1 1465 81 DISSECTING THE ROLE OF ABERRANT DNA METHYLATION IN HUMAN LEUKAEMIA. CHRONIC MYELOID LEUKAEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY THE GENETIC TRANSLOCATION T(9;22)(Q34;Q11.2) ENCODING FOR THE BCR-ABL FUSION ONCOGENE. HOWEVER, MANY MOLECULAR MECHANISMS OF THE DISEASE PROGRESSION STILL REMAIN POORLY UNDERSTOOD. A GROWING BODY OF EVIDENCE SUGGESTS THAT THE EPIGENETIC ABNORMALITIES ARE INVOLVED IN TYROSINE KINASE RESISTANCE IN CML, LEADING TO LEUKAEMIC CLONE ESCAPE AND DISEASE PROPAGATION. HERE WE SHOW THAT, BY APPLYING CELLULAR REPROGRAMMING TO PRIMARY CML CELLS, ABERRANT DNA METHYLATION CONTRIBUTES TO THE DISEASE EVOLUTION. IMPORTANTLY, USING A BCR-ABL INDUCIBLE MURINE MODEL, WE DEMONSTRATE THAT A SINGLE ONCOGENIC LESION TRIGGERS DNA METHYLATION CHANGES, WHICH IN TURN ACT AS A PRECIPITATING EVENT IN LEUKAEMIA PROGRESSION. 2015 2 5549 23 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 3 2393 30 EPIGENETIC REPROGRAMMING AND EMERGING EPIGENETIC THERAPIES IN CML. CHRONIC MYELOID LEUKEMIA (CML) IS A HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY BCR-ABL1, AN ONCOGENIC FUSION GENE ARISING FROM THE PHILADELPHIA CHROMOSOME. THE DEVELOPMENT OF TYROSINE KINASE INHIBITORS (TKIS) TO OVERCOME THE CONSTITUTIVE TYROSINE KINASE ACTIVITY OF THE BCR-ABL PROTEIN HAS DRAMATICALLY IMPROVED DISEASE MANAGEMENT AND PATIENT OUTCOMES OVER THE PAST 20 YEARS. HOWEVER, THE MAJORITY OF PATIENTS ARE NOT CURED AND DEVELOPING NOVEL THERAPEUTIC STRATEGIES THAT TARGET EPIGENETIC PROCESSES ARE A PROMISING AVENUE TO IMPROVE CURE RATES. A NUMBER OF EPIGENETIC MECHANISMS ARE ALTERED OR REPROGRAMMED DURING THE DEVELOPMENT AND PROGRESSION OF CML, RESULTING IN ALTERATIONS IN HISTONE MODIFICATIONS, DNA METHYLATION AND DYSREGULATION OF THE TRANSCRIPTIONAL MACHINERY. IN THIS REVIEW THESE EPIGENETIC ALTERATIONS ARE EXAMINED AND THE POTENTIAL OF EPIGENETIC THERAPIES ARE DISCUSSED AS A MEANS OF ERADICATING RESIDUAL DISEASE AND OFFERING A POTENTIAL CURE FOR CML IN COMBINATION WITH CURRENT THERAPIES. 2019 4 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 5 3234 26 HEMATOPOIETIC AND CHRONIC MYELOID LEUKEMIA STEM CELLS: MULTI-STABILITY VERSUS LINEAGE RESTRICTION. THERE IS COMPELLING EVIDENCE TO SUPPORT THE VIEW THAT THE CELL-OF-ORIGIN FOR CHRONIC MYELOID LEUKEMIA IS A HEMATOPOIETIC STEM CELL. UNLIKE NORMAL HEMATOPOIETIC STEM CELLS, THE PROGENY OF THE LEUKEMIA STEM CELLS ARE PREDOMINANTLY NEUTROPHILS DURING THE DISEASE CHRONIC PHASE AND THERE IS A MILD ANEMIA. THE HALLMARK ONCOGENE FOR CHRONIC MYELOID LEUKEMIA IS THE BCR-ABLP210 FUSION GENE. VARIOUS STUDIES HAVE EXCLUDED A ROLE FOR BCR-ABLP210 EXPRESSION IN MAINTAINING THE POPULATION OF LEUKEMIA STEM CELLS. STUDIES OF BCR-ABLP210 EXPRESSION IN EMBRYONAL STEM CELLS THAT WERE DIFFERENTIATED INTO HEMATOPOIETIC STEM CELLS AND OF THE EXPRESSION IN TRANSGENIC MICE HAVE REVEALED THAT BCR-ABLP210 IS ABLE TO VEER HEMATOPOIETIC STEM AND PROGENITOR CELLS TOWARDS A MYELOID FATE. FOR THE TRANSGENIC MICE, GLOBAL CHANGES TO THE EPIGENETIC LANDSCAPE WERE OBSERVED. IN CHRONIC MYELOID LEUKEMIA, THE ABILITY OF THE LEUKEMIA STEM CELLS TO CHOOSE FROM THE MANY FATES THAT ARE AVAILABLE TO NORMAL HEMATOPOIETIC STEM CELLS APPEARS TO BE DEREGULATED BY BCR-ABLP210 AND CHANGES TO THE EPIGENOME ARE ALSO IMPORTANT. EVEN SO, WE STILL DO NOT HAVE A PRECISE PICTURE AS TO WHY NEUTROPHILS ARE ABUNDANTLY PRODUCED IN CHRONIC MYELOID LEUKEMIA. 2022 6 1507 31 DNA METHYLATION AND INTRA-CLONAL HETEROGENEITY: THE CHRONIC MYELOID LEUKEMIA MODEL. CHRONIC MYELOID LEUKEMIA (CML) IS A MODEL TO INVESTIGATE THE IMPACT OF TUMOR INTRA-CLONAL HETEROGENEITY IN PERSONALIZED MEDICINE. INDEED, TYROSINE KINASE INHIBITORS (TKIS) TARGET THE BCR-ABL FUSION PROTEIN, WHICH IS CONSIDERED THE MAJOR CML DRIVER. TKI USE HAS HIGHLIGHTED THE EXISTENCE OF INTRA-CLONAL HETEROGENEITY, AS INDICATED BY THE PERSISTENCE OF A MINORITY SUBCLONE FOR SEVERAL YEARS DESPITE THE PRESENCE OF THE TARGET FUSION PROTEIN IN ALL CELLS. EPIGENETIC MODIFICATIONS COULD PARTLY EXPLAIN THIS HETEROGENEITY. THIS REVIEW SUMMARIZES THE RESULTS OF DNA METHYLATION STUDIES IN CML. NEXT-GENERATION SEQUENCING TECHNOLOGIES ALLOWED FOR MOVING FROM SINGLE-GENE TO GENOME-WIDE ANALYSES SHOWING THAT METHYLATION ABNORMALITIES ARE MUCH MORE WIDESPREAD IN CML CELLS. THESE DATA SHOWED THAT GLOBAL HYPOMETHYLATION IS ASSOCIATED WITH HYPERMETHYLATION OF SPECIFIC SITES ALREADY AT DIAGNOSIS IN THE EARLY PHASE OF CML. THE BCR-ABL-INDEPENDENCE OF SOME METHYLATION PROFILE ALTERATIONS AND THE RECENT DEMONSTRATION OF THE INITIAL INTRA-CLONAL DNA METHYLATION HETEROGENEITY SUGGESTS THAT SOME DNA METHYLATION ALTERATIONS MAY BE BIOMARKERS OF TKI SENSITIVITY/RESISTANCE AND OF DISEASE PROGRESSION RISK. THESE RESULTS ALSO OPEN PERSPECTIVES FOR UNDERSTANDING THE EPIGENETIC/GENETIC BACKGROUND OF CML PREDISPOSITION AND FOR DEVELOPING NEW THERAPEUTIC STRATEGIES. 2021 7 4124 29 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 8 358 29 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 9 6198 31 THE IMPLICATION OF CANCER PROGENITOR CELLS AND THE ROLE OF EPIGENETICS IN THE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES FOR CHRONIC MYELOID LEUKEMIA. SIGNIFICANCE: CHRONIC MYELOID LEUKEMIA (CML) INVOLVES THE MALIGNANT TRANSFORMATION OF HEMATOPOIETIC STEM CELLS, DEFINED LARGELY BY THE PHILADELPHIA CHROMOSOME AND EXPRESSION OF THE BREAKPOINT CLUSTER REGION-ABELSON (BCR-ABL) ONCOPROTEIN. PHARMACOLOGICAL TYROSINE KINASE INHIBITORS (TKIS), INCLUDING IMATINIB MESYLATE, HAVE OVERCOME LIMITATIONS IN CONVENTIONAL TREATMENT FOR THE IMPROVED CLINICAL MANAGEMENT OF CML. RECENT ADVANCES: ACCUMULATED EVIDENCE HAS LED TO THE IDENTIFICATION OF A SUBPOPULATION OF QUIESCENT LEUKEMIA PROGENITOR CELLS WITH STEM-LIKE SELF RENEWAL PROPERTIES THAT MAY INITIATE LEUKEMOGENESIS, WHICH ARE ALSO SHOWN TO BE PRESENT IN RESIDUAL DISEASE DUE TO THEIR INSENSITIVITY TO TYROSINE KINASE INHIBITION. CRITICAL ISSUES: THE CHARACTERIZATION OF QUIESCENT LEUKEMIA PROGENITOR CELLS AS A UNIQUE CELL POPULATION IN CML PATHOGENESIS HAS BECOME CRITICAL WITH THE COMPLETE ELUCIDATION OF MECHANISMS INVOLVED IN THEIR SURVIVAL INDEPENDENT OF BCR-ABL THAT IS IMPORTANT IN THE DEVELOPMENT OF NOVEL ANTICANCER STRATEGIES. UNDERSTANDING OF THESE FUNCTIONAL PATHWAYS IN CML PROGENITOR CELLS WILL ALLOW FOR THEIR SELECTIVE THERAPEUTIC TARGETING. IN ADDITION, DISEASE PATHOGENESIS AND DRUG RESPONSIVENESS IS ALSO THOUGHT TO BE MODULATED BY EPIGENETIC REGULATORY MECHANISMS SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION, WITH A CAPACITY TO CONTROL CML-ASSOCIATED GENE TRANSCRIPTION. FUTURE DIRECTIONS: A NUMBER OF COMPOUNDS IN COMBINATION WITH TKIS ARE UNDER PRECLINICAL AND CLINICAL INVESTIGATION TO ASSESS THEIR SYNERGISTIC POTENTIAL IN TARGETING LEUKEMIC PROGENITOR CELLS AND/OR THE EPIGENOME IN CML. DESPITE THE COLLECTIVE PROMISE, FURTHER RESEARCH IS REQUIRED IN ORDER TO REFINE UNDERSTANDING, AND, ULTIMATELY, ADVANCE ANTILEUKEMIC THERAPEUTIC STRATEGIES. 2015 10 954 28 CHRONIC MYELOID LEUKEMIA: CURRENT PERSPECTIVES. CHRONIC MYELOID LEUKEMIA (CML), CHARACTERIZED BY THE T(9;22) AND BCR/ABL1 FUSION, IS A DISEASE MODEL FOR STUDYING THE MECHANISMS OF GENETIC ABNORMALITIES IN LEUKEMOGENESIS. THE DETECTION OF THE T(9;22), CHARACTERIZATION OF THE BCR/ABL FUSION, AND THE DISCOVERY OF IMATINIB HAVE ELEGANTLY REFLECTED THE SUCCESS OF OUR RESEARCH EFFORTS IN CML. HOWEVER, GENOMIC INSTABILITIES THAT LEAD TO THE FORMATION OF THE BCR/ ABL1 FUSION ARE NOT FULLY UNDERSTOOD. IT IS IMPORTANT TO UNDERSTAND HOW VARIOUS GENES THAT ARE INVOLVED IN REGULATING THE SIGNALING PATHWAY AND EPIGENETIC DEREGULATION COOPERATE WITH THE BCR/ABL1 FUSION IN THE INITIATION AND PROGRESSION OF CML. 2011 11 109 32 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 12 1082 27 CML - NOT ONLY BCR-ABL1 MATTERS. BCR-ABL1 IS IN THE CENTER OF CHRONIC MYELOID LEUKEMIA (CML) PATHOLOGY, DIAGNOSIS AND TREATMENT, AS CONFIRMED BY THE SUCCESS OF TYROSINE KINASE INHIBITOR (TKI) THERAPY. HOWEVER, ADDITIONAL MECHANISMS AND EVENTS, MANY OF WHICH FUNCTION INDEPENDENTLY OF BCR-ABL1, PLAY IMPORTANT ROLES, PARTICULARLY IN TERMS OF LEUKEMIC STEM CELL (LSC) PERSISTENCE, PRIMARY AND SECONDARY RESISTANCE, AND DISEASE PROGRESSION. PROMISING THERAPEUTIC APPROACHES AIM TO DISRUPT PATHWAYS WHICH MEDIATE LSC SURVIVAL DURING SUCCESSFUL TKI TREATMENT, IN THE HOPE OF IMPROVING LONG-TERM TREATMENT-FREE-REMISSION AND PERHAPS PROVIDE A FUNCTIONAL CURE FOR SOME PATIENTS. OVER THE YEARS THROUGH ADVANCES IN SEQUENCING TECHNOLOGY FREQUENT MOLECULAR ABERRATIONS IN ADDITION TO BCR-ABL1 HAVE BEEN IDENTIFIED NOT ONLY IN ADVANCED DISEASE BUT ALSO IN CHRONIC PHASE CML, OFTEN AFFECTING EPIGENETIC REGULATORS SUCH AS ASXL1, DNMT3A AND TET2. ANALYSES OF SERIAL SAMPLES HAVE REVEALED VARIOUS PATTERNS OF CLONAL EVOLUTION WITH SOME MUTATIONS PRECEDING THE BCR-ABL1 ACQUISITION. SUCH MUTATIONS CAN BE CONSIDERED TO BE IMPORTANT CO-FACTORS IN THE PATHOGENESIS OF CML AND COULD POTENTIALLY INFLUENCE THERAPEUTIC STRATEGIES IN THE FUTURE. 2020 13 2652 26 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 14 952 25 CHRONIC MYELOID LEUKEMIA STEM CELL BIOLOGY. LEUKEMIA PROGRESSION AND RELAPSE IS FUELED BY LEUKEMIA STEM CELLS (LSC) THAT ARE RESISTANT TO CURRENT TREATMENTS. IN THE PROGRESSION OF CHRONIC MYELOID LEUKEMIA (CML), BLAST CRISIS PROGENITORS ARE CAPABLE OF ADOPTING MORE PRIMITIVE BUT DEREGULATED STEM CELL FEATURES WITH ACQUIRED RESISTANCE TO TARGETED THERAPIES. THIS IN TURN PROMOTES LSC BEHAVIOR CHARACTERIZED BY ABERRANT SELF-RENEWAL, DIFFERENTIATION, AND SURVIVAL CAPACITY. MULTIPLE REPORTS SUGGEST THAT CELL CYCLE ALTERATIONS, ACTIVATION OF CRITICAL SIGNALING PATHWAYS, ABERRANT MICROENVIRONMENTAL CUES FROM THE HEMATOPOIETIC NICHE, AND ABERRANT EPIGENETIC EVENTS AND DEREGULATION OF RNA PROCESSING MAY FACILITATE THE ENHANCED SURVIVAL AND MALIGNANT TRANSFORMATION OF CML PROGENITORS. HERE WE REVIEW THE MOLECULAR EVOLUTION OF CML LSC THAT PROMOTES CML PROGRESSION AND RELAPSE. RECENT ADVANCES IN THESE AREAS HAVE IDENTIFIED NOVEL TARGETS THAT REPRESENT IMPORTANT AVENUES FOR FUTURE THERAPEUTIC APPROACHES AIMED AT SELECTIVELY ERADICATING THE LSC POPULATION WHILE SPARING NORMAL HEMATOPOIETIC PROGENITORS IN PATIENTS SUFFERING FROM CHRONIC MYELOID MALIGNANCIES. 2012 15 2781 28 EZH2 IN MYELOID MALIGNANCIES. OUR UNDERSTANDING OF THE SIGNIFICANCE OF EPIGENETIC DYSREGULATION IN THE PATHOGENESIS OF MYELOID MALIGNANCIES HAS GREATLY ADVANCED IN THE PAST DECADE. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS THE CATALYTIC CORE COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), WHICH IS RESPONSIBLE FOR GENE SILENCING THROUGH TRIMETHYLATION OF H3K27. EZH2 DYSREGULATION IS HIGHLY TUMORIGENIC AND HAS BEEN OBSERVED IN VARIOUS CANCERS, WITH EZH2 ACTING AS AN ONCOGENE OR A TUMOR-SUPPRESSOR DEPENDING ON CELLULAR CONTEXT. WHILE LOSS-OF-FUNCTION MUTATIONS OF EZH2 FREQUENTLY AFFECT PATIENTS WITH MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS, MYELODYSPLASTIC SYNDROME AND MYELOFIBROSIS, CASES OF CHRONIC MYELOID LEUKEMIA (CML) SEEM TO BE LARGELY CHARACTERIZED BY EZH2 OVEREXPRESSION. A VARIETY OF OTHER FACTORS FREQUENTLY ABERRANT IN MYELOID LEUKEMIA CAN AFFECT PRC2 FUNCTION AND DISEASE PATHOGENESIS, INCLUDING ADDITIONAL SEX COMBS LIKE 1 (ASXL1) AND SPLICING GENE MUTATIONS. AS THE GENETIC BACKGROUND OF MYELOID MALIGNANCIES IS LARGELY HETEROGENEOUS, IT IS NOT SURPRISING THAT EZH2 MUTATIONS ACT IN CONJUNCTION WITH OTHER ABERRATIONS. SINCE EZH2 MUTATIONS ARE CONSIDERED TO BE EARLY EVENTS IN DISEASE PATHOGENESIS, THEY ARE OF THERAPEUTIC INTEREST TO RESEARCHERS, THOUGH TARGETING OF EZH2 LOSS-OF-FUNCTION DOES PRESENT UNIQUE CHALLENGES. PRELIMINARY RESEARCH INDICATES THAT COMBINED TYROSINE KINASE INHIBITOR (TKI) AND EZH2 INHIBITOR THERAPY MAY PROVIDE A STRATEGY TO ELIMINATE THE RESIDUAL DISEASE BURDEN IN CML TO ALLOW PATIENTS TO REMAIN IN TREATMENT-FREE REMISSION. 2020 16 5405 28 REGULATED EXPRESSION OF P210 BCR-ABL DURING EMBRYONIC STEM CELL DIFFERENTIATION STIMULATES MULTIPOTENTIAL PROGENITOR EXPANSION AND MYELOID CELL FATE. P210 BCR-ABL IS AN ACTIVATED TYROSINE KINASE ONCOGENE ENCODED BY THE PHILADELPHIA CHROMOSOME ASSOCIATED WITH HUMAN CHRONIC MYELOGENOUS LEUKEMIA (CML). THE DISEASE REPRESENTS A CLONAL DISORDER ARISING IN THE PLURIPOTENT HEMATOPOIETIC STEM CELL. DURING THE CHRONIC PHASE, PATIENTS PRESENT WITH A DRAMATIC EXPANSION OF MYELOID CELLS AND A MILD ANEMIA. RETROVIRAL GENE TRANSFER AND TRANSGENIC EXPRESSION IN RODENTS HAVE DEMONSTRATED THE ABILITY OF BCR-ABL TO INDUCE VARIOUS TYPES OF LEUKEMIA. HOWEVER, STUDY OF HUMAN CML OR RODENT MODELS HAS NOT DETERMINED THE DIRECT AND IMMEDIATE EFFECTS OF BCR-ABL ON HEMATOPOIETIC CELLS FROM THOSE REQUIRING SECONDARY GENETIC OR EPIGENETIC CHANGES SELECTED DURING THE PATHOGENIC PROCESS. WE UTILIZED TETRACYCLINE-REGULATED EXPRESSION OF BCR-ABL FROM A PROMOTER ENGINEERED FOR ROBUST EXPRESSION IN PRIMITIVE STEM CELLS THROUGH MULTILINEAGE BLOOD CELL DEVELOPMENT IN COMBINATION WITH THE IN VITRO DIFFERENTIATION OF EMBRYONAL STEM CELLS INTO HEMATOPOIETIC ELEMENTS. OUR RESULTS DEMONSTRATE THAT BCR-ABL EXPRESSION ALONE IS SUFFICIENT TO INCREASE THE NUMBER OF MULTIPOTENT AND MYELOID LINEAGE COMMITTED PROGENITORS IN A DOSE-DEPENDENT MANNER WHILE SUPPRESSING THE DEVELOPMENT OF COMMITTED ERYTHROID PROGENITORS. THESE EFFECTS ARE REVERSIBLE UPON EXTINGUISHING BCR-ABL EXPRESSION. THESE FINDINGS ARE CONSISTENT WITH BCR-ABL BEING THE SOLE GENETIC CHANGE NEEDED FOR THE ESTABLISHMENT OF THE CHRONIC PHASE OF CML AND PROVIDE A POWERFUL SYSTEM FOR THE ANALYSIS OF ANY GENETIC CHANGE THAT ALTERS CELL GROWTH AND LINEAGE CHOICES OF THE HEMATOPOIETIC STEM CELL. 2000 17 6773 19 [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 18 2085 32 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 19 160 25 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 20 2237 20 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