1 2991 129 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 2 2652 31 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 3 358 28 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 4 3565 33 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 5 3089 22 GENOMIC AND EPIGENOMIC ALTERATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA IS A COMMON DISEASE IN WESTERN COUNTRIES AND HAS HETEROGENEOUS CLINICAL BEHAVIOR. THE RELEVANCE OF THE GENETIC BASIS OF THE DISEASE HAS COME TO THE FOREFRONT RECENTLY, WITH GENOME-WIDE STUDIES THAT HAVE PROVIDED A COMPREHENSIVE VIEW OF STRUCTURAL VARIANTS, SOMATIC MUTATIONS, AND DIFFERENT LAYERS OF EPIGENETIC CHANGES. THE MUTATIONAL LANDSCAPE IS CHARACTERIZED BY RELATIVELY COMMON COPY NUMBER ALTERATIONS, A FEW MUTATED GENES OCCURRING IN 10-15% OF CASES, AND A LARGE NUMBER OF GENES MUTATED IN A SMALL NUMBER OF CASES. THE EPIGENOMIC PROFILE HAS REVEALED A MARKED REPROGRAMMING OF REGULATORY REGIONS IN TUMOR CELLS COMPARED WITH NORMAL B CELLS. ALL OF THESE ALTERATIONS ARE DIFFERENTIALLY DISTRIBUTED IN CLINICAL AND BIOLOGICAL SUBSETS OF THE DISEASE, INDICATING THAT THEY MAY UNDERLIE THE HETEROGENEOUS EVOLUTION OF THE DISEASE. THESE GLOBAL STUDIES ARE REVEALING THE MOLECULAR COMPLEXITY OF CHRONIC LYMPHOCYTIC LEUKEMIA AND PROVIDE NEW PERSPECTIVES THAT HAVE HELPED TO UNDERSTAND ITS PATHOGENIC MECHANISMS AND IMPROVE THE CLINICAL MANAGEMENT OF PATIENTS. 2020 6 389 20 AN INTEGRATIVE HYPOTHESIS LINKING CANCER, DIABETES AND ATHEROSCLEROSIS: THE ROLE OF MUTATIONS AND EPIGENETIC CHANGES. IT APPEARS THAT THE DISEASE STATES OF CANCER, ALTHEROSCLEROSIS AND DIABETES MIGHT SHARE A COMMON ETIOLOGY. THESE CHRONIC DISEASES APPEAR TO BE MULTI-STAGED IN THEIR PROGRESSION, WITH GENETIC, NUTRITIONAL, PSYCHO-SOCIAL, ENVIRONMENTAL AND VIRAL FACTORS INFLUENCING THEIR APPEARANCE. WE OFFERED A HYPOTHESIS (A "MUTATION THEORY OF DISEASE"), STATING THAT THESE DISEASES CAN BE DESCRIBED BY INITIATION AND PROMOTION PHASES; INITIATION BEING THE RESULT OF THE PRODUCTION OF MUTATED CELLS AFTER UNREPAIRED DAMAGED DNA IS REPLICATED; PROMOTION BEING THE SELECTIVE PROLIFERATION OF THE INITIATED CELLS TO FORM CLONES OF MUTATED CELLS. IT WAS FURTHER POSTULATED THAT PROMOTION AFFECTS CELL PROLIFERATION BY ALTERING A MEMBRANE-CA++ REGULATORY SYSTEM. DEPENDING ON THE NATURE OF THE MUTATION IN THE CLONE OF CELLS, SPECIFIC DISEASE STATES WOULD RESULT. THE ROLES OF RADIATIONS, CHEMICALS, VIRUSES, GENES, NUTRITION AND PSYCHO-SOCIAL STRESS WERE RELATED TO EITHER THE INITIATION (MUTATION PRODUCTION) OR THE PROMOTION (CELL PROLIFERATION) PHASE OF THESE DISEASES. 1980 7 2535 25 EPIGENETICS IN CHRONIC LYMPHOCYTIC LEUKEMIA. ENORMOUS EVIDENCE HAS ACCUMULATED IN THE PAST DECADES THAT ESTABLISHES THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN CANCER AND HAS RESULTED IN SHIFTING THE FOCUS FROM ENTIRELY GENETIC-BASED STUDIES TO INTEGRATED STUDIES INVOLVING BOTH GENETIC AND EPIGENETIC ALTERATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS ONE SUCH EXAMPLE WHERE STUDIES INVOLVING EPIGENETIC ABERRATIONS HAVE ACCELERATED THE SEARCH FOR AFFECTED GENES, WHICH WAS INITIALLY RESTRICTED TO COMMONLY DELETED CHROMOSOMAL REGIONS. MANY NOVEL GENES THAT ARE EPIGENETICALLY SILENCED IN CLL HAVE BEEN IDENTIFIED. ADVANCES IN THE UNDERSTANDING OF POST-TRANSLATIONAL HISTONE MODIFICATIONS AND DNA METHYLATION IN NORMAL AND IN CLL CELLS HAVE PROVEN TO BE EXTREMELY BENEFICIAL IN FINDING POWERFUL DIAGNOSTIC MARKERS, AS WELL AS IN EXPLORING NOVEL THERAPIES. AT PRESENT, THE FIELD OF EPIGENETICS IS AT AN EVOLVING STAGE, BUT THERE IS NO DOUBT THAT FURTHER UNRAVELING OF ITS CAUSE AND EFFECTS IN TRANSFORMED CELLS WILL BRING A NEW REVOLUTION IN CANCER THERAPEUTICS. 2006 8 2752 26 EXPRESSION OF ANGIOGENIC FACTORS IN CHRONIC MYELOID LEUKAEMIA: ROLE OF THE BCR/ABL ONCOGENE, BIOCHEMICAL MECHANISMS, AND POTENTIAL CLINICAL IMPLICATIONS. CHRONIC MYELOID LEUKAEMIA (CML) IS A STEM CELL DISEASE CHARACTERIZED BY AN INCREASED PRODUCTION AND ACCUMULATION OF CLONAL BCR/ABL-POSITIVE CELLS IN HAEMATOPOIETIC TISSUES. THE CHRONIC PHASE OF CML IS INEVITABLY FOLLOWED BY AN ACCELERATED PHASE OF THE DISEASE, WITH CONSECUTIVE BLAST CRISIS. HOWEVER, DEPENDING ON GENETIC STABILITY, EPIGENETIC EVENTS, AND SEVERAL OTHER FACTORS, THE CLINICAL COURSE AND SURVIVAL APPEAR TO VARY AMONG PATIENTS. RECENT DATA SUGGEST THAT ANGIOGENIC CYTOKINES SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), ARE UP-REGULATED IN CML, AND PLAY A ROLE IN THE PATHOGENESIS OF THE DISEASE. THESE FACTORS APPEAR TO BE PRODUCED AND RELEASED IN LEUKAEMIC CELLS IN PATIENTS WITH CML. IN LINE WITH THIS NOTION, INCREASED SERUM-LEVELS OF ANGIOGENIC GROWTH FACTORS ARE MEASURABLE IN CML PATIENTS. IN THIS STUDY WE PROVIDE AN OVERVIEW OF ANGIOGENIC GROWTH FACTORS EXPRESSED IN CML CELLS, DISCUSS THE POSSIBLE PATHOGENETIC ROLE OF THESE CYTOKINES, THE BIOCHEMICAL BASIS OF THEIR PRODUCTION IN LEUKAEMIC CELLS, AND THEIR POTENTIAL CLINICAL IMPLICATIONS. 2004 9 6326 28 THE ROLE OF BCL-2 FAMILY PROTEINS IN CHRONIC LYMPHOCYTIC LEUKAEMIA. BCL-2 FAMILY PROTEINS HAVE LONG BEEN IMPLICATED IN THE PATHOLOGY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). INDEED, A NUMBER OF THESE PROTEINS HAVE BEEN SHOWN TO HAVE PROGNOSTIC IMPORTANCE IN THIS DISEASE. THE PRECISE WAYS IN WHICH THESE PROTEINS IMPACT UPON CLL AND THE WAYS IN WHICH THEY ARE REGULATED REMAIN INCOMPLETELY RESOLVED. HOWEVER, SIGNIFICANT ADVANCES HAVE BEEN RECENTLY MADE IN OUR UNDERSTANDING OF HOW THESE PROTEINS ARE CONTROLLED BY GENETIC, EPIGENETIC AND MICROENVIRONMENTAL CUES. FURTHERMORE, MAJOR PROGRESS HAS BEEN MADE IN TRYING TO TARGET THESE PROTEINS THERAPEUTICALLY. HERE WE REVIEW THE CURRENT KNOWLEDGE ABOUT THIS FAMILY OF APOPTOSIS-REGULATING PROTEINS AND HOW THEY IMPACT UPON DRUG RESISTANCE AND DISEASE PROGRESSION. WE ALSO SUMMARISE EVOLUTION IN THE DEVELOPMENT OF BCL-2 FAMILY INHIBITORS FOR THE TREATMENT OF CLL AND OTHER CANCERS. 2010 10 2944 25 GENETIC AND EPIGENETIC BASIS OF CHRONIC LYMPHOCYTIC LEUKEMIA. PURPOSE OF REVIEW: NEXT-GENERATION SEQUENCING OF WHOLE GENOMES, EXOMES AND DNA METHYLOMES IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAS PROVIDED THE FIRST COMPREHENSIVE VIEW OF SOMATIC MUTATIONS AND METHYLATION CHANGES IN THIS DISEASE. THIS REVIEW SUMMARIZES THE RECENT FINDINGS IN THIS FIELD AND THEIR IMPACT ON OUR CURRENT UNDERSTANDING OF THIS NEOPLASM. RECENT FINDINGS: GENOMIC STUDIES HAVE REVEALED A REMARKABLE MOLECULAR HETEROGENEITY OF THE DISEASE, WITH ONLY FEW GENES MUTATED IN UP TO 10-15% OF THE PATIENTS AND A RELATIVELY LARGE NUMBER OF GENES RECURRENTLY MUTATED AT LOW FREQUENCY. THE MUTATED GENES TEND TO CLUSTER IN DIFFERENT PATHWAYS THAT INCLUDE NOTCH1 SIGNALING, RNA SPLICING, PROCESSING AND TRANSPORT MACHINERY, INNATE INFLAMMATORY RESPONSE, AND DNA DAMAGE AND CELL CYCLE CONTROL, AMONG OTHERS. NOTCH1 AND SF3B1 MUTATIONS ARE EMERGING AS NEW DRIVERS OF AGGRESSIVE FORMS OF THE DISEASE. GENOME-WIDE METHYLATION STUDIES HAVE SHOWN THAT CLL TRANSFORMATION IS ASSOCIATED WITH A MASSIVE HYPOMETHYLATION PHENOMENON FREQUENTLY AFFECTING THE ENHANCER REGIONS. THIS EPIGENETIC REPROGRAMMING MAINTAINS AN IMPRINT OF THE PUTATIVE CELL OF ORIGIN FROM NAIVE AND MEMORY B-CELLS. SUMMARY: GENOMIC AND EPIGENOMIC STUDIES OF CLL ARE RESHAPING OUR UNDERSTANDING OF THE DISEASE AND PROVIDE NEW PERSPECTIVE FOR A MORE INDIVIDUALIZED DIAGNOSIS AND NEW POTENTIAL THERAPEUTIC TARGETS. 2013 11 4124 33 MECHANISMS OF DISEASE PROGRESSION AND RESISTANCE TO TYROSINE KINASE INHIBITOR THERAPY IN CHRONIC MYELOID LEUKEMIA: AN UPDATE. CHRONIC MYELOID LEUKEMIA (CML) IS CHARACTERIZED BY THE PRESENCE OF THE BCR-ABL1 FUSION GENE, WHICH ENCODES A CONSTITUTIVE ACTIVE TYROSINE KINASE CONSIDERED TO BE THE PATHOGENIC DRIVER CAPABLE OF INITIATING AND MAINTAINING THE DISEASE. DESPITE THE REMARKABLE EFFICACY OF TYROSINE KINASE INHIBITORS (TKIS) TARGETING BCR-ABL1, SOME PATIENTS MAY NOT RESPOND (PRIMARY RESISTANCE) OR MAY RELAPSE AFTER AN INITIAL RESPONSE (SECONDARY RESISTANCE). IN A SMALL PROPORTION OF CASES, DEVELOPMENT OF RESISTANCE IS ACCOMPANIED OR SHORTLY FOLLOWED BY PROGRESSION FROM CHRONIC TO BLASTIC PHASE (BP), CHARACTERIZED BY A DISMAL PROGNOSIS. EVOLUTION FROM CP INTO BP IS A MULTIFACTORIAL AND PROBABLY MULTISTEP PHENOMENON. INCREASE IN BCR-ABL1 TRANSCRIPT LEVELS IS THOUGHT TO PROMOTE THE ONSET OF SECONDARY CHROMOSOMAL OR GENETIC DEFECTS, INDUCE DIFFERENTIATION ARREST, PERTURB RNA TRANSCRIPTION, EDITING AND TRANSLATION THAT TOGETHER WITH EPIGENETIC AND METABOLIC CHANGES MAY ULTIMATELY LEAD TO THE EXPANSION OF HIGHLY PROLIFERATING, DIFFERENTIATION-ARRESTED MALIGNANT CELLS. A MULTITUDE OF STUDIES OVER THE PAST TWO DECADES HAVE INVESTIGATED THE MECHANISMS UNDERLYING THE CLOSELY INTERTWINED PHENOMENA OF DRUG RESISTANCE AND DISEASE PROGRESSION. HERE, WE PROVIDE AN UPDATE ON WHAT IS CURRENTLY KNOWN ON THE MECHANISMS UNDERLYING PROGRESSION AND PRESENT THE LATEST ACQUISITIONS ON BCR-ABL1-INDEPENDENT RESISTANCE AND LEUKEMIA STEM CELL PERSISTENCE. 2019 12 606 31 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 13 1542 34 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 14 2033 29 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 15 736 28 CANCER STEM CELLS--NEW APPROACH TO CANCEROGENENSIS AND TREATMENT. RECENTLY, THERE IS AN INCREASING EVIDENCE SUPPORTING THE THEORY OF CANCER STEM CELLS NOT ONLY IN LEUKEMIA BUT ALSO IN SOLID CANCER. TO DATE, THE EXISTENCE OF CANCER STEM CELLS HAS BEEN PROVEN IN ACUTE AND CHRONIC MYELOID LEUKEMIA, IN BREAST CANCER, IN BRAIN TUMORS, IN LUNG CANCER AND GASTROINTESTINAL TUMORS. THIS REVIEW IS FOCUSING ON THE RECENT DISCOVERY OF STEM CELLS IN LEUKEMIA, HUMAN BRAIN TUMORS AND BREAST CANCER. A SMALL POPULATION OF CELLS IN THE TUMOR (LESS THAN 1%) SHOWS THE POTENTIAL TO GIVE RISE TO THE TUMOR AND ITS GROWTH. THESE CELLS HAVE A SUBSTANTIAL CHARACTERISTIC OF STEM CELLS--ABILITY FOR SELF-RENEWAL WITHOUT LOSS OF PROLIFERATION CAPACITY WITH EACH CELL DIVISION. FURTHERMORE THEY ARE IMMORTAL, RATHER RESISTANT TO TREATMENT AND EXPRESS TYPICAL MARKERS OF STEM CELLS. THE ORIGIN OF THESE RESIDENT CANCER STEM CELLS IS NOT CLEAR. WHETHER THE CANCER STEM CELLS ORIGINATE FROM NORMAL STEM CELLS IN CONSEQUENCE OF GENETIC AND EPIGENETIC CHANGES AND/OR REDIFFERENTIATION FROM SOMATIC TUMOR CELLS TO THE STEM-LIKE CELLS REMAINS TO BE INVESTIGATED. WE PROPOSE THE IDEA OF THE RELATION BETWEEN NORMAL TISSUE STEM CELLS AND CANCER STEM CELLS AND THEIR POPULATIONS--PROGENITOR CELLS. BASED ON THIS WE HIGHLIGHT ONE OF THE MAJOR CHARACTERISTIC OF STEM CELL--PLASTICITY, WHICH IS EQUALLY IMPORTANT IN THE PHYSIOLOGICAL REGENERATION PROCESS AS WELL AS CARCINOGENESIS. FURTHERMORE, WE CONSIDER THE MICROENVIRONMENT AS A LIMITING FACTOR FOR TUMOR GENESIS IN AML, BREAST CANCER AND BRAIN TUMORS. THUS THE BIOLOGICAL PROPERTIES OF CANCER STEM CELLS ARE JUST BEGINNING TO BE REVEALED, THE CONTINUATION OF THESE STUDIES SHOULD LEAD TO THE DEVELOPMENT OF CANCER STEM CELLS TARGET THERAPIES FOR CANCER TREATMENT. 2008 16 6773 24 [ADVANCES OF RESEARCH ON DEMETHYLATION THERAPY FOR HEMATOLOGIC MALIGNANCIES]. DNA METHYLATION IS AN IMPORTANT AND REVERSIBLE EPIGENETIC MODIFICATION WHICH REGULATES GENOMIC STABILITY. METHYLATION IS ESSENTIAL FOR MAMMALIAN DEVELOPMENT. GENERALLY, GENE EXPRESSION LEVEL AND DNA METHYLATION ARE NEGATIVE CORRELATION. TRANSCRIPTIONAL SILENCING VIA METHYLATION OF CPG ISLANDS IN THE PROMOTER IS IMPORTANT FOR CELL GROWTH AND DIFFERENTIATION AND PLAYS A KEY ROLE IN TUMORIGENESIS. DEMETHYLATION DRUG CAN MODIFY CHROMATIN AND RESTORE THE ABILITY OF ANTI-ONCOGENE. DEMETHYLATION THERAPY AS A NEW THERAPY MAY TREAT EFFICIENTLY HEMATOLOGICAL MALIGNANCIES WITH RESISTANCE AND RELAPSE. IN THIS REVIEW, DNA METHYLATION MECHANISM, RELATIONSHIP BETWEEN ABERRANT METHYLATION AND HEMATOLOGIC MALIGNANCIES, MECHANISM OF DEMETHYLATION THERAPY, THE ADVANCE OF RESEARCH ON THE DEMETHYLATION THERAPY OF HEMATOLOGICAL MALIGNANCIES, SUCH AS ACUTE AND CHRONIC LEUKEMIA, LYMPHOMA, MYELODYSPLASTIC SYNDROME WERE SUMMARIZED. 2009 17 4429 30 MOLECULAR BIOLOGY AS A TOOL FOR THE TREATMENT OF CANCER. CANCER IS A GENETIC DISEASE CHARACTERIZED BY UNCONTROLLED CELL GROWTH AND METASTASIS. CANCER CAN HAVE A NUMBER OF CAUSES, SUCH THE ACTIVATION OF ONCOGENES, THE INACTIVATION OF TUMOR-SUPPRESSING GENES, MUTAGENESIS PROVOKED BY EXTERNAL FACTORS, AND EPIGENETIC MODIFICATIONS. THE DEVELOPMENT OF DIAGNOSTIC TOOLS AND TREATMENTS USING A MOLECULAR BIOLOGICAL APPROACH PERMITS THE USE OF SENSITIVE, LOW-COST, NONINVASIVE TESTS FOR CANCER PATIENTS. BIOMARKERS CAN BE USED TO PROVIDE RAPID, PERSONALIZED ONCOLOGY, IN PARTICULAR THE MOLECULAR DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA, AND GASTRIC, COLON, AND BREAST CANCERS. MOLECULAR TESTS BASED ON DNA METHYLATION CAN ALSO BE USED TO DIRECT TREATMENTS OR EVALUATE THE TOXIC EFFECTS OF CHEMOTHERAPY. THE ADEQUATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RESPONSE OF CANCER PATIENTS TO TREATMENT ARE ESSENTIAL TO ENSURE THE MOST EFFECTIVE THERAPY, REDUCE THE DAMAGING EFFECTS OF TREATMENT, AND DIRECT THE THERAPY TO SPECIFIC TARGETS, AND IN THIS CONTEXT, MOLECULAR BIOLOGY HAS BECOME INCREASINGLY IMPORTANT IN ONCOLOGY. IN THIS BRIEF REVIEW, WE WILL DEMONSTRATE THE FUNDAMENTAL IMPORTANCE OF MOLECULAR BIOLOGY FOR THE TREATMENT OF THREE TYPES OF CANCER-CHRONIC MYELOID LEUKEMIA, HEREDITARY DIFFUSE GASTRIC CANCER, AND ASTROCYTOMAS (SPORADIC TUMORS OF THE CENTRAL NERVOUS SYSTEM). IN EACH OF THESE THREE MODELS, DISTINCT BIOLOGICAL MECHANISMS ARE INVOLVED IN THE TRANSFORMATION OF THE CELLS, BUT IN ALL CASES, MOLECULAR BIOLOGY IS FUNDAMENTAL TO THE DEVELOPMENT OF PERSONALIZED ANALYSES FOR EACH PATIENT AND EACH TYPE OF NEOPLASIA, AND TO GUARANTEE THE SUCCESS OF THE TREATMENT. 2018 18 2085 35 EPIGENETIC DYSREGULATION IN CHRONIC MYELOID LEUKAEMIA: A MYRIAD OF MECHANISMS AND THERAPEUTIC OPTIONS. THE ONSET OF GLOBAL EPIGENETIC CHANGES IN CHROMATIN THAT DRIVE TUMOR PROLIFERATION AND HETEROGENEITY IS A HALLMARK OF MANY FORMS OF CANCER. IDENTIFYING THE EPIGENETIC MECHANISMS THAT GOVERN THESE CHANGES AND DEVELOPING THERAPEUTIC APPROACHES TO MODULATE THEM, IS A WELL-ESTABLISHED AVENUE PURSUED IN TRANSLATIONAL CANCER MEDICINE. CHRONIC MYELOID LEUKEMIA (CML) ARISES CLONALLY WHEN A HEMATOPOIETIC STEM CELL (HSC) ACQUIRES THE CAPACITY TO PRODUCE THE CONSTITUTIVELY ACTIVE TYROSINE KINASE BCR-ABL1 FUSION PROTEIN WHICH DRIVES TUMOR DEVELOPMENT. TREATMENT WITH TYROSINE KINASE INHIBITORS (TKI) THAT TARGET BCR-ABL1 HAS BEEN TRANSFORMATIVE IN CML MANAGEMENT BUT IT DOES NOT LEAD TO CURE IN THE VAST MAJORITY OF PATIENTS. THUS NOVEL THERAPEUTIC APPROACHES ARE REQUIRED AND THESE MUST TARGET CHANGES TO BIOLOGICAL PATHWAYS THAT ARE ABERRANT IN CML - INCLUDING THOSE THAT OCCUR WHEN EPIGENETIC MECHANISMS ARE ALTERED. THESE CHANGES MAY BE DUE TO ALTERATIONS IN DNA OR HISTONES, THEIR BIOCHEMICAL MODIFICATIONS AND REQUISITE 'WRITER' PROTEINS, OR TO DYSREGULATION OF VARIOUS TYPES OF NON-CODING RNAS THAT COLLECTIVELY FUNCTION AS MODULATORS OF TRANSCRIPTIONAL CONTROL AND DNA INTEGRITY. HERE, WE REVIEW THE EVIDENCE FOR SUBVERTED EPIGENETIC MECHANISMS IN CML AND HOW THESE IMPACT ON A DIVERSE SET OF BIOLOGICAL PATHWAYS, ON DISEASE PROGRESSION, PROGNOSIS AND DRUG RESISTANCE. WE WILL ALSO DISCUSS RECENT PROGRESS TOWARDS DEVELOPING EPIGENETIC THERAPIES THAT SHOW PROMISE TO IMPROVE CML PATIENT CARE AND MAY LEAD TO IMPROVED CURE RATES. 2018 19 3651 25 INCREASING COMPLEXITY OF MOLECULAR LANDSCAPES IN HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS DURING DEVELOPMENT AND AGING. THE PAST FIVE DECADES HAVE SEEN SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF HUMAN HEMATOPOIESIS. THIS HAS IN PART BEEN DUE TO THE UNPRECEDENTED DEVELOPMENT OF ADVANCED TECHNOLOGIES, WHICH HAVE ALLOWED THE IDENTIFICATION AND CHARACTERIZATION OF RARE SUBSETS OF HUMAN HEMATOPOIETIC STEM AND PROGENITOR CELLS AND THEIR LINEAGE TRAJECTORIES FROM EMBRYONIC THROUGH TO ADULT LIFE. ADDITIONALLY, SURROGATE IN VITRO AND IN VIVO MODELS, ALTHOUGH NOT FULLY RECAPITULATING HUMAN HEMATOPOIESIS, HAVE SPURRED ON THESE SCIENTIFIC ADVANCES. THESE APPROACHES HAVE HEIGHTENED OUR KNOWLEDGE OF HEMATOLOGICAL DISORDERS AND DISEASES AND HAVE LED TO THEIR IMPROVED DIAGNOSIS AND THERAPIES. HERE, WE REVIEW HUMAN HEMATOPOIESIS AT EACH END OF THE AGE SPECTRUM, DURING EMBRYONIC AND FETAL DEVELOPMENT AND ON AGING, PROVIDING EXEMPLARS OF RECENT PROGRESS IN DECIPHERING THE INCREASINGLY COMPLEX CELLULAR AND MOLECULAR HEMATOPOIETIC LANDSCAPES IN HEALTH AND DISEASE. THIS REVIEW CONCLUDES BY HIGHLIGHTING LINKS BETWEEN CHRONIC INFLAMMATION AND METABOLIC AND EPIGENETIC CHANGES ASSOCIATED WITH AGING AND IN THE DEVELOPMENT OF CLONAL HEMATOPOIESIS. 2022 20 5549 15 ROLE OF EPIGENETICS IN CHRONIC MYELOID LEUKEMIA. THE EFFICACY OF THERAPEUTIC MODALITIES IN CHRONIC MYELOID LEUKEMIA (CML) DEPENDS ON BOTH GENETIC AND EPIGENETIC MECHANISMS. THIS REVIEW FOCUSES ON EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF CML AND IN RESISTANCE OF TUMOR CELLS TO TYROSINE KINASE INHIBITORS LEADING TO THE LEUKEMIC CLONE ESCAPE AND PROPAGATION. REGULATORY EVENTS AT THE LEVELS OF GENE REGULATION BY TRANSCRIPTION FACTORS AND MICRORNAS ARE DISCUSSED IN THE CONTEXT OF CML PATHOGENESIS AND THERAPEUTIC MODALITIES. 2013