1 6574 97 TREATMENT OF CHRONIC MYELOMONOCYTIC LEUKEMIA WITH 5-AZACYTIDINE: CASE REPORTS. EPIGENETIC THERAPY WITH HYPOMETHYLATING AGENT (5-AZACYTIDINE; AZA) IS COMMON IN THE MANAGEMENT OF SPECIFIC SUBTYPES OF MYELODYSPLASTIC SYNDROME (MDS), BUT THERE ARE ONLY FEW STUDIES IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) PATIENTS. IN THIS PAPER OUR EXPERIENCE WITH 3 CMML PATIENTS TREATED WITH AZA IS DESCRIBED. IN ONE PATIENT TRANSFUSION INDEPENDENCY WAS OBSERVED AFTER 4 TREATMENT CYCLES; IN ONE CASE A PARTIAL RESPONSE WAS RECORDED, BUT A PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML) AFTER 13 AZA CYCLES HAS APPEARED. IN ONE PATIENT, AZA IN REDUCED DOSAGE WAS ADMINISTERED AS A BRIDGING TREATMENT BEFORE ALLOGENEIC STEM CELL TRANSPLANTATION (ASCT), BUT IN THE CONTROL BONE MARROW ASPIRATE (BEFORE ASCT) A PROGRESSION TO AML WAS RECORDED. FUTURE STUDIES ARE MANDATORY FOR EVALUATION OF NEW MOLECULAR AND CLINICAL FEATURES WHICH COULD PREDICT THE EFFICIENCY OF HYPOMETHYLATING AGENTS IN CMML THERAPY WITH RESPECT TO OVERALL SURVIVAL, EVENT-FREE SURVIVAL, QUALITY-ADJUSTED LIFE YEAR, AND PHARMACOECONOMY. 2012 2 1046 28 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 3 957 28 CHRONIC MYELOMONOCYTIC LEUKAEMIA: A CONCISE CLINICAL AND PATHOPHYSIOLOGICAL REVIEW. CHRONIC MYELOMONOCYTIC LEUKAEMIA (CMML) IS A CLONAL HAEMATOPOIETIC STEM CELL DISORDER WITH MYELODYSPLASTIC AND MYELOPROLIFERATIVE OVERLAP FEATURES, AND AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKAEMIA. APPROXIMATELY 30% OF PATIENTS PRESENT WITH CLONAL CYTOGENETIC ABNORMALITIES, WHILE ALMOST 90% HAVE MOLECULAR ABERRATIONS INVOLVING EPIGENETIC REGULATION, THE SPLICEOSOME COMPONENT MACHINERY, TUMOUR SUPPRESSOR GENES AND TRANSCRIPTION FACTORS/REGULATORS. NUMEROUS PROGNOSTIC MODELS EXIST FOR CMML, WITH MORE RECENT MODELS INCORPORATING PROGNOSTIC MUTATIONS, SUCH AS THOSE INVOLVING ASXL1. OTHER VARIABLES THAT SEEM TO CONSISTENTLY AFFECT OUTCOMES INCLUDE THE DEGREE OF LEUCOCYTOSIS/MONOCYTOSIS, ANAEMIA AND THROMBOCYTOPENIA. ALLOGENEIC STEM CELL TRANSPLANT REMAINS THE ONLY CURATIVE OPTION FOR CMML, WHILE HYPOMETHYLATING AGENTS CAN BE USED FOR TRANSPLANT-INELIGIBLE PATIENTS OR THOSE WITHOUT SUITABLE STEM CELL SOURCES. TARGETING BIOLOGICAL PATHWAYS ACTIVATED IN CMML OFFERS POTENTIAL HOPE FOR MORE EFFECTIVE AND LESS TOXIC THERAPIES. 2014 4 1616 30 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 5 1242 39 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 6 5284 39 PROPOSALS FOR CLINICAL TRIALS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOLOGIC MALIGNANCY OF MOSTLY OLDER INDIVIDUALS THAT EXHIBITS BOTH MYELODYSPLASTIC AND MYELOPROLIFERATIVE FEATURES. CMML PRESENTATION AND OUTCOME ARE VARIABLE, REFLECTING GENETIC AND CLINICAL HETEROGENEITY. HYPOMETHYLATING AGENTS ARE THE MAINSTAY OF THERAPY BUT INDUCE COMPLETE REMISSIONS IN LESS THAN 20% OF PATIENTS AND DO NOT PROLONG SURVIVAL COMPARED TO HYDROXYUREA. ALLOGENEIC STEM CELL TRANSPLANT (ASCT) IS POTENTIALLY CURATIVE, BUT FEW PATIENTS QUALIFY DUE TO ADVANCED AGE AND/OR COMORBIDITIES. WORK OF THE PAST SEVERAL YEARS HAS IDENTIFIED KEY MOLECULAR PATHWAYS THAT DRIVE DISEASE PROLIFERATION AND TRANSFORMATION TO ACUTE LEUKEMIA, INCLUDING JAK/STAT AND MAPK SIGNALING AND EPIGENETIC DYSREGULATION. THERE IS INCREASINGLY COMPELLING EVIDENCE THAT INFLAMMATION IS A MAJOR DRIVER OF CMML PROGRESSION. THUS FAR HOWEVER, THIS MECHANISTIC KNOWLEDGE HAS NOT YET BEEN TRANSLATED INTO IMPROVED OUTCOMES, SUGGESTING THAT FUNDAMENTALLY NEW APPROACHES ARE REQUIRED. IN THIS REVIEW, WE DISCUSS THE DISEASE COURSE, NEW CLASSIFICATIONS, AND CURRENT TREATMENT LANDSCAPE OF CMML. WE REVIEW ONGOING CLINICAL STUDIES AND DISCUSS OPTIONS FOR RATIONALLY BASED FUTURE CLINICAL TRIALS. 2023 7 18 35 5-AZACYTIDINE MODULATES CPG METHYLATION LEVELS OF EZH2 AND NOTCH1 IN MYELODYSPLASTIC SYNDROMES. PURPOSE: MOLECULAR MECHANISMS OF RESPONSE TO HYPOMETHYLATING AGENTS IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) AND CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) STILL REMAIN LARGELY UNKNOWN. THEREFORE, THE EFFECTS OF 5-AZACYTIDINE (AZA) ON CLONAL ARCHITECTURE AND DNA METHYLATION WERE INVESTIGATED IN THIS STUDY. METHODS: USING NEXT-GENERATION SEQUENCING (NGS), 30 MYELOID LEUKEMIA-ASSOCIATED GENES WERE ANALYZED IN 15 MDS/CMML PATIENTS WITH EXCELLENT RESPONSE TO AZA. EFFECTS ON METHYLATION LEVELS WERE ANALYZED BY QUANTITATIVE METHYLATION ANALYSIS USING PYROSEQUENCING FOR THE GLOBAL METHYLATION MARKER LINE-1 IN PATIENTS AND MYELOID CELL LINES. VARIOUS MYELOID CELL LINES AND A HEALTHY COHORT WERE SCREENED FOR METHYLATION LEVELS IN 23 GENES. SELECTED TARGETS WERE VERIFIED ON THE MDS/CMML COHORT. RESULTS: THE STUDY PRESENTED HERE SHOWED A STABLE VARIANT ALLELE FREQUENCY AND STABLE GLOBAL METHYLATION LEVELS IN RESPONDING PATIENTS. A SIGNIFICANT DEMETHYLATION OF EZH2 AND NOTCH1 WAS REVEALED IN PATIENTS WITH AZA RESPONSE. CONCLUSIONS: A RESPONSE TO AZA IS NOT ASSOCIATED WITH ERADICATION OF MALIGNANT CLONES, BUT RATHER WITH A STABILIZATION OF THE CLONAL ARCHITECTURE. WE SUGGEST CHANGES IN CPG METHYLATION LEVELS OF EZH2 AND NOTCH1 AS POTENTIAL TARGETS OF EPIGENETIC RESPONSE TO AZA TREATMENT WHICH MAY ALSO SERVE AS USEFUL BIOMARKERS AFTER CLINICAL EVALUATION. 2019 8 2237 36 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 9 2547 30 EPIGENETICS IN MYELOID MALIGNANCIES. MYELOID HEMATOLOGICAL MALIGNANCIES ARE AMONG THE EPIGENETICALLY BEST CHARACTERIZED NEOPLASMS. THE COMPARATIVELY LOW NUMBER OF RECURRING BALANCED AND UNBALANCED CHROMOSOMAL ABNORMALITIES AS WELL AS COMMON GENETIC MUTATIONS HAS ENABLED SCIENTISTS TO RELATE EPIGENETIC STATES TO THESE. THE EASE OF ACCESSING MALIGNANT CELLS THROUGH BONE MARROW ASPIRATION HAS CERTAINLY CONTRIBUTED TO THE FAST EXPANSION OF KNOWLEDGE. EVEN SO, THE CLINICAL AND PATHOGENETIC RELEVANCE OF EPIGENETIC CHANGES IS STILL NOT KNOWN, AND THE FIELD WILL CERTAINLY EVOLVE VERY FAST WITH THE DEVELOPMENT OF NEW ANALYTIC TECHNIQUES. THE FIRST EXAMPLE OF SUCCESSFUL EPIGENETIC THERAPY IS SEEN IN MYELOID MALIGNANCIES, IN THE HIGH-RISK MYELODYSPLASTIC SYNDROMES (MDS) WHICH ARE ROUTINELY TREATED WITH THE DEMETHYLATING AGENT AZACYTIDINE.THIS CHAPTER WILL CONCENTRATE ON DESCRIBING THE EPIGENETIC CHANGES IN ACUTE MYELOID LEUKEMIA (AML), CHRONIC MYELOID LEUKEMIA (CML) AND MDS. AN OVERVIEW OF CLINICAL RELEVANCE AND EPIGENETIC THERAPEUTIC APPROACHES IS ALSO MADE. 2012 10 4551 31 MUTATIONAL HIERARCHIES IN MYELODYSPLASTIC SYNDROMES DYNAMICALLY ADAPT AND EVOLVE UPON THERAPY RESPONSE AND FAILURE. CLONAL EVOLUTION IS BELIEVED TO BE A MAIN DRIVER FOR PROGRESSION OF VARIOUS TYPES OF CANCER AND IMPLICATED IN FACILITATING RESISTANCE TO DRUGS. HOWEVER, THE HIERARCHICAL ORGANIZATION OF MALIGNANT CLONES IN THE HEMATOPOIESIS OF MYELODYSPLASTIC SYNDROMES (MDS) AND ITS IMPACT ON RESPONSE TO DRUG THERAPY REMAIN POORLY UNDERSTOOD. USING HIGH-THROUGHPUT SEQUENCING OF PATIENT AND XENOGRAFTED CELLS, WE EVALUATED THE INTRATUMORAL HETEROGENEITY (N= 54) AND RECONSTRUCTED MUTATIONAL TRAJECTORIES (N = 39) IN PATIENTS SUFFERING FROM MDS (N = 52) AND CHRONIC MYELOMONOCYTIC LEUKEMIA-1 (N = 2). WE IDENTIFIED LINEAR AND ALSO BRANCHING EVOLUTION PATHS AND CONFIRMED ON A PATIENT-SPECIFIC LEVEL THAT SOMATIC MUTATIONS IN EPIGENETIC REGULATORS AND RNA SPLICING GENES FREQUENTLY CONSTITUTE ISOLATED DISEASE-INITIATING EVENTS. USING HIGH-THROUGHPUT EXOME- AND/OR DEEP-SEQUENCING, WE ANALYZED 103 CHRONOLOGICALLY ACQUIRED SAMPLES FROM 22 PATIENTS COVERING A CUMULATIVE OBSERVATION TIME OF 75 YEARS MDS DISEASE PROGRESSION. OUR DATA REVEALED HIGHLY DYNAMIC SHAPING OF COMPLEX OLIGOCLONAL ARCHITECTURES, SPECIFICALLY UPON TREATMENT WITH LENALIDOMIDE AND OTHER DRUGS. DESPITE INITIAL CLINICAL RESPONSE TO TREATMENT, PATIENTS' MARROW PERSISTENTLY REMAINED CLONAL WITH RAPID OUTGROWTH OF FOUNDER-, SUB-, OR EVEN FULLY INDEPENDENT CLONES, INDICATING AN INCREASED DYNAMIC RATE OF CLONAL TURNOVER. THE EMERGENCE AND DISAPPEARANCE OF SPECIFIC CLONES FREQUENTLY CORRELATED WITH CHANGES OF CLINICAL PARAMETERS, HIGHLIGHTING THEIR DISTINCT AND FAR-REACHING FUNCTIONAL PROPERTIES. INTRIGUINGLY, INCREASINGLY COMPLEX MUTATIONAL TRAJECTORIES ARE FREQUENTLY ACCOMPANIED BY CLINICAL PROGRESSION DURING THE COURSE OF DISEASE. THESE DATA SUBSTANTIATE A NEED FOR REGULAR BROAD MOLECULAR MONITORING TO GUIDE CLINICAL TREATMENT DECISIONS IN MDS. 2016 11 4681 26 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 12 5499 31 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 13 5687 27 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 14 2277 27 EPIGENETIC REGULATION BY ASXL1 IN MYELOID MALIGNANCIES. MYELOID MALIGNANCIES ARE CLONAL HEMATOPOIETIC DISORDERS THAT ARE COMPRISED OF A SPECTRUM OF GENETICALLY HETEROGENEOUS DISORDERS, INCLUDING MYELODYSPLASTIC SYNDROMES (MDS), MYELOPROLIFERATIVE NEOPLASMS (MPN), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), AND ACUTE MYELOID LEUKEMIA (AML). MYELOID MALIGNANCIES ARE CHARACTERIZED BY EXCESSIVE PROLIFERATION, ABNORMAL SELF-RENEWAL, AND/OR DIFFERENTIATION DEFECTS OF HEMATOPOIETIC STEM CELLS (HSCS) AND MYELOID PROGENITOR CELLS HEMATOPOIETIC STEM/PROGENITOR CELLS (HSPCS). MYELOID MALIGNANCIES CAN BE CAUSED BY GENETIC AND EPIGENETIC ALTERATIONS THAT PROVOKE KEY CELLULAR FUNCTIONS, SUCH AS SELF-RENEWAL, PROLIFERATION, BIASED LINEAGE COMMITMENT, AND DIFFERENTIATION. ADVANCES IN NEXT-GENERATION SEQUENCING LED TO THE IDENTIFICATION OF MULTIPLE MUTATIONS IN MYELOID NEOPLASMS, AND MANY NEW GENE MUTATIONS WERE IDENTIFIED AS KEY FACTORS IN DRIVING THE PATHOGENESIS OF MYELOID MALIGNANCIES. THE POLYCOMB PROTEIN ASXL1 WAS IDENTIFIED TO BE FREQUENTLY MUTATED IN ALL FORMS OF MYELOID MALIGNANCIES, WITH MUTATIONAL FREQUENCIES OF 20%, 43%, 10%, AND 20% IN MDS, CMML, MPN, AND AML, RESPECTIVELY. SIGNIFICANTLY, ASXL1 MUTATIONS ARE ASSOCIATED WITH A POOR PROGNOSIS IN ALL FORMS OF MYELOID MALIGNANCIES. THE FACT THAT ASXL1 MUTATIONS ARE ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH CMML, MDS, AND AML, POINTS TO THE POSSIBILITY THAT ASXL1 MUTATION IS A KEY FACTOR IN THE DEVELOPMENT OF MYELOID MALIGNANCIES. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN UNDERSTANDING MYELOID MALIGNANCIES WITH A SPECIFIC FOCUS ON ASXL1 MUTATIONS. 2023 15 6437 30 THERAPEUTIC ADVANCES IN LEUKEMIA AND MYELODYSPLASTIC SYNDROME OVER THE PAST 40 YEARS. MAJOR THERAPEUTIC PROGRESS HAS BEEN ACCOMPLISHED IN LEUKEMIA AND MYELODYSPLASTIC SYNDROME (MDS) OVER THE PAST 40 YEARS, WHICH MAY NOT BE FULLY APPRECIATED BY THE LARGER MEDICAL COMMUNITY. THE OBJECTIVE OF THIS REVIEW WAS TO BRIEFLY HIGHLIGHT THE TREATMENT BREAKTHROUGHS IN LEUKEMIA AND MDS. THERAPEUTIC PROGRESS HAPPENED THROUGH BETTER UNDERSTANDING OF DISEASE PATHOPHYSIOLOGIES AND RATIONAL DEVELOPMENT OF TARGETED AGENTS, LIKE IMATINIB MESYLATE IN CHRONIC MYELOID LEUKEMIA (CML), AND THROUGH ASTUTE, EMPIRICAL DISCOVERIES IN THE CLINIC, LIKE ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE IN ACUTE PROMYELOCYTIC LEUKEMIA (APL) AND CHLORODEOXYADENOSINE IN HAIRY CELL LEUKEMIA (HCL). TODAY, THE 5- TO 10-YEAR SURVIVAL RATES IN PATIENTS WITH APL AND HCL EXCEED 80%. IN PATIENTS WITH CML, IMATINIB THERAPY HAS BEEN ASSOCIATED WITH ESTIMATED 5- TO 7-YEAR SURVIVAL RATES FROM 85% TO 90%. IN PATIENTS WITH ADULT ACUTE LYMPHOCYTIC LEUKEMIA, MODERN INTENSIVE REGIMENS HAVE IMPROVED THE 5-YEAR SURVIVAL RATES FROM 20% UP TO 40%. IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA, CHEMOIMMUNOTHERAPY RECENTLY PRODUCED HIGH RATES OF QUALITY RESPONSES AND IMPROVED LONG-TERM OUTCOME. IN YOUNGER PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML), THE 5-YEAR SURVIVAL RATES RANGE FROM 40% TO 50%, ALTHOUGH ELDERLY AML REMAINS A THERAPEUTIC CHALLENGE. IN PATIENTS WITH MDS, IT WAS RECENTLY DEMONSTRATED THAT EPIGENETIC THERAPY WITH HYPOMETHYLATING AGENTS IMPROVED SURVIVAL. MUCH THERAPEUTIC PROGRESS HAS BEEN WITNESSED IN LEUKEMIA AND MDS, AND MUCH MORE IS EXPECTED TO OCCUR SOON. 2008 16 4487 26 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 17 2981 21 GENETIC COMPLEXITY OF CHRONIC MYELOMONOCYTIC LEUKEMIA. IN RECENT YEARS CMML HAS RECEIVED INCREASED ATTENTION AS THE MOST COMMONLY OBSERVED MDS/MPN OVERLAP SYNDROME. RENEWED INTEREST HAS OCCURRED IN PART DUE TO WIDESPREAD ADOPTION OF NEXT-GENERATION SEQUENCING PANELS THAT HELP RENDER THE DIAGNOSIS IN THE ABSENCE OF MORPHOLOGIC DYSPLASIA. ALTHOUGH MOST CMML PATIENTS EXHIBIT SOMATIC MUTATIONS IN EPIGENETIC MODIFIERS, SPLICEOSOME COMPONENTS, TRANSCRIPTION FACTORS AND SIGNAL TRANSDUCTION GENES, IT IS INCREASINGLY CLEAR THAT A SMALL SUBSET HARBORS AN INHERITED PREDISPOSITION TO CMML AND OTHER MYELOID NEOPLASMS. MORE INTRIGUING IS THE FACT THAT THE MUTATIONAL SPECTRUM OBSERVED IN CMML IS FOUND IN OTHER TYPES OF MYELOID LEUKEMIAS, BEGGING THE QUESTION OF HOW SIMILAR GENETIC BACKGROUNDS CAN LEAD TO SUCH DIVERGENT CLINICAL PHENOTYPES. IN THIS REVIEW WE PRESENT A CONTEMPORARY SNAPSHOT OF THE GENETIC COMPLEXITY INHERENT TO CMML, EXPLORE THE RELATIONSHIP BETWEEN GENOTYPE-PHENOTYPE AND PRESENT A STEPWISE MODEL OF CMML PATHOGENESIS AND PROGRESSION. 2021 18 2582 27 EPIGENETICS OF MYELODYSPLASTIC SYNDROMES. MYELODYSPLASTIC SYNDROMES (MDS) ARE CLONAL DISEASES OF THE ELDERLY CHARACTERIZED BY CHRONIC CYTOPENIAS, DYSPLASIA AND A VARIABLE RISK OF PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML). ABERRANT METHYLATION OF TUMOR-SUPPRESSOR GENE PROMOTERS HAS BEEN ESTABLISHED FOR MANY YEARS AND RECENTLY TRACKED TO THE MOST IMMATURE CELLS OF MDS, SUGGESTING THAT THESE ALTERATIONS ARE DRIVERS OF MDS PATHOGENESIS. IN RECENT YEARS, RECURRENT SOMATIC MUTATIONS IN GENES ENCODING PROTEINS INVOLVED IN DNA METHYLATION AND DEMETHYLATION AND IN COVALENT HISTONE MODIFICATIONS HAVE BEEN REPORTED IN MYELOID MALIGNANCIES, INCLUDING MDS. WHOLE-GENOME EPIGENETIC PROFILES OF MDS ARE ALSO EMERGING. IN PARALLEL WITH THESE ADVANCES IN THE MOLECULAR PATHOGENESIS OF MDS, CLINICAL TRIALS HAVE ESTABLISHED HYPOMETHYLATING AGENTS (HMAS) AS THE MAINSTAY OF THERAPY IN THE ADVANCED FORMS OF THE DISEASE. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF THE MOLECULAR MACHINERY INVOLVED IN EPIGENETIC REGULATION, DISCUSS HOW EPIGENETIC ALTERATIONS ARISE IN MDS AND CONTRIBUTE TO ITS PATHOGENESIS AND THEN DISCUSS THE MODE OF ACTION OF HMAS IN MDS. 2014 19 2083 30 EPIGENETIC DRUGS: A LONGSTANDING STORY. IN THIS CHAPTER, THE DEVELOPMENT OF DECITABINE FROM ITS SYNTHESIS IN 1964 TO THE SUBMISSION OF A REGISTRATION FILE IN 2004 IS REVIEWED. THE PROPER APPLICATION OF THE UNIQUE PROPERTIES OF DECITABINE TOOK QUITE SOME TIME TO ELUCIDATE. IN ADDITION, THE PRACTICAL HANDLING IN THE CLINIC WAS NOT EASY AS THE PROLONGED MYELOSUPPRESSION OF DECITABINE MADE IT DIFFICULT TO DETERMINE THE PREFERRED DOSE AND SCHEDULE. LABORATORY STUDIES ON DNA METHYLATION AND CELL DIFFERENTIATION SHOWED POSSIBLE APPLICATIONS IN SOLID AND HEMATOLOGIC MALIGNANCIES. HOWEVER, DESPITE MANY ATTEMPTS, RESULTS IN SOLID TUMORS HAVE BEEN DISAPPOINTING THUS FAR. AFTER THOROUGH INVESTIGATION, DECITABINE ACHIEVED THERAPEUTIC APPLICATION IN MYELODYSPLASTIC SYNDROME (MDS), IN PARTICULAR IN PATIENTS WITH A POOR PROGNOSIS. FURTHER INDICATIONS MAY INCLUDE ACUTE MYELOID LEUKEMIA (AML), CHRONIC MYELOGENOUS LEUKEMIA (CML), HEMATOPOIETIC STEM CELL TRANSPLANTATION, SICKLE CELL ANEMIA, AND THALASSEMIA. WHEREAS MOST DRUGS ARE ALREADY AT THE END OF THEIR LIFE CYCLE AFTER 40 YEARS, DECITABINE IS ONLY AT THE BEGINNING. ITS APPLICATION WILL BROADEN WITH THE INCREASE IN KNOWLEDGE OF EPIGENETIC MECHANISMS AND THEIR RELATIONSHIP TO DRUG THERAPY. 2005 20 4530 22 MULTILAYER INTRACLONAL HETEROGENEITY IN CHRONIC MYELOMONOCYTIC LEUKEMIA. THE FUNCTIONAL DIVERSITY OF CELLS THAT COMPOSE MYELOID MALIGNANCIES, I.E., THE RESPECTIVE ROLES OF GENETIC AND EPIGENETIC HETEROGENEITY IN THIS DIVERSITY, REMAINS POORLY UNDERSTOOD. THIS QUESTION IS ADDRESSED IN CHRONIC MYELOMONOCYTIC LEUKEMIA, A MYELOID NEOPLASM IN WHICH CLINICAL DIVERSITY CONTRASTS WITH LIMITED GENETIC HETEROGENEITY. TO GENERATE INDUCED PLURIPOTENT STEM CELL CLONES, WE REPROGRAMMED CD34(+) CELLS COLLECTED FROM A PATIENT WITH A CHRONIC MYELOMONOCYTIC LEUKEMIA IN WHICH WHOLE EXOME SEQUENCING OF PERIPHERAL BLOOD MONOCYTE DNA HAD IDENTIFIED 12 GENE MUTATIONS, INCLUDING A MUTATION IN KDM6A AND TWO HETEROZYGOUS MUTATIONS IN TET2 IN THE FOUNDING CLONE AND A SECONDARY KRAS(G12D) MUTATION. CD34(+) CELLS FROM AN AGE-MATCHED HEALTHY DONOR WERE ALSO REPROGRAMMED. WE CAPTURED A PART OF THE GENETIC HETEROGENEITY OBSERVED IN THE PATIENT, I.E. WE ANALYZED FIVE CLONES WITH TWO GENETIC BACKGROUNDS, WITHOUT AND WITH THE KRAS(G12D) MUTATION. HEMATOPOIETIC DIFFERENTIATION OF THESE CLONES RECAPITULATED THE MAIN FEATURES OF THE PATIENT'S DISEASE, INCLUDING OVERPRODUCTION OF GRANULOMONOCYTES AND DYSMEGAKARYOPOIESIS. THESE ANALYSES ALSO DISCLOSED SIGNIFICANT DISCREPANCIES IN THE BEHAVIOR OF HEMATOPOIETIC CELLS DERIVED FROM INDUCED PLURIPOTENT STEM CELL CLONES WITH SIMILAR GENETIC BACKGROUND, CORRELATING WITH LIMITED EPIGENETIC CHANGES. THESE ANALYSES SUGGEST THAT, BEYOND THE CODING MUTATIONS, SEVERAL LEVELS OF INTRACLONAL HETEROGENEITY MAY PARTICIPATE IN THE YET UNEXPLAINED CLINICAL HETEROGENEITY OF THE DISEASE. 2020