1  4928 107 PARP-1 AND PARP-2 ACTIVITY IN CANCER-INDUCED CACHEXIA: POTENTIAL THERAPEUTIC IMPLICATIONS. SKELETAL MUSCLE DYSFUNCTION AND MASS LOSS IS A CHARACTERISTIC FEATURE IN PATIENTS WITH CHRONIC DISEASES INCLUDING CANCER AND ACUTE CONDITIONS SUCH AS CRITICAL ILLNESS. MAINTENANCE OF AN ADEQUATE MUSCLE MASS IS CRUCIAL FOR THE PATIENTS' PROGNOSIS IRRESPECTIVE OF THE UNDERLYING CONDITION. MOREOVER, AGING-RELATED SARCOPENIA MAY FURTHER AGGRAVATE THE MUSCLE WASTING PROCESS ASSOCIATED WITH CHRONIC DISEASES AND CANCER. POLY(ADENOSINE DIPHOSPHATE-RIBOSE) POLYMERASE (PARP) ACTIVATION HAS BEEN DEMONSTRATED TO CONTRIBUTE TO THE PATHOPHYSIOLOGY OF MUSCLE MASS LOSS AND DYSFUNCTION IN ANIMAL MODELS OF CANCER-INDUCED CACHEXIA. GENETIC INHIBITION OF PARP ACTIVITY ATTENUATED THE DELETERIOUS EFFECTS SEEN ON DEPLETED MUSCLES IN MOUSE MODELS OF ONCOLOGIC CACHEXIA. IN THE PRESENT MINIREVIEW THE MECHANISMS WHEREBY PARP ACTIVITY INHIBITION MAY IMPROVE MUSCLE MASS AND PERFORMANCE IN MODELS OF CANCER-INDUCED CACHEXIA ARE DISCUSSED. SPECIFICALLY, THE BENEFICIAL EFFECTS OF INHIBITION OF PARP ACTIVITY ON ATTENUATION OF INCREASED OXIDATIVE STRESS, PROTEIN CATABOLISM, POOR MUSCLE ANABOLISM AND MITOCHONDRIAL CONTENT AND EPIGENETIC MODULATION OF MUSCLE PHENOTYPE ARE REVIEWED IN THIS ARTICLE. FINALLY, THE POTENTIAL THERAPEUTIC STRATEGIES OF PHARMACOLOGICAL PARP ACTIVITY INHIBITION FOR THE TREATMENT OF CANCER-INDUCED CACHEXIA ARE ALSO BEING DESCRIBED IN THIS REVIEW.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2  1311  28 DEFINITIONS, BIOLOGY, AND CURRENT THERAPEUTIC LANDSCAPE OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS. MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE HEMATOLOGICAL DISORDERS CHARACTERIZED BY BOTH PROLIFERATIVE AND DYSPLASTIC FEATURES. ACCORDING TO THE 2022 INTERNATIONAL CONSENSUS CLASSIFICATION (ICC), MDS/MPN CONSISTS OF CLONAL MONOCYTOSIS OF UNDETERMINED SIGNIFICANCE (CMUS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML), MDS/MPN WITH SF3B1 MUTATION (MDS/MPN-T-SF3B1), MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS NOT OTHERWISE SPECIFIED (MDS/MPN-RS-T-NOS), AND MDS/MPN-NOS. THESE DISORDERS EXHIBIT A DIVERSE RANGE OF GENETIC ALTERATIONS INVOLVING VARIOUS TRANSCRIPTION FACTORS (E.G., RUNX1), SIGNALING MOLECULES (E.G., NRAS, JAK2), SPLICING FACTORS (E.G., SF3B, SRSF2), AND EPIGENETIC REGULATORS (E.G., TET2, ASXL1, DNMT3A), AS WELL AS SPECIFIC CYTOGENETIC ABNORMALITIES (E.G., 8 TRISOMIES, 7 DELETIONS/MONOSOMIES). CLINICAL STUDIES EXPLORING THERAPEUTIC OPTIONS FOR HIGHER-RISK MDS/MPN OVERLAP SYNDROMES MOSTLY INVOLVE HYPOMETHYLATING AGENTS, BUT OTHER TREATMENTS SUCH AS LENALIDOMIDE AND TARGETED AGENTS SUCH AS JAK INHIBITORS AND INHIBITORS TARGETING PARP, HISTONE DEACETYLASES, AND THE RAS PATHWAY ARE UNDER INVESTIGATION. WHILE THESE TREATMENT MODALITIES CAN PROVIDE PARTIAL DISEASE CONTROL, ALLOGENEIC BONE MARROW TRANSPLANTATION (ALLO-BMT) IS THE ONLY POTENTIALLY CURATIVE OPTION FOR PATIENTS. IMPORTANT PROGNOSTIC FACTORS CORRELATING WITH OUTCOMES AFTER ALLO-BMT INCLUDE COMORBIDITIES, SPLENOMEGALY, KARYOTYPE ALTERATIONS, AND THE BONE MARROW BLASTS PERCENTAGE AT THE TIME OF TRANSPLANTATION. FUTURE RESEARCH IS IMPERATIVE TO OPTIMIZING THERAPEUTIC STRATEGIES AND ENHANCING PATIENT OUTCOMES IN MDS/MPN NEOPLASMS. IN THIS REVIEW, WE SUMMARIZE MDS/MPN DIAGNOSTIC CRITERIA, BIOLOGY, AND CURRENT AND FUTURE TREATMENT OPTIONS, INCLUDING BONE MARROW TRANSPLANTATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                               
3   813  28 CHANGES IN POLY(ADP-RIBOSYL)ATION PATTERNS IN WORKERS EXPOSED TO BTX. OCCUPATIONAL EXPOSURE TO (BENZENE, TOLUENE AND XYLENE, BTX IS COMMON IN THE CHINESE WORKPLACE. CHRONIC OCCUPATIONAL EXPOSURE TO BENZENE IS ASSOCIATED WITH AN INCREASED RISK OF HEMATOLOGICAL MALIGNANCIES SUCH AS ACUTE MYELOID LEUKEMIA (AML), BUT THE UNDERLYING MECHANISMS ARE STILL UNCLEAR. THIS STUDY INVESTIGATES CHANGES IN POLY(ADP-RIBOSYL)ATION AND DNA METHYLATION IN SUBJECTS OCCUPATIONALLY EXPOSED TO A BTX. BLOOD DNA SAMPLES AND EXPOSURE DATA WERE OBTAINED FROM SUBJECTS WITH DIFFERENT LEVELS OF EXPOSURE, INCLUDING 132 DECORATORS, 129 PAINTERS, AND 130 UNEXPOSED REFERENTS IN A CONTAINER-MANUFACTURING FACTORY IN SHENZHEN, CHINA. OCCUPATIONAL EXPOSURE ASSESSMENT INCLUDED PERSONAL MONITORING OF AIRBORNE BENZENE, TOLUENE AND XYLENE. HEMATOLOGICAL PARAMETERS WERE MEASURED AND THE CYTOKINESIS-BLOCK MICRONUCLEUS (CBMN) ASSAY WAS USED TO DETECT DNA DAMAGE IN PERIPHERAL LYMPHOCYTES. QUANTITATIVE REAL-TIME PCR WAS USED TO DETECT THE MRNA EXPRESSION OF POLY(ADP-RIBOSE) POLYMERASE 1 (PARP1) AND POLY(ADP-RIBOSE) GLYCOHYDROLASE (PARG), DNA METHYLTRANSFERASES (DNMTS) INCLUDING DNMT1, DNMT3A AND DNMT3B, METHYL-CPG-BINDING DOMAIN PROTEIN 2(MBD2). PARP1 ASSAY WAS USED TO MEASURE PARP ACTIVITY. AIRBORNE LEVELS OF BENZENE, TOLUENE AND XYLENE IN THE TWO EXPOSED GROUPS WERE SIGNIFICANTLY HIGHER THAN THOSE OF CONTROLS (P<0.001). THE TWO EXPOSED GROUPS (DECORATORS, PAINTERS) SHOWED DECREASED PARP1, DNMTS AND MBD2 EXPRESSION RELATIVE TO CONTROLS (P<0.05), AND PARP ACTIVITY WAS ALSO DECREASED (P<0.05). DECREASED PARP1, DNMT1, DNMT3A, DNMT3B AND MBD2 MRNA EXPRESSION WAS CORRELATED WITH INCREASED AIRBORNE BTX (PEARSON'S R: -0.587, -0.314, -0.636, -0.567 AND -0.592 RESPECTIVELY, P<0.001). NO SIGNIFICANT DIFFERENCES IN HEMATOLOGICAL PARAMETERS AND CBMN WERE FOUND AMONG THE THREE GROUPS. TOGETHER, THESE RESULTS SUGGEST THAT DECREASED DNMTS, MBD2 AND PARP1 MIGHT BE INVOLVED IN THE GLOBAL HYPOMETHYLATION ASSOCIATED WITH BTX EXPOSURE, AND THE IMBALANCE OF PARP/PARG MIGHT PARTICIPATE IN THE DOWN-REGULATION OF DNMTS. THIS IS THE FIRST HUMAN STUDY TO LINK ALTERED POLY(ADP-RIBOSYL)ATION PATTERNS, WHICH REPRODUCE THE ABERRANT EPIGENETIC PATTERNS FOUND IN BENZENE-TREATED CELLS, TO CHRONIC OCCUPATIONAL EXPOSURE TO BTX.	2014	
      
4  4902  31 OXIDATIVE-STRESS-INDUCED EPIGENETIC CHANGES IN CHRONIC DIABETIC COMPLICATIONS. OXIDATIVE STRESS PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC DIABETIC COMPLICATIONS. DIABETES CAUSES MITOCHONDRIAL SUPEROXIDE OVERPRODUCTION IN THE ENDOTHELIAL CELLS OF BOTH LARGE AND SMALL VESSELS. THIS INCREASED SUPEROXIDE PRODUCTION CAUSES THE ACTIVATION OF SEVERAL SIGNAL PATHWAYS INVOLVED IN THE PATHOGENESIS OF CHRONIC COMPLICATIONS. IN PARTICULAR, ENDOTHELIAL CELLS ARE MAJOR TARGETS OF GLUCOSE-INDUCED OXIDATIVE DAMAGE IN THE TARGET ORGANS. OXIDATIVE STRESS ACTIVATES CELLULAR SIGNALING PATHWAYS AND TRANSCRIPTION FACTORS IN ENDOTHELIAL CELLS INCLUDING PROTEIN KINASE C (PKC), C-JUN-N-TERMINAL KINASE (JNK), P38 MITOGEN-ACTIVATED PROTEIN KINASE (MAPK), FORKHEAD BOX O (FOXO), AND NUCLEAR FACTOR KAPPA-B (NF-KAPPAB). OXIDATIVE STRESS ALSO CAUSES DNA DAMAGE AND ACTIVATES DNA NUCLEOTIDE EXCISION REPAIR ENZYMES INCLUDING THE EXCISION REPAIR CROSS COMPLIMENTING 1(ERCC1), ERCC4, AND POLY(ADP-RIBOSE) POLYMERASE (PARP). AUGMENTED PRODUCTION OF HISTONE ACETYLTRANSFERASE P300, AND ALTERATIONS OF HISTONE DEACETYLASES, INCLUDING CLASS III DEACETYLASES SIRTUINS, ARE ALSO INVOLVED IN THIS PROCESS. RECENT RESEARCH HAS FOUND THAT SMALL NONCODING RNAS, LIKE MICRORNA, ARE A NEW KIND OF REGULATOR ASSOCIATED WITH CHRONIC DIABETIC COMPLICATIONS. THERE ARE EXTENSIVE AND COMPLICATED INTERACTIONS AND AMONG THESE MOLECULES. THE PURPOSE OF THIS REVIEW IS TO DEMONSTRATE THE ROLE OF OXIDATIVE STRESS IN THE DEVELOPMENT OF DIABETIC COMPLICATIONS IN RELATION TO EPIGENETIC CHANGES SUCH AS ACETYLATION AND MICRORNA ALTERATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
5  4471  24 MOLECULAR PATHOGENESIS OF ATYPICAL CML, CMML AND MDS/MPN-UNCLASSIFIABLE. ACCORDING TO THE 2008 WHO CLASSIFICATION, THE CATEGORY OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) INCLUDES ATYPICAL CHRONIC MYELOID LEUKAEMIA (ACML), CHRONIC MYELOMONOCYTIC LEUKAEMIA (CMML), MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U), JUVENILE MYELOMONOCYTIC LEUKAEMIA (JMML) AND A "PROVISIONAL" ENTITY, REFRACTORY ANAEMIA WITH RING SIDEROBLASTS AND THROMBOCYTOSIS (RARS-T). THE REMARKABLE PROGRESS IN OUR UNDERSTANDING OF THE SOMATIC PATHOGENESIS OF MDS/MPN HAS MADE IT CLEAR THAT THERE IS CONSIDERABLE OVERLAP AMONG THESE DISEASES AT THE MOLECULAR LEVEL, AS WELL AS LAYERS OF UNEXPECTED COMPLEXITY. DEREGULATION OF SIGNALLING PLAYS AN IMPORTANT ROLE IN MANY CASES, AND IS CLEARLY LINKED TO MORE HIGHLY PROLIFERATIVE DISEASE. OTHER MUTATIONS AFFECT A RANGE OF OTHER ESSENTIAL, INTERRELATED CELLULAR MECHANISMS, INCLUDING EPIGENETIC REGULATION, RNA SPLICING, TRANSCRIPTION, AND DNA DAMAGE RESPONSE. THE VARIOUS COMBINATIONS OF MUTATIONS INDICATE A MULTI-STEP PATHOGENESIS, WHICH LIKELY CONTRIBUTES TO THE MARKED CLINICAL HETEROGENEITY OF THESE DISORDERS. THE DELINEATION OF COMPLEX CLONAL ARCHITECTURES MAY SERVE AS THE CORNERSTONE FOR THE IDENTIFICATION OF NOVEL THERAPEUTIC TARGETS AND LEAD TO BETTER PATIENT OUTCOMES. THIS REVIEW SUMMARIZES SOME OF THE CURRENT KNOWLEDGE OF MOLECULAR PATHOGENETIC LESIONS IN THE MDS/MPN SUBTYPES THAT ARE SEEN IN ADULTS: ATYPICAL CML, CMML AND MDS/MPN-U.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  4562  25 MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROMES: A FOCUSED REVIEW. MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) OVERLAP SYNDROMES ARE UNIQUE MYELOID NEOPLASMS, WITH OVERLAPPING FEATURES OF MDS AND MPN. THEY CONSIST OF FOUR ADULT ONSET ENTITIES INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), MDS/MPN-RING SIDEROBLASTS-THROMBOCYTOSIS (MDS/MPN-RS-T), BCR-ABL1 NEGATIVE ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) AND MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U); WITH JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) BEING THE ONLY PEDIATRIC ONSET ENTITY. AMONG THESE OVERLAP NEOPLASMS, CMML IS THE MOST FREQUENT AND IS HALLMARKED BY THE PRESENCE OF SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS WITH RECURRENT MUTATIONS INVOLVING TET2 (60%), SRSF2 (50%) AND ASXL1 (40%); WITH RAS PATHWAY MUTATIONS AND JAK2V617F BEING RELATIVELY ENRICHED IN PROLIFERATIVE CMML SUBTYPES (WBC >/=13 X 109/L). CMML USUALLY PRESENTS IN THE 7TH DECADE OF LIFE, WITH A MALE PREPONDERANCE AND IS ASSOCIATED WITH A MEDIAN OVERALL SURVIVAL OF <36 MONTHS. ADVERSE PROGNOSTICATORS IN CMML INCLUDE INCREASING AGE, HIGH WBC, PRESENCE OF CIRCULATING IMMATURE MYELOID CELLS, ANEMIA, THROMBOCYTOPENIA AND TRUNCATING ASXL1 MUTATIONS. WHILE ALLOGENEIC STEM CELL TRANSPLANTATION REMAINS THE ONLY CURATIVE OPTION, GIVEN THE LATE ONSET OF THIS NEOPLASM AND HIGH FREQUENCY OF COMORBIDITIES, MOST PATIENTS REMAIN INELIGIBLE. HYPOMETHYLATING AGENTS SUCH AS AZACITIDINE, DECITABINE AND ORAL DECITABINE/CEDAZURIDINE HAVE BEEN US FDA APPROVED FOR THE MANAGEMENT OF CMML, WITH OVERALL RESPONSE RATES OF 40-50% AND COMPLETE REMISSION RATES OF <20%. WHILE THESE AGENTS EPIGENETICALLY RESTORE HEMATOPOIESIS IN A SUBSET OF RESPONDING PATIENTS, THEY DO NOT IMPACT MUTATIONAL ALLELE BURDENS AND EVENTUAL DISEASE PROGRESSION TO AML REMAINS INEVITABLE. NEWER TREATMENT MODALITIES EXPLOITING EPIGENETIC, SIGNALING AND SPLICING ABNORMALITIES COMMONLY SEEN IN CMML ARE MUCH NEEDED.	2020	
                                                                                                                                                                                                                                                                                                                                                                  
7  1184  18 COOPERATIVE EPIGENETIC REMODELING BY TET2 LOSS AND NRAS MUTATION DRIVES MYELOID TRANSFORMATION AND MEK INHIBITOR SENSITIVITY. MUTATIONS IN EPIGENETIC MODIFIERS AND SIGNALING FACTORS OFTEN CO-OCCUR IN MYELOID MALIGNANCIES, INCLUDING TET2 AND NRAS MUTATIONS. CONCURRENT TET2 LOSS AND NRAS(G12D) EXPRESSION IN HEMATOPOIETIC CELLS INDUCED MYELOID TRANSFORMATION, WITH A FULLY PENETRANT, LETHAL CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), WHICH WAS SERIALLY TRANSPLANTABLE. TET2 LOSS AND NRAS MUTATION COOPERATIVELY LED TO DECREASE IN NEGATIVE REGULATORS OF MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) ACTIVATION, INCLUDING SPRY2, THEREBY CAUSING SYNERGISTIC ACTIVATION OF MAPK SIGNALING BY EPIGENETIC SILENCING. TET2/NRAS DOUBLE-MUTANT LEUKEMIA SHOWED PREFERENTIAL SENSITIVITY TO MAPK KINASE (MEK) INHIBITION IN BOTH MOUSE MODEL AND PATIENT SAMPLES. THESE DATA PROVIDE INSIGHTS INTO HOW EPIGENETIC AND SIGNALING MUTATIONS COOPERATE IN MYELOID TRANSFORMATION AND PROVIDE A RATIONALE FOR MECHANISM-BASED THERAPY IN CMML PATIENTS WITH THESE HIGH-RISK GENETIC LESIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8  3605  32 IMPROVING PARP INHIBITOR EFFICACY IN HIGH-GRADE SEROUS OVARIAN CARCINOMA: A FOCUS ON THE IMMUNE SYSTEM. HIGH-GRADE SEROUS OVARIAN CARCINOMA (HGSOC) IS A GENOMICALLY UNSTABLE MALIGNANCY RESPONSIBLE FOR OVER 70% OF ALL DEATHS DUE TO OVARIAN CANCER. WITH ROUGHLY 50% OF ALL HGSOC HARBORING DEFECTS IN THE HOMOLOGOUS RECOMBINATION (HR) DNA REPAIR PATHWAY (E.G., BRCA1/2 MUTATIONS), THE INTRODUCTION OF POLY ADP-RIBOSE POLYMERASE INHIBITORS (PARPI) HAS DRAMATICALLY IMPROVED OUTCOMES FOR WOMEN WITH HR DEFECTIVE HGSOC. BY BLOCKING THE REPAIR OF SINGLE-STRANDED DNA DAMAGE IN CANCER CELLS ALREADY LACKING HIGH-FIDELITY HR PATHWAYS, PARPI CAUSES THE ACCUMULATION OF DOUBLE-STRANDED DNA BREAKS, LEADING TO CELL DEATH. THUS, THIS SYNTHETIC LETHALITY RESULTS IN PARPI SELECTIVELY TARGETING CANCER CELLS, RESULTING IN IMPRESSIVE EFFICACY. DESPITE THIS, RESISTANCE TO PARPI COMMONLY DEVELOPS THROUGH DIVERSE MECHANISMS, SUCH AS THE ACQUISITION OF SECONDARY BRCA1/2 MUTATIONS. PERHAPS LESS WELL DOCUMENTED IS THAT PARPI CAN IMPACT BOTH THE TUMOUR MICROENVIRONMENT AND THE IMMUNE RESPONSE, THROUGH UPREGULATION OF THE STIMULATOR OF INTERFERON GENES (STING) PATHWAY, UPREGULATION OF IMMUNE CHECKPOINTS SUCH AS PD-L1, AND BY STIMULATING THE PRODUCTION OF PRO-INFLAMMATORY CYTOKINES. WHILST TARGETED IMMUNOTHERAPIES HAVE NOT YET FOUND THEIR PLACE IN THE CLINIC FOR HGSOC, THE EVIDENCE ABOVE, AS WELL AS ONGOING STUDIES EXPLORING THE SYNERGISTIC EFFECTS OF PARPI WITH IMMUNE AGENTS, INCLUDING IMMUNE CHECKPOINT INHIBITORS, SUGGESTS POTENTIAL FOR TARGETING THE IMMUNE RESPONSE IN HGSOC. ADDITIONALLY, COMBINING PARPI WITH EPIGENETIC-MODULATING DRUGS MAY IMPROVE PARPI EFFICACY, BY INDUCING A BRCA-DEFECTIVE PHENOTYPE TO SENSITISE RESISTANT CANCER CELLS TO PARPI. FINALLY, INVIGORATING AN IMMUNE RESPONSE DURING PARPI THERAPY MAY ENGAGE ANTI-CANCER IMMUNE RESPONSES THAT POTENTIATE EFFICACY AND MITIGATE THE DEVELOPMENT OF PARPI RESISTANCE. HERE, WE WILL REVIEW THE EMERGING PARPI LITERATURE WITH A FOCUS ON PARPI EFFECTS ON THE IMMUNE RESPONSE IN HGSOC, AS WELL AS THE POTENTIAL OF EPIGENETIC COMBINATION THERAPIES. WE HIGHLIGHT THE POTENTIAL OF TRANSFORMING HGSOC FROM A LETHAL TO A CHRONIC DISEASE AND INCREASING THE LIKELIHOOD OF CURE.	2022	
                                                                           
9  2326  25 EPIGENETIC REGULATION OF HOTAIR IN ADVANCED CHRONIC MYELOID LEUKEMIA. PURPOSE: CHRONIC MYELOID LEUKEMIA (CML) ACCOUNTS FOR ~10% OF LEUKEMIA CASES, AND ITS PROGRESSION INVOLVES EPIGENETIC GENE REGULATION. THIS STUDY INVESTIGATED EPIGENETIC REGULATION OF HOTAIR AND ITS TARGET MICRORNA, MIR-143, IN ADVANCED CML. PATIENTS AND METHODS: WE FIRST ISOLATED BONE MARROW MONONUCLEAR CELLS FROM 70 PATIENTS WITH DIFFERENT PHASES OF CML AND FROM HEALTHY DONORS AS NORMAL CONTROL; WE ALSO CULTURED K562 AND KCL22 CELLS, TREATED WITH DEMETHYLATION DRUG; MTT ASSAY, FLOW CYTOMETRY, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR), METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), WESTERN BLOT, LUCIFERASE ASSAY, RNA PULL-DOWN ASSAY AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION (RIP) ASSAY WERE PERFORMED. RESULT: AS MEASURED BY QPCR, HOTAIR EXPRESSION IN K562 CELLS, KCL22 CELLS, AND SAMPLES FROM CASES OF ADVANCED-STAGE CML INCREASED WITH LEVELS OF SEVERAL DNA METHYLTRANSFERASES AND HISTONE DEACETYLATES, INCLUDING DNMT1, DNMT3A, HDAC1, EZH2, AND LSD1, AND MIR-143 LEVELS WERE DECREASED AND HOTAIR LEVELS WERE INCREASED. TREATMENT WITH 5-AZACYTIDINE, A DNA METHYLATION INHIBITOR, DECREASED DNMT1, DNMT3A, HDAC1, EZH2, LSD1 MRNA, PROTEIN LEVELS, AND HOTAIR MRNA LEVELS BUT INCREASED MIR-143 LEVELS. HOTAIR KNOCKDOWN AND MIR-143 OVEREXPRESSION BOTH INHIBITED PROLIFERATION AND PROMOTED APOPTOSIS IN KCL22 AND K562 CELLS THROUGH THE PI3K/AKT PATHWAY. RNA PULL-DOWN, MASS SPECTROMETRY, AND RIP ASSAYS SHOWED THAT HOTAIR INTERACTED WITH EZH2 AND LSD1. A DUAL-LUCIFERASE ASSAY DEMONSTRATED THAT HOTAIR INTERACTED WITH MIR-143. CONCLUSION: OUR FINDINGS DEMONSTRATE THE KEY EPIGENETIC INTERACTIONS OF HOTAIR RELATED TO CML PROGRESSION AND SUGGEST HOTAIR AS A POTENTIAL THERAPEUTIC TARGET FOR ADVANCED CML. FURTHERMORE, OUR RESULTS SUPPORT THE USE OF DEMETHYLATION DRUGS AS A CML TREATMENT STRATEGY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                   
10  4565  17 MYELOID MALIGNANCIES: MUTATIONS, MODELS AND MANAGEMENT. MYELOID MALIGNANT DISEASES COMPRISE CHRONIC (INCLUDING MYELODYSPLASTIC SYNDROMES, MYELOPROLIFERATIVE NEOPLASMS AND CHRONIC MYELOMONOCYTIC LEUKEMIA) AND ACUTE (ACUTE MYELOID LEUKEMIA) STAGES. THEY ARE CLONAL DISEASES ARISING IN HEMATOPOIETIC STEM OR PROGENITOR CELLS. MUTATIONS RESPONSIBLE FOR THESE DISEASES OCCUR IN SEVERAL GENES WHOSE ENCODED PROTEINS BELONG PRINCIPALLY TO FIVE CLASSES: SIGNALING PATHWAYS PROTEINS (E.G. CBL, FLT3, JAK2, RAS), TRANSCRIPTION FACTORS (E.G. CEBPA, ETV6, RUNX1), EPIGENETIC REGULATORS (E.G. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), TUMOR SUPPRESSORS (E.G. TP53), AND COMPONENTS OF THE SPLICEOSOME (E.G. SF3B1, SRSF2). LARGE-SCALE SEQUENCING EFFORTS WILL SOON LEAD TO THE ESTABLISHMENT OF A COMPREHENSIVE REPERTOIRE OF THESE MUTATIONS, ALLOWING FOR A BETTER DEFINITION AND CLASSIFICATION OF MYELOID MALIGNANCIES, THE IDENTIFICATION OF NEW PROGNOSTIC MARKERS AND THERAPEUTIC TARGETS, AND THE DEVELOPMENT OF NOVEL THERAPIES. GIVEN THE IMPORTANCE OF EPIGENETIC DEREGULATION IN MYELOID DISEASES, THE USE OF DRUGS TARGETING EPIGENETIC REGULATORS APPEARS AS A MOST PROMISING THERAPEUTIC APPROACH.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
11  4442  17 MOLECULAR GENETICS OF MDS/MPN OVERLAP SYNDROMES. THE MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE A HETEROGENOUS GROUP OF MYELOID MALIGNANCIES HALLMARKED BY CLINICOPATHOLOGIC FEATURES THAT OVERLAP WITH MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. FORMALLY RECOGNIZED BY THE WORLD HEALTH ORGANIZATION, THIS GROUP INCLUDES THE ENTITIES CHRONIC MYELOMONOCYTIC LEUKEMIA, JUVENILE MYELOMONOCYTIC LEUKEMIA, ATYPICAL CHRONIC MYELOID LEUKEMIA, MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS AND MDS/MPN, UNCLASSIFIABLE. ADVANCEMENTS IN NEXT GENERATION SEQUENCING HAVE BEGUN TO UNRAVEL THE MOLECULAR UNDERPINNINGS OF THESE DISEASES, IDENTIFYING AN ARRAY OF RECURRENTLY MUTATED GENES INVOLVED IN EPIGENETIC REGULATION, RNA SPLICING, TRANSCRIPTION, AND CELL SIGNALING. DESPITE MOLECULAR OVERLAP WITH OTHER MYELOID MALIGNANCIES, EACH ENTITY DISPLAYS A UNIQUE SPECTRUM OF SOMATIC MUTATIONS SUPPORTING THEIR UNIQUE PATHOBIOLOGY AND CLINICAL FEATURES. IMPORTANTLY, MOLECULAR PROFILING IS BECOMING AN INTEGRAL TOOL UTILIZED IN ROUTINE CLINICAL PRACTICE. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF OVERLAP SYNDROMES AND DETAILS THE IMPACT OF SOMATIC MUTATIONS IN DIAGNOSTIC, PROGNOSTIC, AND THERAPEUTIC DECISION-MAKING.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12  4877  27 OVEREXPRESSION OF MIR-4433 BY SUBEROYLANILIDE HYDROXAMIC ACID SUPPRESSES GROWTH OF CML CELLS AND INDUCES APOPTOSIS THROUGH TARGETING BCR-ABL. BACKGROUND: TARGETING BCR-ABL IS THE KEY FOR THE TREATMENT OF CML. ALTHOUGH GREAT PROGRESS HAS BEEN ACHIEVED FOR THE TREATMENT OF CML PATIENTS IN CHRONIC STAGE, EFFECTIVE DRUGS WITH GOOD SAFETY ARE NOT AVAILABLE FOR THOSE IN ADVANCED STAGES OF CML PATIENTS. IN PRESENT STUDY, A HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), WAS USED TO SCREEN FOR MICRORNA THAT CAN TARGET BCR-ABL. METHODS: RT-QPCR WAS USED TO DETERMINE BCR-ABL AND MIR-4433 TRANSCRIPTION LEVEL IN CML CELLS. IN CML CELLS, PROTEINS INCLUDING PARP, CASPASE-3, ACETYL-HISTONE 3, HISTONE 3 AND BCR-ABL, AS WELL AS BCR-ABL DOWNSTREAM PROTEINS WERE DETECTED USING WESTERN BLOT. CELL VIABILITY AND APOPTOSIS WERE MONITORED RESPECTIVELY BY MTS ASSAY AND FLOW CYTOMETRY. THE CORRELATION BETWEEN MIR-4433 AND BCR-ABL WAS DETERMINED BY LUCIFERASE REPORTER ASSAY. THE ANTI-TUMOR EFFECT OF MIR-4433 TO K562 CELLS WAS EVALUATED BY NUDE MOUSE XENOGRAFT MODEL IN VIVO. RESULTS: SAHA UP-REGULATED THE ACETYLATION LEVEL OF HISTONE 3, AND EFFECTIVELY INHIBITED BCR-ABL MRNA LEVEL AND ITS DOWNSTREAM SIGNAL TRANSDUCTION PATHWAY, WHILE INHIBITING THE GROWTH OF CML CELLS AND INDUCING APOPTOSIS. FURTHERMORE, BIOINFORMATICS TOOLS PREDICTED THAT MIR-4433 IS A PUTATIVE MICRORNA TARGETING BCR-ABL AND THAT THE EXPRESSION LEVEL OF MIR-4433 WAS SIGNIFICANTLY INCREASED AFTER SAHA TREATMENT IN K562 CELLS. LUCIFERASE ACTIVITY ANALYSIS REVEALED THAT MIR-4433 DIRECTLY TARGETS BCR-ABL. ADDITIONALLY, TRANSIENT EXPRESSION OF MIR-4433 ABROGATED BCR-ABL ACTIVITY AND ITS DOWNSTREAM SIGNALING PATHWAYS WHILE INDUCING APOPTOSIS IN K562 CELLS. MOREOVER, STABLE EXPRESSION OF MIR-4433 SUPPRESSED BCR-ABL AND ITS DOWNSTREAM SIGNALING PATHWAY, AND INHIBITED THE GROWTH OF K562 CELLS IN VITRO AND THE GROWTH OF K562-XENOGRAFTS IN NUDE MICE. CONCLUSION: MIR-4433 WAS IDENTIFIED AS A MICRORNA TARGETING BCR-ABL, WHICH MAY BE SUBJECT TO EPIGENETIC REGULATION OF SAHA, A HISTONE DEACETYLASE INHIBITOR THAT HAS BEEN APPROVED BY THE US FDA FOR THE TREATMENT OF CUTANEOUS T-CELL LYMPHOMA. THE FINDINGS OF THIS STUDY PROVIDE A MOLECULAR BASIS FROM ANOTHER ANGLE FOR THE USE OF SAHA IN THE TREATMENT OF CML.	2019	

13  3872  27 JUVENILE MYELOMONOCYTIC LEUKEMIA-A COMPREHENSIVE REVIEW AND RECENT ADVANCES IN MANAGEMENT. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A RARE PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP DISEASE. JMML IS ASSOCIATED WITH MUTATIONS IN THE RAS PATHWAY GENES RESULTING IN THE MYELOID PROGENITORS BEING SENSITIVE TO GRANULOCYTE MONOCYTE COLONY-STIMULATING FACTOR (GM-CSF). KARYOTYPE ABNORMALITIES AND ADDITIONAL EPIGENETIC ALTERATIONS CAN ALSO BE FOUND IN JMML. NEUROFIBROMATOSIS AND NOONAN'S SYNDROME HAVE A PREDISPOSITION FOR JMML. IN A FEW PATIENTS, THE RAS GENES (NRAS, KRAS, AND PTPN11) ARE MUTATED AT THE GERMLINE AND THIS USUALLY RESULTS IN A TRANSIENT MYELOPROLIFERATIVE DISORDER WITH A GOOD PROGNOSIS. JMML WITH SOMATIC RAS MUTATION BEHAVES AGGRESSIVELY. JMML PRESENTS WITH CYTOPENIAS AND LEUKEMIC INFILTRATION INTO ORGANS. THE LABORATORY FINDINGS INCLUDE HYPERLEUKOCYTOSIS, MONOCYTOSIS, INCREASED HEMOGLOBIN-F LEVELS, AND CIRCULATING MYELOID PRECURSORS. THE BLAST CELLS IN THE PERIPHERAL BLOOD/BONE-MARROW ASPIRATE ARE LESS THAN 20% AND THE ABSENCE OF THE BCR-ABL TRANSLOCATION HELPS TO DIFFERENTIATE FROM CHRONIC MYELOID LEUKEMIA. JMML SHOULD BE DIFFERENTIATED FROM IMMUNODEFICIENCIES, VIRAL INFECTIONS, INTRAUTERINE INFECTIONS, HEMOPHAGOLYMPHOHISTIOCYTOSIS, OTHER MYELOPROLIFERATIVE DISORDERS, AND LEUKEMIAS. CHEMOTHERAPY IS EMPLOYED AS A BRIDGE TO HSCT, EXCEPT IN FEW WITH LESS AGGRESSIVE DISEASE, IN WHICH CHEMOTHERAPY ALONE CAN RESULT IN LONG TERM REMISSION. AZACITIDINE HAS SHOWN PROMISE AS A SINGLE AGENT TO STABILIZE THE DISEASE. THE PROGNOSIS OF JMML IS POOR WITH ABOUT 50% OF PATIENTS SURVIVING AFTER AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). ALLOGENEIC HSCT IS THE ONLY KNOWN CURE FOR JMML TO DATE. MYELOABLATIVE CONDITIONING IS MOST COMMONLY USED WITH GRAFT VERSUS HOST DISEASE (GVHD) PROPHYLAXIS TAILORED TO THE AGGRESSIVENESS OF THE DISEASE. RELAPSES ARE COMMON EVEN AFTER HSCT AND A SECOND HSCT CAN SALVAGE A THIRD OF THESE PATIENTS. NOVEL OPTIONS IN THE TREATMENT OF JMML E.G., HYPOMETHYLATING AGENTS, MEK INHIBITORS, JAK INHIBITORS, TYROSINE KINASE INHIBITORS, ETC. ARE BEING EXPLORED.	2021	
                                                                                                                                                           
14  5459  20 RESEARCH ON THE EPIGENETIC REGULATION MECHANISM OF THE PTPN6 GENE IN ADVANCED CHRONIC MYELOID LEUKAEMIA. PTPN6, A TYROSINE PHOSPHATASE PROTEIN, PLAYS A NEGATIVE ROLE IN CELL SIGNAL TRANSDUCTION AND IS NEGATIVELY CORRELATED WITH TUMOUR FORMATION AND GROWTH. HOWEVER, EPIGENETIC REGULATION MECHANISM OF THE PTPN6 GENE IN ADVANCED CHRONIC MYELOID LEUKAEMIA (CML) REMAINS UNCLEAR. THIS STUDY INVESTIGATED BONE MARROW OR BLOOD SAMPLES FROM 44 CML PATIENTS AND 10 HEALTHY VOLUNTEERS. KCL22 AND K562 CELLS WERE CULTURED AND TREATED WITH DEMETHYLATION DRUGS AND HISTONE DEACETYLASE INHIBITORS. REAL TIME QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR), METHYLATION-SPECIFIC PCR, BISULFITE SEQUENCING PCR, WESTERN BLOTTING, CO-IMMUNOPRECIPITATION AND CHROMATIN IMMUNOPRECIPITATION (CHIP) WAS PERFORMED. PTPN6 WAS DOWN-REGULATED IN CELL LINES AND PATIENTS WITH ADVANCED PHASE CML, WHEREAS DNMT1, DNMT3A, MECP2, MBD2 AND HDAC1 WERE UP-REGULATED. TREATMENT WITH 5-AZACYTIDINE, DECITABINE, SODIUM VALPROATE AND LBH589 INCREASED PTPN6 EXPRESSION, BUT DECREASED THAT OF DNMT1, DNMT3A, MECP2, MBD2 AND HDAC1. IMMUNOPRECIPITATION AND MASS SPECTROMETRY SHOWED THAT HDAC1 COMBINED DIRECTLY WITH PTPN6. CHIP-SEQ SHOWED THAT HDAC1 DID NOT COMBINE WITH THE PROMOTER REGION OF PTPN6, WHILE MAPK, AKT, STAT5, JAK2 AND MYC PROMOTER REGIONS ALL COMBINED WITH HDAC1. PTPN6 IS ASSOCIATED WITH PROGRESSION OF CML. LOW EXPRESSION LEVEL OF PTPN6 WAS ASSOCIATED WITH DNA METHYLATION AND REGULATED BY HISTONE ACETYLATION. HDAC1 PARTICIPATES IN THE REGULATION OF PTPN6.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15   957  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16   959  22 CHRONIC MYELOMONOCYTIC LEUKEMIA AND ATYPICAL CHRONIC MYELOID LEUKEMIA: NOVEL PATHOGENETIC LESIONS. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) ARE DISTINCT, YET RELATED, ENTITIES OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) CHARACTERIZED BY MORPHOLOGIC DYSPLASIA WITH ACCUMULATION OF MONOCYTES OR NEUTROPHILS, RESPECTIVELY. OUR UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CMML AND ACML HAS ADVANCED, MAINLY DUE TO THE APPLICATION OF NOVEL TECHNOLOGIES SUCH AS ARRAY-BASED KARYOTYPING AND NEXT-GENERATION SEQUENCING. IN ADDITION TO PREVIOUSLY KNOWN RECURRENT ABERRATIONS, SOMATIC UNIPARENTAL DISOMY AFFECTING CHROMOSOMES 3, 4, 7, AND 11 FREQUENTLY OCCURS IN CMML. NOVEL SOMATIC MUTATIONS OF GENES, INCLUDING THOSE ASSOCIATED WITH PROLIFERATION SIGNALING (CBL, RAS, RUNX1, JAK2 (V617F)) AND WITH MODIFICATION OF EPIGENETIC STATUS (TET2, ASXL1, UTX, EZH2) HAVE BEEN FOUND. VARIOUS COMBINATIONS OF MUTATIONS SUGGEST A MULTISTEP PATHOGENESIS AND MAY ACCOUNT FOR CLINICAL HETEROGENEITY. MOST RECENTLY, SEVERAL SPLICEOSOME-ASSOCIATED-GENE MUTATIONS WERE REPORTED AND SRSF2 MUTATIONS ARE FREQUENTLY DETECTED IN CMML. THE PROGNOSTIC AND DIAGNOSTIC SIGNIFICANCE OF THESE MOLECULAR LESIONS, IN PARTICULAR THEIR VALUE AS BIOMARKERS OF RESPONSE OR RESISTANCE TO SPECIFIC THERAPIES, WHILE UNCERTAIN NOW IS LIKELY TO BE CLARIFIED AS LARGE SYSTEMATIC STUDIES COME TO COMPLETION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17   826  24 CHARACTERIZATION OF K562 CELLS: UNCOVERING NOVEL CHROMOSOMES, ASSESSING TRANSFERRIN RECEPTOR EXPRESSION, AND PROBING PHARMACOLOGICAL THERAPIES. HUMAN ERYTHROLEUKEMIC K562 CELLS REPRESENT THE PROTOTYPICAL CELL CULTURE MODEL OF CHRONIC MYELOID LEUKEMIA (CML). THE CELLS ARE PSEUDO-TRIPLOID AND POSITIVE FOR THE PHILADELPHIA CHROMOSOME. THEREFORE, K562 CELLS HAVE BEEN WIDELY USED FOR INVESTIGATING THE BCR/ABL1 ONCOGENE AND THE TYROSINE KINASE INHIBITOR, IMATINIB-MESYLATE. FURTHER, K562 CELLS OVEREXPRESS TRANSFERRIN RECEPTORS (TFR) AND HAVE BEEN USED AS A MODEL FOR TARGETING CYTOTOXIC THERAPIES, VIA RECEPTOR-MEDIATED ENDOCYTOSIS. HERE, WE HAVE CHARACTERIZED K562 CELLS FOCUSING ON THE KARYOTYPE OF CELLS IN PROLONGED CULTURE, REGULATION OF EXPRESSION OF TFR IN WILDTYPE (WT) AND DOXORUBICIN-RESISTANT CELLS, AND RESPONSES TO HISTONE DEACETYLASE INHIBITION (HDACI). KARYOTYPE ANALYSIS INDICATES NOVEL CHROMOSOMES AND GENE EXPRESSION ANALYSIS SUGGESTS A SHIFT OF CULTURED K562 CELLS AWAY FROM PATIENT-DERIVED LEUKEMIC CELLS. WE CONFIRM THE HIGH EXPRESSION OF TFR ON K562 CELLS USING IMMUNOFLUORESCENCE AND CELL-SURFACE RECEPTOR BINDING RADIOASSAYS. IMPORTANTLY, HIGH TFR EXPRESSION IS OBSERVED IN PATIENT-DERIVED CELLS, AND WE HIGHLIGHT THE PERSISTENT EXPRESSION OF TFR FOLLOWING DOXORUBICIN ACQUIRED RESISTANCE. EPIGENETIC ANALYSIS INDICATES THAT PERMISSIVE HISTONE ACETYLATION AND METHYLATION AT THE PROMOTER REGION REGULATES THE TRANSCRIPTION OF TFR IN K562 CELLS. FINALLY, WE SHOW RELATIVELY HIGH EXPRESSION OF HDAC ENZYMES IN K562 CELLS AND DEMONSTRATE THE CHEMOTOXIC EFFECTS OF HDACI, USING THE FDA-APPROVED HYDROXAMIC ACID, VORINOSTAT. TOGETHER WITH A DESCRIPTION OF MORPHOLOGY, INFRARED SPECTRAL ANALYSIS, AND EXAMINATION OF METABOLIC PROPERTIES, WE PROVIDE A COMPREHENSIVE CHARACTERIZATION OF K562 CELLS. OVERALL, K562 CELL CULTURE SYSTEMS REMAIN WIDELY USED FOR THE INVESTIGATION OF NOVEL THERAPEUTICS FOR CML, WHICH IS PARTICULARLY IMPORTANT IN CASES OF IMATINIB-MESYLATE RESISTANCE.	2023	
                                                                                                                                                                                                                                                                                                           
18  4485  16 MOLECULAR SIMILARITY BETWEEN MYELODYSPLASTIC FORM OF CHRONIC MYELOMONOCYTIC LEUKEMIA AND REFRACTORY ANEMIA WITH RING SIDEROBLASTS. CHRONIC MYELOMONOCYTIC LEUKEMIA IS SIMILAR TO BUT A SEPARATE ENTITY FROM BOTH MYELOPROLIFERATIVE NEOPLASMS AND MYELODYSPLASTIC SYNDROMES, AND SHOWS EITHER MYELOPROLIFERATIVE OR MYELODYSPLASTIC FEATURES. WE ASK WHETHER THIS DISTINCTION MAY HAVE A MOLECULAR BASIS. WE ESTABLISHED THE GENE EXPRESSION PROFILES OF 39 SAMPLES OF CHRONIC MYELOMONOCYTIC LEUKEMIA (INCLUDING 12 CD34-POSITIVE) AND 32 CD34-POSITIVE SAMPLES OF MYELODYSPLASTIC SYNDROMES BY USING AFFYMETRIX MICROARRAYS, AND STUDIED THE STATUS OF 18 GENES BY SANGER SEQUENCING AND ARRAY-COMPARATIVE GENOMIC HYBRIDIZATION IN 53 SAMPLES. ANALYSIS OF 12 MRNAS FROM CHRONIC MYELOMONOCYTIC LEUKEMIA ESTABLISHED A GENE EXPRESSION SIGNATURE OF 122 PROBE SETS DIFFERENTIALLY EXPRESSED BETWEEN PROLIFERATIVE AND DYSPLASTIC CASES OF CHRONIC MYELOMONOCYTIC LEUKEMIA. AS COMPARED TO PROLIFERATIVE CASES, DYSPLASTIC CASES OVER-EXPRESSED GENES INVOLVED IN RED BLOOD CELL BIOLOGY. WHEN APPLIED TO 32 MYELODYSPLASTIC SYNDROMES, THIS GENE EXPRESSION SIGNATURE WAS ABLE TO DISCRIMINATE REFRACTORY ANEMIAS WITH RING SIDEROBLASTS FROM REFRACTORY ANEMIAS WITH EXCESS OF BLASTS. BY COMPARING MRNAS FROM THESE TWO FORMS OF MYELODYSPLASTIC SYNDROMES WE DERIVED A SECOND GENE EXPRESSION SIGNATURE. THIS SIGNATURE SEPARATED THE MYELODYSPLASTIC AND MYELOPROLIFERATIVE FORMS OF CHRONIC MYELOMONOCYTIC LEUKEMIAS. THESE RESULTS WERE VALIDATED USING TWO INDEPENDENT GENE EXPRESSION DATA SETS. WE FOUND THAT MYELODYSPLASTIC CHRONIC MYELOMONOCYTIC LEUKEMIAS ARE CHARACTERIZED BY MUTATIONS IN TRANSCRIPTION/EPIGENETIC REGULATORS (ASXL1, RUNX1, TET2) AND SPLICING GENES (SRSF2) AND THE ABSENCE OF MUTATIONS IN SIGNALING GENES. MYELODYSPLASTIC CHRONIC MYELOMONOCYTIC LEUKEMIAS AND REFRACTORY ANEMIAS WITH RING SIDEROBLASTS SHARE A COMMON EXPRESSION PROGRAM SUGGESTING THEY ARE PART OF A CONTINUUM, WHICH IS NOT TOTALLY EXPLAINED BY THEIR SIMILAR BUT NOT, HOWEVER, IDENTICAL MUTATION SPECTRUM.	2013	
                                                                                                                                                                                                                                                           
19  4557  18 MUTATIONS IN ASXL1 ARE ASSOCIATED WITH POOR PROGNOSIS ACROSS THE SPECTRUM OF MALIGNANT MYELOID DISEASES. THE ASXL1 GENE IS ONE OF THE MOST FREQUENTLY MUTATED GENES IN MALIGNANT MYELOID DISEASES. THE ASXL1 PROTEIN BELONGS TO PROTEIN COMPLEXES INVOLVED IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. ASXL1 MUTATIONS ARE FOUND IN MYELOPROLIFERATIVE NEOPLASMS (MPN), MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ACUTE MYELOID LEUKEMIA (AML). THEY ARE GENERALLY ASSOCIATED WITH SIGNS OF AGGRESSIVENESS AND POOR CLINICAL OUTCOME. BECAUSE OF THIS, A SYSTEMATIC DETERMINATION OF ASXL1 MUTATIONAL STATUS IN MYELOID MALIGNANCIES SHOULD HELP IN PROGNOSIS ASSESSMENT.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20  2189  25 EPIGENETIC MECHANISMS UNDERLYING THE THERAPEUTIC EFFECTS OF HDAC INHIBITORS IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A HEMATOLOGICAL DISORDER CAUSED BY THE ONCOGENIC BCR-ABL FUSION PROTEIN IN MORE THAN 90% OF PATIENTS. DESPITE THE STRIKING IMPROVEMENTS IN THE MANAGEMENT OF CML PATIENTS SINCE THE INTRODUCTION OF TYROSINE KINASE INHIBITORS (TKIS), THE APPEARANCE OF TKI RESISTANCE AND SIDE EFFECTS LEAD TO TREATMENT FAILURE, JUSTIFYING THE NEED OF NOVEL THERAPEUTIC APPROACHES. HISTONE DEACETYLASE INHIBITORS (HDACIS), ABLE TO MODULATE GENE EXPRESSION PATTERNS AND IMPORTANT CELLULAR SIGNALING PATHWAYS THROUGH THE REGULATION OF THE ACETYLATION STATUS OF BOTH HISTONE AND NON-HISTONE PROTEIN TARGETS, HAVE BEEN REPORTED TO DISPLAY PROMISING ANTI-LEUKEMIC PROPERTIES ALONE OR IN COMBINATION WITH TKIS. THIS REVIEW SUMMARIZES PRE-CLINICAL AND CLINICAL STUDIES THAT INVESTIGATED THE MECHANISMS UNDERLYING THE ANTICANCER POTENTIAL OF HDACIS AND DISCUSSES THE RATIONALE FOR A COMBINATION OF HDACIS WITH TKIS AS A THERAPEUTIC OPTION IN CML.	2020