1 3985 120 LONG-TERM MAINTENANCE OF THE MUCOSAL HEALING INDUCED BY AZACITIDINE THERAPY IN A PATIENT WITH INTESTINAL BEHCET'S-LIKE DISEASE ACCOMPANIED WITH MYELODYSPLASTIC SYNDROME INVOLVING TRISOMY 8. MYELODYSPLASTIC SYNDROMES (MDSS) ARE A GROUP OF MYELOID NEOPLASMS CHARACTERIZED BY BLOOD CELL DEFORMATION AND DYSFUNCTION, AND MDS WITH TRISOMY 8 IS CLOSELY LINKED WITH INTESTINAL BEHCET'S-LIKE DISEASES. INTESTINAL BEHCET'S-LIKE DISEASE IS REFRACTORY TO CONVENTIONAL THERAPIES, INCLUDING PREDNISOLONE, IMMUNOMODULATORS, AND ANTI-TUMOR NECROSIS FACTOR ALPHA AGENTS. HERE, WE DESCRIBE A 56-YEAR-OLD WOMAN WITH INTESTINAL BEHCET'S-LIKE DISEASE ASCRIBED TO MDS WITH TRISOMY 8 WHO HAD MULTIPLE INTRACTABLE INTESTINAL ULCERS. SHE PRESENTED WITH PERIODIC FEVER AND ABDOMINAL PAIN. THE GENETIC ANALYSIS SHOWED A HETEROZYGOUS E148Q MUTATION IN THE MEDITERRANEAN FEVER GENE. THE PATIENT DID NOT TOLERATE TREATMENT WITH COLCHICINE BECAUSE OF DIARRHEA; THEREFORE, AZACITIDINE THERAPY WAS INITIATED. ONE CYCLE OF AZACITIDINE THERAPY IMPROVED THE MULTIPLE INTESTINAL ULCERS, AND THE PERIODIC FEVER AND ABDOMINAL PAIN GRADUALLY DISAPPEARED. AFTER EIGHT CYCLES OF AZACITIDINE THERAPY, ILEOCOLONOSCOPY, HISTOLOGICAL ASSESSMENT AND CAPSULE ENDOSCOPY REVEALED MUCOSAL HEALING. AZACITIDINE THERAPY WAS CONTINUED, AND MUCOSAL HEALING WAS MAINTAINED FOR MORE THAN 2 YEARS. THIS CASE SUGGESTS THAT AZACITIDINE THERAPY WHICH HAS IMMUNOREGULATORY EFFECTS AND EPIGENETIC MODULATIONS, MIGHT CONTROL INTESTINAL BEHCET'S-LIKE DISEASE ASSOCIATED WITH MDS INVOLVING TRISOMY 8. 2019 2 4681 29 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 3 5499 27 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 4 4551 29 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 5 2981 19 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 6 2237 28 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 7 3316 26 HISTIOCYTIC SARCOMA AS A SECONDARY MALIGNANCY: PATHOBIOLOGY, DIAGNOSIS, AND TREATMENT. HISTIOCYTIC SARCOMA (HS) IS AN EXTREMELY RARE NON-LANGERHANS CELL DISORDER WITH AN AGGRESSIVE COURSE AND LIMITED TREATMENT OPTIONS. RECENT ADVANCES IN MOLECULAR/GENETIC SEQUENCING HAVE SUGGESTED A COMMON CLONAL ORIGIN BETWEEN VARIOUS HEMATOLYMPHOID DISORDERS AND CASES OF SECONDARY HS. DERIVING CONCLUSIONS FROM PREVIOUSLY REPORTED CASES OF HS ARISING SECONDARILY TO CERTAIN HEMATOLYMPHOID DISORDERS, HERE WE HAVE TRIED TO PROVIDE INSIGHT INTO THE MECHANISMS INFLUENCING THIS EVOLUTION. WE ALSO DISCUSS A CLINICAL CASE OF A 72-YEAR-OLD MAN WITH A DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA (CML), PRESENTING SUBSEQUENTLY WITH A HETEROGENEOUS LIVER MASS POSITIVE WITH A DIAGNOSIS OF HS. THE LIVER MASS SHOWED A RETAINED BCR-ABL1 TRANSLOCATION SUGGESTING CLONALITY BETWEEN THE CML AND HS. AS SEEN IN OUR CASE AND OTHER REPORTED CASES OF HS DERIVED SECONDARILY, THE CONCURRENT EXPRESSION OF IMMUNOGLOBULIN HEAVY (IGH)-/LIGHT-CHAIN REARRANGEMENTS OR CYTOGENETIC MARKERS COMMON TO THE PRIMARY MALIGNANCY SUGGESTS AN EVOLUTIONARY MECHANISM INVOLVING LINEAGE SWITCHING THAT COULD POTENTIALLY BE INFLUENCED BY GENETIC OR EPIGENETIC CUES WHICH MAY OCCUR AT THE LEVEL OF A PROGENITOR OR THE MALIGNANT CELL ITSELF. 2016 8 3565 32 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 9 732 27 CANCER DRUG RESISTANCE: THE CENTRAL ROLE OF THE KARYOTYPE. CURRENT GENETIC AND EPIGENETIC THEORIES OF CANCER-SPECIFIC DRUG RESISTANCE DO NOT ADEQUATELY EXPLAIN: (I) THE KARYOTYPIC CHANGES THAT COINCIDE WITH RESISTANCE, (II) THE HIGH RATES AT WHICH CANCER CELLS ACQUIRE AND ENHANCE RESISTANCE COMPARED TO THE RATES OF CONVENTIONAL MUTATION, (III) THE WIDE RANGES OF RESISTANCE SUCH AS MULTIDRUG RESISTANCE, (IV) THE FREQUENT OCCURRENCE OF INTRINSIC DRUG RESISTANCE. WE HAVE RECENTLY PROPOSED, THAT SPECIFIC KARYOTYPIC ALTERATIONS ARE SUFFICIENT FOR DRUG RESISTANCE VIA NEW TRANSCRIPTOMES OF COOPERATIVE GENES, INDEPENDENT OF GENE MUTATION. THIS MECHANISM GENERATES NEW PHENOTYPES JUST LIKE TRISOMY 21 GENERATES DOWN SYNDROME. THESE KARYOTYPIC CHANGES ARE GENERATED BY CANCER-SPECIFIC ANEUPLOIDY AUTOCATALYTICALLY, BECAUSE ANEUPLOIDY DESTABILIZES THE KARYOTYPE BY MISBALANCING TEAMS OF PROTEINS THAT SYNTHESIZE, REPAIR AND SEGREGATE CHROMOSOMES. EVIDENCE FOR THIS CHROMOSOMAL MECHANISM IS AS FOLLOWS: (I) RESISTANCE IS PROPORTIONAL TO THE NUMBER OF CLONAL CHROMOSOMAL ALTERATIONS COMPARED TO DRUG-SENSITIVE PRECURSORS. (II) THE HIGH RATES AT WHICH CANCER CELLS ACQUIRE DRUG RESISTANCE ARE COMPARABLE WITH THE RATES, AS HIGH AS 10(-2) PER CELL GENERATION, AT WHICH THEIR KARYOTYPES CHANGE-DIMMING HOPES FOR GENE-SPECIFIC THERAPIES. (III) MULTIDRUG RESISTANCE PROBABLY REFLECTS UN-SELECTED TRANSCRIPTOMES OF KARYOTYPES SELECTED FOR RESISTANCE AGAINST SPECIFIC DRUGS. (IV) INTRINSIC DRUG RESISTANCE PROBABLY REFLECTS UNSELECTED TRANSCRIPTOMES OF KARYOTYPES SELECTED FOR ONCOGENICITY. WE ALSO ADDUCE EVIDENCE THAT RESISTANCE OF CHRONIC MYELOID LEUKEMIA AGAINST THE DRUG IMATINIB IS CHROMOSOMAL, ALTHOUGH IT IS WIDELY BELIEVED TO BE DUE TO MUTATION OF A KINASE. 2007 10 1628 25 DNMT3A AND TET2 DOMINATE CLONAL HEMATOPOIESIS AND DEMONSTRATE BENIGN PHENOTYPES AND DIFFERENT GENETIC PREDISPOSITIONS. AGE-ASSOCIATED CLONAL HEMATOPOIESIS CAUSED BY ACQUIRED MUTATIONS IN MYELOID CANCER-ASSOCIATED GENES IS HIGHLY PREVALENT IN THE NORMAL POPULATION. ITS ETIOLOGY, BIOLOGICAL IMPACT ON HEMATOPOIESIS, AND ONCOGENIC RISK IS POORLY DEFINED AT THIS TIME. TO GAIN INSIGHT INTO THIS PHENOMENON, WE ANALYZED A COHORT OF 2530 RELATED AND UNRELATED HEMATOLOGICALLY NORMAL INDIVIDUALS (AGES 55 TO 101 YEARS). WE USED A SENSITIVE GENE-TARGETED DEEP SEQUENCING APPROACH TO GAIN PRECISION ON THE EXACT PREVALENCE OF DRIVER MUTATIONS AND THE PROPORTIONS OF AFFECTED GENES. MUTATIONAL STATUS WAS CORRELATED WITH BIOLOGICAL PARAMETERS. WE REPORT A HIGHER OVERALL PREVALENCE OF DRIVER MUTATIONS (13.7%), WHICH OCCURRED MOSTLY (93%) IN DNMT3A OR TET2 AND WERE HIGHLY AGE-CORRELATED. MUTATION IN THESE 2 GENES HAD SOME DISTINCTIVE EFFECTS ON END POINTS. TET2 MUTATIONS WERE MORE AGE-DEPENDENT, ASSOCIATED WITH A MODEST NEUTROPENIC EFFECT (9%, P = .012), DEMONSTRATED FAMILIAL AGGREGATION, AND ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. MUTATIONS IN DNMT3A HAD NO IMPACT ON BLOOD COUNTS OR INDICES. MUTATIONAL BURDEN OF BOTH GENES CORRELATED WITH X-INACTIVATION SKEWING BUT NO SIGNIFICANT ASSOCIATION WITH AGE-ADJUSTED TELOMERE LENGTH REDUCTION WAS DOCUMENTED. THE DISCORDANCE BETWEEN THE HIGH PREVALENCE OF MUTATIONS IN THESE 2 GENES AND THEIR LIMITED BIOLOGICAL IMPACT RAISE THE QUESTION OF THE POTENTIAL ROLE OF DYSREGULATED EPIGENETIC MODIFIERS IN NORMAL AGING HEMATOPOIESIS, WHICH MAY INCLUDE SUPPORT TO FAILING HEMATOPOIESIS. 2017 11 4547 23 MUTATION ALLELE BURDEN REMAINS UNCHANGED IN CHRONIC MYELOMONOCYTIC LEUKAEMIA RESPONDING TO HYPOMETHYLATING AGENTS. THE CYTIDINE ANALOGUES AZACYTIDINE AND 5-AZA-2'-DEOXYCYTIDINE (DECITABINE) ARE COMMONLY USED TO TREAT MYELODYSPLASTIC SYNDROMES, WITH OR WITHOUT A MYELOPROLIFERATIVE COMPONENT. IT REMAINS UNCLEAR WHETHER THE RESPONSE TO THESE HYPOMETHYLATING AGENTS RESULTS FROM A CYTOTOXIC OR AN EPIGENETIC EFFECT. IN THIS STUDY, WE ADDRESS THIS QUESTION IN CHRONIC MYELOMONOCYTIC LEUKAEMIA. WE DESCRIBE A COMPREHENSIVE ANALYSIS OF THE MUTATIONAL LANDSCAPE OF THESE TUMOURS, COMBINING WHOLE-EXOME AND WHOLE-GENOME SEQUENCING. WE IDENTIFY AN AVERAGE OF 14+/-5 SOMATIC MUTATIONS IN CODING SEQUENCES OF SORTED MONOCYTE DNA AND THE SIGNATURES OF THREE MUTATIONAL PROCESSES. SERIAL SEQUENCING DEMONSTRATES THAT THE RESPONSE TO HYPOMETHYLATING AGENTS IS ASSOCIATED WITH CHANGES IN DNA METHYLATION AND GENE EXPRESSION, WITHOUT ANY DECREASE IN THE MUTATION ALLELE BURDEN, NOR PREVENTION OF NEW GENETIC ALTERATION OCCURENCE. OUR FINDINGS INDICATE THAT CYTOSINE ANALOGUES RESTORE A BALANCED HAEMATOPOIESIS WITHOUT DECREASING THE SIZE OF THE MUTATED CLONE, ARGUING FOR A PREDOMINANTLY EPIGENETIC EFFECT. 2016 12 2083 24 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 13 6437 32 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 14 1682 21 DRUG-MICROENVIRONMENT PERTURBATIONS REVEAL RESISTANCE MECHANISMS AND PROGNOSTIC SUBGROUPS IN CLL. THE TUMOUR MICROENVIRONMENT AND GENETIC ALTERATIONS COLLECTIVELY INFLUENCE DRUG EFFICACY IN CANCER, BUT CURRENT EVIDENCE IS LIMITED AND SYSTEMATIC ANALYSES ARE LACKING. USING CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AS A MODEL DISEASE, WE INVESTIGATED THE INFLUENCE OF 17 MICROENVIRONMENTAL STIMULI ON 12 DRUGS IN 192 GENETICALLY CHARACTERISED PATIENT SAMPLES. BASED ON MICROENVIRONMENTAL RESPONSE, WE IDENTIFIED FOUR SUBGROUPS WITH DISTINCT CLINICAL OUTCOMES BEYOND KNOWN PROGNOSTIC MARKERS. RESPONSE TO MULTIPLE MICROENVIRONMENTAL STIMULI WAS AMPLIFIED IN TRISOMY 12 SAMPLES. TRISOMY 12 WAS ASSOCIATED WITH A DISTINCT EPIGENETIC SIGNATURE. BROMODOMAIN INHIBITION REVERSED THIS EPIGENETIC PROFILE AND COULD BE USED TO TARGET MICROENVIRONMENTAL SIGNALLING IN TRISOMY 12 CLL. WE QUANTIFIED THE IMPACT OF MICROENVIRONMENTAL STIMULI ON DRUG RESPONSE AND THEIR DEPENDENCE ON GENETIC ALTERATIONS, IDENTIFYING INTERLEUKIN 4 (IL4) AND TOLL-LIKE RECEPTOR (TLR) STIMULATION AS THE STRONGEST ACTUATORS OF DRUG RESISTANCE. IL4 AND TLR SIGNALLING ACTIVITY WAS INCREASED IN CLL-INFILTRATED LYMPH NODES COMPARED WITH HEALTHY SAMPLES. HIGH IL4 ACTIVITY CORRELATED WITH FASTER DISEASE PROGRESSION. THE PUBLICLY AVAILABLE DATASET CAN FACILITATE THE INVESTIGATION OF CELL-EXTRINSIC MECHANISMS OF DRUG RESISTANCE AND DISEASE PROGRESSION. 2022 15 2462 27 EPIGENETIC THERAPY OF MYELODYSPLASTIC SYNDROMES CONNECTS TO CELLULAR DIFFERENTIATION INDEPENDENTLY OF ENDOGENOUS RETROELEMENT DEREPRESSION. BACKGROUND: MYELODYSPLASTIC SYNDROMES (MDS) AND ACUTE MYELOID LEUKAEMIA (AML) ARE CHARACTERISED BY ABNORMAL EPIGENETIC REPRESSION AND DIFFERENTIATION OF BONE MARROW HAEMATOPOIETIC STEM CELLS (HSCS). DRUGS THAT REVERSE EPIGENETIC REPRESSION, SUCH AS 5-AZACYTIDINE (5-AZA), INDUCE HAEMATOLOGICAL IMPROVEMENT IN HALF OF TREATED PATIENTS. ALTHOUGH THE MECHANISMS UNDERLYING THERAPY SUCCESS ARE NOT YET CLEAR, INDUCTION OF ENDOGENOUS RETROELEMENTS (ERES) HAS BEEN HYPOTHESISED. METHODS: USING RNA SEQUENCING (RNA-SEQ), WE COMPARED THE TRANSCRIPTION OF ERES IN BONE MARROW HSCS FROM A NEW COHORT OF MDS AND CHRONIC MYELOMONOCYTIC LEUKAEMIA (CMML) PATIENTS BEFORE AND AFTER 5-AZA TREATMENT WITH HSCS FROM HEALTHY DONORS AND AML PATIENTS. WE FURTHER EXAMINED ERE TRANSCRIPTION USING THE MOST COMPREHENSIVE ANNOTATION OF ERE-OVERLAPPING TRANSCRIPTS EXPRESSED IN HSCS, GENERATED HERE BY DE NOVO TRANSCRIPT ASSEMBLY AND SUPPORTED BY FULL-LENGTH RNA-SEQ. RESULTS: CONSISTENT WITH PRIOR REPORTS, WE FOUND THAT TREATMENT WITH 5-AZA INCREASED THE REPRESENTATION OF ERE-DERIVED RNA-SEQ READS IN THE TRANSCRIPTOME. HOWEVER, SUCH INCREASES WERE COMPARABLE BETWEEN TREATMENT RESPONSES AND FAILURES. THE EXTENDED VIEW OF HSC TRANSCRIPTIONAL DIVERSITY OFFERED BY DE NOVO TRANSCRIPT ASSEMBLY ARGUED AGAINST 5-AZA-RESPONSIVE ERES AS DETERMINANTS OF THE OUTCOME OF THERAPY. INSTEAD, IT UNCOVERED PRE-TREATMENT EXPRESSION AND ALTERNATIVE SPLICING OF DEVELOPMENTALLY REGULATED GENE TRANSCRIPTS AS PREDICTORS OF THE RESPONSE OF MDS AND CMML PATIENTS TO 5-AZA TREATMENT. CONCLUSIONS: OUR STUDY IDENTIFIES THE DEVELOPMENTALLY REGULATED TRANSCRIPTIONAL SIGNATURES OF PROTEIN-CODING AND NON-CODING GENES, RATHER THAN ERES, AS CORRELATES OF A FAVOURABLE RESPONSE OF MDS AND CMML PATIENTS TO 5-AZA TREATMENT AND OFFERS NOVEL CANDIDATES FOR FURTHER EVALUATION. 2019 16 2582 30 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 17 5055 30 PHASE 2 TRIAL OF THE HISTONE DEACETYLASE INHIBITOR ROMIDEPSIN FOR THE TREATMENT OF REFRACTORY MULTIPLE MYELOMA. BACKGROUND: EPIGENETIC DYSREGULATION IS A HALLMARK OF CANCER, INCLUDING MULTIPLE MYELOMA. INHIBITORS OF HISTONE DEACETYLASES (HDACS) INDUCE DNA HYPERACETYLATION BY INHIBITING REMOVAL OF ACETYL GROUPS FROM AMINO TAILS ON HISTONE PROTEINS, THEREBY UNCOILING CONDENSED CHROMATIN FAVORING TRANSCRIPTION OF SILENCED GENES, INCLUDING TUMOR SUPPRESSOR GENES. ROMIDEPSIN IS AN HDAC INHIBITOR THAT EXHIBITS ANTIPROLIFERATIVE AND APOPTOTIC EFFECTS AGAINST MULTIPLE MYELOMA CELL LINES. METHODS: A PHASE 2 TRIAL WAS PERFORMED OF ROMIDEPSIN IN PATIENTS WITH MULTIPLE MYELOMA WHO WERE REFRACTORY TO STANDARD THERAPY. TREATMENT WAS COMPRISED OF ROMIDEPSIN (13 MG/M(2)) GIVEN AS A 4-HOUR INTRAVENOUS INFUSION ON DAYS 1, 8, AND 15 EVERY 28 DAYS). THIRTEEN PATIENTS RECEIVED A MEDIAN OF 2 CYCLES OF THERAPY (RANGE, 1-7 CYCLES). RESULTS: ALTHOUGH NO PATIENTS HAD AN OBJECTIVE RESPONSE, 4 OF 12 PATIENTS WITH SECRETORY MYELOMA EXHIBITED EVIDENCE OF M-PROTEIN STABILIZATION, AND SEVERAL OTHER PATIENTS EXPERIENCED IMPROVEMENT IN BONE PAIN AND RESOLUTION OF HYPERCALCEMIA. CONCLUSIONS: THE RESULTS OF THE CURRENT STUDY DEMONSTRATE THAT ROMIDEPSIN, AS A SINGLE AGENT, IS UNLIKELY TO BE ASSOCIATED WITH A RESPONSE RATE OF >/=30% IN PATIENTS WITH REFRACTORY MYELOMA, ALTHOUGH THERE WAS SOME CLINICAL EVIDENCE SUGGESTING A BIOLOGICAL EFFECT ASSOCIATED WITH THERAPY. 2011 18 1242 29 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 19 1046 25 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 20 1616 28 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