FOCUSED ON HDACS AND DNMTS INHIBITION. THE AZACITIDINE AND THE DECITABINE, THE VORINOSTAT AND THE ROMIDEPSIN WERE APPROVED BY US-FDA FOR TREATMENT OF MYELODYSPLASTIC SYNDROME, AND CUTANEOUS T-CELL LYMPHOMA, RESPECTIVELY. EPIGENETIC AND EPIGENOMIC CHANGES IN SINGLE OR MULTIPLE GENES HAVE SHOWED POTENTIAL IMPACT IN CANCER AS EARLY DETECTION, PROGNOSIS AND PREDICTIVE MARKS. THE EPIGENETIC REVOLUTION HAS ARRIVED FOR BIOLOGY. THE SIGNIFICANT PROGRESS IN EPIGENETIC STUDIES HAVE ALLOWED US, TO UNDERSTAND NEW LOOKS IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF EMBRYONIC DEVELOPMENT, CANCER AND OTHER CHRONIC DISEASES. SPECIFIC MOLECULAR EPIGENETIC ALTERATIONS IN DIFFERENT CANCER TYPES, GIVE US NEW STRATEGIES TO DESIGN IMPROVED CANCER THERAPY. THE CHALLENGE FOR EPIGENETIC INVESTIGATORS IS DESIGN MORE SPECIFIC EPIDRUGS WITH LESSER SIDE EFFECTS. 2012 5 358 51 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 6 6773 37 [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 5499 55 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 8 2728 50 EXPLORING EPIGENETIC AND MICRORNA APPROACHES FOR GAMMA-GLOBIN GENE REGULATION. THERAPEUTIC INTERVENTIONS AIMED AT INDUCING FETAL HEMOGLOBIN AND REDUCING THE CONCENTRATION OF SICKLE HEMOGLOBIN IS AN EFFECTIVE APPROACH TO AMELIORATING ACUTE AND CHRONIC COMPLICATIONS OF SICKLE CELL DISEASE, EXEMPLIFIED BY THE LONG-TERM USE OF HYDROXYUREA. HOWEVER, THERE REMAINS AN UNMET NEED FOR THE DEVELOPMENT OF ADDITIONAL SAFE AND EFFECTIVE DRUGS FOR SINGLE AGENT OR COMBINATION THERAPY FOR INDIVIDUALS WITH BETA-HEMOGLOBINOPATHIES. REGULATION OF THE GAMMA-GLOBIN TO BETA-GLOBIN SWITCH IS ACHIEVED BY CHROMATIN REMODELING AT THE HBB LOCUS ON CHROMOSOME 11 AND INTERACTIONS OF MAJOR DNA BINDING PROTEINS, SUCH AS KLF1 AND BCL11A IN THE PROXIMAL PROMOTERS OF THE GLOBIN GENES. EXPERIMENTAL EVIDENCE ALSO SUPPORTS A ROLE OF EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION, HISTONE ACETYLATION/METHYLATION, AND MICRORNA EXPRESSION IN GAMMA-GLOBIN GENE SILENCING DURING DEVELOPMENT. IN THIS REVIEW, WE WILL CRITICALLY EVALUATE THE ROLE OF EPIGENETIC MECHANISMS IN GAMMA-GLOBIN GENE REGULATION AND DISCUSS DATA GENERATED IN TISSUE CULTURE, PRE-CLINICAL ANIMAL MODELS, AND CLINICAL TRIALS TO SUPPORT DRUG DEVELOPMENT TO DATE. THE QUESTION REMAINS WHETHER MODULATION OF EPIGENETIC PATHWAYS WILL PRODUCE SUFFICIENT EFFICACY AND SPECIFICITY FOR FETAL HEMOGLOBIN INDUCTION AND TO WHAT EXTENT TARGETING THESE PATHWAYS FORM THE BASIS OF PROSPECTS FOR CLINICAL THERAPY. 2021 9 160 47 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 10 2991 37 GENETIC INSTABILITY IN INHERITED AND SPORADIC LEUKEMIAS. GENETIC INSTABILITY DUE TO INCREASED DNA DAMAGE AND ALTERED DNA REPAIR IS OF CENTRAL SIGNIFICANCE IN THE INITIATION AND PROGRESSION OF INHERITED AND SPORADIC HUMAN LEUKEMIAS. ALTHOUGH VERY RARE, SOME INHERITED DNA REPAIR INSUFFICIENCY SYNDROMES (E.G., FANCONI ANEMIA, BLOOM'S SYNDROME) HAVE ADDED SUBSTANTIALLY TO OUR UNDERSTANDING OF CRUCIAL MECHANISMS OF LEUKEMOGENESIS IN RECENT YEARS. CONVERSELY, SPORADIC LEUKEMIAS ACCOUNT FOR THE MAIN PROPORTION OF LEUKEMIAS AND HERE DNA DAMAGING REACTIVE OXYGEN SPECIES (ROS) PLAY A CENTRAL ROLE. ALTHOUGH THE EXACT MECHANISMS OF INCREASED ROS PRODUCTION REMAIN LARGELY UNKNOWN AND NO SINGLE PATHWAY HAS BEEN DETECTED THUS FAR, SOME ONCOGENIC PROTEINS (E.G., THE ACTIVATED TYROSINE KINASES BCR-ABL1 AND FLT3-ITD) SEEM TO PLAY A KEY ROLE IN DRIVING GENETIC INSTABILITY BY INCREASED ROS GENERATION WHICH INFLUENCES THE DISEASE COURSE (E.G., BLAST CRISIS IN CHRONIC MYELOID LEUKEMIA OR RELAPSE IN FLT3-ITD POSITIVE ACUTE MYELOID LEUKEMIA). OF COURSE OTHER MECHANISMS, WHICH PROMOTE GENETIC INSTABILITY IN LEUKEMIA ALSO EXIST. A NEWLY EMERGING MECHANISM IS THE GENOME-WIDE ALTERATION OF EPIGENETIC MARKS (E.G., HYPOMETHYLATION OF HISTONE H3K79), WHICH PROMOTES CHROMOSOMAL INSTABILITY. TAKEN TOGETHER GENETIC INSTABILITY PLAYS A CRITICAL ROLE BOTH IN INHERITED AND SPORADIC LEUKEMIAS AND EMERGES AS A COMMON THEME IN BOTH INHERITED AND SPORADIC LEUKEMIAS. BEYOND ITS THEORETICAL IMPACT, THE ANALYSIS OF GENETIC INSTABILITY MAY LEAD THE WAY TO THE DEVELOPMENT OF INNOVATIVE THERAPY STRATEGIES. 2010 11 3565 46 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 12 1616 43 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 13 4660 61 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 14 2033 46 EPIGENETIC CHANGES IN SOLID AND HEMATOPOIETIC TUMORS. THERE ARE THREE CONNECTED MOLECULAR MECHANISMS OF EPIGENETIC CELLULAR MEMORY IN MAMMALIAN CELLS: DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA INTERFERENCE. THE FIRST TWO HAVE NOW BEEN FIRMLY LINKED TO NEOPLASTIC TRANSFORMATION. HYPERMETHYLATION OF CPG-RICH PROMOTERS TRIGGERS LOCAL HISTONE CODE MODIFICATIONS RESULTING IN A CELLULAR CAMOUFLAGE MECHANISM THAT SEQUESTERS GENE PROMOTERS AWAY FROM TRANSCRIPTION FACTORS AND RESULTS IN STABLE SILENCING. THIS NORMALLY RESTRICTED MECHANISM IS UBIQUITOUSLY USED IN CANCER TO SILENCE HUNDREDS OF GENES, AMONG WHICH SOME CRITICALLY CONTRIBUTE TO THE NEOPLASTIC PHENOTYPE. VIRTUALLY EVERY PATHWAY IMPORTANT TO CANCER FORMATION IS AFFECTED BY THIS PROCESS. METHYLATION PROFILING OF HUMAN CANCERS REVEALS TISSUE-SPECIFIC EPIGENETIC SIGNATURES, AS WELL AS TUMOR-SPECIFIC SIGNATURES, REFLECTING IN PARTICULAR THE PRESENCE OF EPIGENETIC INSTABILITY IN A SUBSET OF CANCERS AFFECTED BY THE CPG ISLAND METHYLATOR PHENOTYPE. GENERALLY, METHYLATION PATTERNS CAN BE TRACED TO A TISSUE-SPECIFIC, PROLIFERATION-DEPENDENT ACCUMULATION OF ABERRANT PROMOTER METHYLATION IN AGING TISSUES, A PROCESS THAT CAN BE ACCELERATED BY CHRONIC INFLAMMATION AND LESS WELL-DEFINED MECHANISMS INCLUDING, POSSIBLY, DIET AND GENETIC PREDISPOSITION. THE EPIGENETIC MACHINERY CAN ALSO BE ALTERED IN CANCER BY SPECIFIC LESIONS IN EPIGENETIC EFFECTOR GENES, OR BY ABERRANT RECRUITMENT OF THESE GENES BY MUTANT TRANSCRIPTION FACTORS AND COACTIVATORS. EPIGENETIC PATTERNS ARE PROVING CLINICALLY USEFUL IN HUMAN ONCOLOGY VIA RISK ASSESSMENT, EARLY DETECTION, AND PROGNOSTIC CLASSIFICATION. PHARMACOLOGIC MANIPULATION OF THESE PATTERNS-EPIGENETIC THERAPY-IS ALSO POISED TO CHANGE THE WAY WE TREAT CANCER IN THE CLINIC. 2005 15 834 45 CHEMICAL BIOLOGY OF LYSINE DEMETHYLASES. ABNORMAL LEVELS OF DNA METHYLATION AND/OR HISTONE MODIFICATIONS ARE OBSERVED IN PATIENTS WITH A WIDE VARIETY OF CHRONIC DISEASES. METHYLATION OF LYSINES WITHIN HISTONE TAILS IS A KEY MODIFICATION THAT CONTRIBUTES TO INCREASED GENE EXPRESSION OR REPRESSION DEPENDING ON THE SPECIFIC RESIDUE AND DEGREE OF METHYLATION, WHICH IS IN TURN CONTROLLED BY THE INTERPLAY OF LYSINE METHYL TRANSFERASES AND DEMETHYLASES. DRUGS THAT TARGET THESE AND OTHER ENZYMES CONTROLLING CHROMATIN MODIFICATIONS CAN MODULATE THE EXPRESSION OF CLUSTERS OF GENES, POTENTIALLY OFFERING HIGHER THERAPEUTIC EFFICACY THAN CLASSICAL AGENTS ACTING ON DOWNSTREAM BIOCHEMICAL PATHWAYS THAT ARE SUSCEPTIBLE TO DEGENERACY. LYSINE DEMETHYLASES, FIRST DISCOVERED IN 2004, ARE THE SUBJECT OF INCREASING INTEREST AS THERAPEUTIC TARGETS. THIS REVIEW PROVIDES AN OVERVIEW OF RECENT FINDINGS IMPLICATING LYSINE DEMETHYLASES IN A RANGE OF THERAPEUTIC AREAS INCLUDING ONCOLOGY, IMMUNOINFLAMMATION, METABOLIC DISORDERS, NEUROSCIENCE, VIROLOGY AND REGENERATIVE MEDICINE, TOGETHER WITH A SUMMARY OF RECENT ADVANCES IN STRUCTURAL BIOLOGY AND SMALL MOLECULE INHIBITOR DISCOVERY, SUPPORTING THE TRACTABILITY OF THE PROTEIN FAMILY FOR THE DEVELOPMENT OF SELECTIVE DRUGLIKE INHIBITORS. 2011 16 208 39 ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) LINKING IMMUNITY, CHRONIC INFLAMMATION, AND CANCER. ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) IS CRITICALLY INVOLVED IN CLASS SWITCH RECOMBINATION AND SOMATIC HYPERMUTATION OF IG LOCI RESULTING IN DIVERSIFICATION OF ANTIBODIES REPERTOIRE AND PRODUCTION OF HIGH-AFFINITY ANTIBODIES AND AS SUCH REPRESENTS A PHYSIOLOGICAL TOOL TO INTRODUCE DNA ALTERATIONS. THESE PROCESSES TAKE PLACE WITHIN GERMINAL CENTERS OF SECONDARY LYMPHOID ORGANS. UNDER PHYSIOLOGICAL CONDITIONS, AID IS EXPRESSED PREDOMINANTLY IN ACTIVATED B LYMPHOCYTES. BECAUSE OF THE MUTAGENIC AND RECOMBINOGENIC POTENTIAL OF AID, ITS EXPRESSION AND ACTIVITY IS TIGHTLY REGULATED ON DIFFERENT LEVELS TO MINIMIZE THE RISK OF UNWANTED DNA DAMAGE. HOWEVER, CHRONIC INFLAMMATION AND, PROBABLY, COMBINATION OF OTHER NOT-YET-IDENTIFIED FACTORS ARE ABLE TO CREATE A MICROENVIRONMENT SUFFICIENT FOR TRIGGERING AN ABERRANT AID EXPRESSION IN B CELLS AND, IMPORTANTLY, IN NON-B-CELL BACKGROUND. UNDER THESE CIRCUMSTANCES, AID MAY TARGET ALSO NON-IG GENES, INCLUDING CANCER-RELATED GENES AS ONCOGENES, TUMOR SUPPRESSOR GENES, AND GENOMIC STABILITY GENES, AND MODULATE BOTH GENETIC AND EPIGENETIC INFORMATION. DESPITE ONGOING PROGRESS, THE COMPLETE UNDERSTANDING OF FUNDAMENTAL ASPECTS IS STILL LACKING AS (1) WHAT ARE THE CRUCIAL FACTORS TRIGGERING AN ABERRANT AID EXPRESSION/ACTIVITY INCLUDING THE IMPACT OF TH2-DRIVEN INFLAMMATION AND (2) TO WHAT EXTENT MAY ABERRANT AID IN HUMAN NON-B CELLS LEAD TO ABNORMAL CELL STATE ASSOCIATED WITH AN INCREASED RATE OF GENOMIC ALTERATIONS AS POINT MUTATIONS, SMALL INSERTIONS OR DELETIONS, AND/OR RECURRENT CHROMOSOMAL TRANSLOCATIONS DURING SOLID TUMOR DEVELOPMENT AND PROGRESSION. 2012 17 6371 48 THE ROLE OF MICRORNAS IN THE PATHOGENESIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES. MICRORNAS (MIRNAS) COMPRISE A RECENTLY DISCOVERED CLASS OF NON-CODING RNAS WITH REGULATORY FUNCTIONS IN POST-TRANSCRIPTIONAL GENE EXPRESSION CONTROL. MANY MIRNAS ARE LOCATED IN GENOMIC REGIONS THAT ARE FREQUENTLY DELETED IN CANCER, OR ARE SUBJECT TO EPIGENETIC AND TRANSCRIPTIONAL DEREGULATION IN CANCER CELLS. THE MIRNA TRANSCRIPTOME OF CANCER CELLS IS VERY DIFFERENT FROM THAT OF THEIR NORMAL CELL COUNTERPARTS. MIRNAS CAN EXHIBIT ONCOGENIC OR TUMOR SUPPRESSIVE OR EVEN BOTH PROPERTIES DEPENDING ON THE SPECIFIC TARGETS AND CELLULAR CONTEXT. IT IS BECOMING INCREASINGLY CLEAR THAT MIRNAS NOT ONLY SERVE AS USEFUL TUMOR BIOMARKERS WITH IMPLICATIONS FOR DIAGNOSIS, PROGNOSIS AND THE PREDICTION OF TREATMENT RESPONSES, BUT MAY ALSO BE USED FOR TARGETED CANCER TREATMENT AND EVEN AS THERAPEUTICS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RECENT ADVANCES IN OUR UNDERSTANDING OF THE TUMOR SUPPRESSOR MIRNAS AND ONCOMIRS INVOLVED IN THE PATHOGENESIS OF LEUKEMIAS AND LYMPHOMAS, AND THEIR TARGET TRANSCRIPTS IN CANCER SIGNALING NETWORKS. IN PARTICULAR, WE FOCUS ON THE ROLE OF MIRNAS IN CHRONIC LYMPHOCYTIC AND ACUTE LYMPHOBLASTIC LEUKEMIA AND IN B-CELL LYMPHOMAS. IN THE SECOND PART, WE REVIEW THE VARIOUS ALTERNATIVE STRATEGIES OF TARGETING MIRNAS IN CANCER THERAPY. METHODS OF ONCOMIR ANTAGONIZATION BY ANTAGOMIRS OR LOCKED NUCLEID ACIDS ARE CONTRASTED WITH STRATEGIES THAT HARNESS THE TUMOR SUPPRESSIVE PROPERTIES OF CERTAIN MIRNAS FOR CANCER TREATMENT. PRECLINICAL PROGRESS, ALSO WITH REGARD TO DELIVERY STRATEGIES, POSSIBLE SIDE EFFECTS AND OTHER PHARMACOLOGICAL ASPECTS, IS PRESENTED ALONG WITH RESULTS FROM THE FIRST HUMAN TRIALS ASSESSING THE SAFETY AND EFFICACY OF MIRNA-TARGETING THERAPEUTICS. 2013 18 2494 40 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 19 606 50 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 20 2652 39 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