1 3520 146 IGLV3-21R110 IDENTIFIES AN AGGRESSIVE BIOLOGICAL SUBTYPE OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH INTERMEDIATE EPIGENETICS. B-CELL RECEPTOR (BCR) SIGNALING IS CRUCIAL FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) BIOLOGY. IGLV3-21-EXPRESSING B CELLS MAY ACQUIRE A SINGLE POINT MUTATION (R110) THAT TRIGGERS AUTONOMOUS BCR SIGNALING, CONFERRING AGGRESSIVE BEHAVIOR. EPIGENETIC STUDIES HAVE DEFINED 3 CLL SUBTYPES BASED ON METHYLATION SIGNATURES REMINISCENT OF NAIVE-LIKE (N-CLL), INTERMEDIATE (I-CLL), AND MEMORY-LIKE (M-CLL) B CELLS WITH DIFFERENT BIOLOGICAL FEATURES. I-CLL CARRIES A BORDERLINE IGHV MUTATIONAL LOAD AND SIGNIFICANTLY HIGHER USE OF IGHV3-21/IGLV3-21. TO DETERMINE THE CLINICAL AND BIOLOGICAL FEATURES OF IGLV3-21R110 CLL AND ITS RELATIONSHIP TO THESE EPIGENETIC SUBTYPES, WE CHARACTERIZED THE IMMUNOGLOBULIN GENE OF 584 CLL CASES USING WHOLE-GENOME/EXOME AND RNA SEQUENCING. IGLV3-21R110 WAS DETECTED IN 6.5% OF CASES: 30 (38%) OF 79 I-CLLS, 5 (1.7%) OF 291 M-CLLS, AND 1 (0.5%) OF 189 N-CLLS. ALL STEREOTYPE SUBSET 2 CASES CARRIED IGLV3-21R110, WHEREAS 62% OF IGLV3-21R110 I-CLL CASES HAD NONSTEREOTYPED BCR IMMUNOGLOBULINS. IGLV3-21R110 I-CLL HAD A SIGNIFICANTLY HIGHER NUMBER OF SF3B1 AND ATM MUTATIONS AND TOTAL NUMBER OF DRIVER ALTERATIONS. HOWEVER, THE R110 MUTATION WAS THE SOLE ALTERATION IN 1 I-CLL AND WAS ACCOMPANIED ONLY BY DEL(13Q) IN 3. ALTHOUGH IGHV MUTATIONAL STATUS VARIED, IGLV3-21R110 I-CLL TRANSCRIPTOMICALLY RESEMBLED N-CLL/UNMUTATED IGHV CLL WITH A SPECIFIC SIGNATURE INCLUDING WNT5A/B OVEREXPRESSION. IN CONTRAST, I-CLL LACKING IGLV3-21R110 MIRRORED M-CLL/MUTATED IGHV. PATIENTS WITH IGLV3-21R110 I-CLL HAD A SHORT TIME TO FIRST TREATMENT AND OVERALL SURVIVAL SIMILAR TO THOSE OF N-CLL/UNMUTATED IGHV PATIENTS, WHEREAS PATIENTS WITH NON-IGLV3-21R110 I-CLL HAD A GOOD PROGNOSIS SIMILAR TO THAT OF PATIENTS WITH M-CLL/MUTATED IGHV. IGLV3-21R110 DEFINES A CLL SUBGROUP WITH SPECIFIC BIOLOGICAL FEATURES AND AN UNFAVORABLE PROGNOSIS INDEPENDENT OF IGHV MUTATIONAL STATUS AND EPIGENETIC SUBTYPE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2 2974  26 GENETIC AND METHYLATION STATUS OF CDKN2A (P14(ARF)/P16(INK4A)) AND TP53 GENES IN RECURRENT RESPIRATORY PAPILLOMATOSIS. RECURRENT RESPIRATORY PAPILLOMATOSIS (RRP) IS A RARE AND CHRONIC DISEASE AFFECTING THE UPPER AIRWAY WITH PAPILLOMATOUS LESIONS CAUSED BY THE HUMAN PAPILLOMAVIRUS (HPV) INFECTION, ESPECIALLY HPV-6 AND/OR HPV-11 TYPES. LITTLE IS KNOWN ABOUT THE GENETIC AND EPIGENETIC DRIVERS IN RRP PATHOPHYSIOLOGY. FOR THIS PURPOSE, WE ANALYZED 27 PAPILLOMATOUS LESIONS FROM PATIENTS WITH RRP TO EVALUATE SOMATIC MUTATIONS AND METHYLATION STATUS IN CDKN2A (P14(ARF)/P16(INK4A)) AND TP53, WHICH ARE KEY TUMOR SUPPRESSOR GENES FOR THE CELL CYCLE CONTROL. SANGER SEQUENCING ANALYSIS REVEALED ONE SOMATIC MUTATION IN TP53 (C.733_734INSA) AND FOUR MUTATIONS IN CDKN2A (C.-30G > T, C.29_30INSA, C.69DELT, AND C.300C > A). THESE MUTATIONS WERE OBSERVED IN 10 PATIENTS, 6 OF WHICH CARRIED DOUBLE MUTATION. FURTHERMORE, 50% (5/10) OF THESE PATIENTS CARRYING SOMATIC MUTATIONS HAD RRP SEVERITY, REPRESENTING 62.5% (5/8) OF THE SEVERITY CASES IN THIS STUDY, ALBEIT NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN SOMATIC MUTATIONS AND DISEASE SEVERITY. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION ASSAYS REVEALED P14(ARF) PROMOTER HYPERMETHYLATION IN 100% OF CASES, FOLLOWED BY TP53 (96.3%) AND P16(INK4A) (55.6%), SUGGESTING THE INFLUENCE OF HPV IN THE DNA METHYLATION MACHINERY. IN CONCLUSION, SOMATIC MUTATIONS WERE NOT COMMON EVENTS IDENTIFIED IN PATIENTS WITH RRP. HOWEVER, EPIGENETIC MODULATION BY HIGH METHYLATION RATES, PARTICULARLY FOR THE P14(ARF)/TP53 PATHWAY, SEEMS TO BE IN THE COURSE OF RRP DEVELOPMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3 2125  29 EPIGENETIC INACTIVATION OF DLX4 IS ASSOCIATED WITH DISEASE PROGRESSION IN CHRONIC MYELOID LEUKEMIA. ABERRANT DNA METHYLATION OF VARIOUS GENES HAS BEEN IDENTIFIED TO BE ASSOCIATED WITH DISEASE PROGRESSION IN CHRONIC MYELOID LEUKEMIA (CML). OUR STUDY WAS INTENDED TO INVESTIGATE DLX4 METHYLATION PATTERN IN DIFFERENT CLINICAL STAGES OF CML AND FURTHER DETERMINE ITS ROLE IN REGULATING DLX4 EXPRESSION. REAL-TIME QUANTITATIVE METHYLATION-SPECIFIC PCR AND BISULFITE SEQUENCING PCR WERE APPLIED TO DETECT DLX4 METHYLATION. 5-AZA-2'-DEOXYCYTIDINE (5-AZA-DC) WAS USED FOR DEMETHYLATION STUDIES. DLX4 WAS SIGNIFICANTLY HYPERMETHYLATED IN CML PATIENTS (P = 0.002) ESPECIALLY IN BLASTIC PHASE (BC) STAGE (P < 0.001) AS COMPARED WITH CONTROLS. MOREOVER, DLX4 METHYLATION LEVEL IN BC STAGE WAS SIGNIFICANTLY HIGHER THAN IN CHRONIC PHASE (CP) STAGE (P < 0.001). DLX4 METHYLATION DENSITY WAS SIGNIFICANTLY INCREASED DURING THE PROGRESSION OF CML AMONG THE TESTED TWO PATIENTS (P < 0.001). DLX4 HYPERMETHYLATION OCCURRED WITH THE HIGHEST INCIDENCE IN BC STAGE (83%), LOWER INCIDENCE IN ACUTE PHASE (AP) STAGE (43%), AND THE LOWEST INCIDENCE IN CP STAGE (26%) (P = 0.001). MOREOVER, T(9; 22) WITH ADDITIONAL ALTERATION CASES HAD SIGNIFICANTLY HIGHER FREQUENCY OF DLX4 HYPERMETHYLATION COMPARED WITH THE OTHER CYTOGENETICS (P = 0.010). SIGNIFICANTLY NEGATIVE CORRELATION WAS OBSERVED BETWEEN DLX4 METHYLATION AND DLX4-TV2 (THE SHORTER DLX4 ISOFORM) EXPRESSION (R = -0.382, P = 0.001, N = 78) BUT NOT BETWEEN DLX4 METHYLATION AND BP1 (THE LONGER DLX4 ISOFORM) EXPRESSION (R = 0.134, P = 0.244, N = 78) IN CML PATIENTS. BOTH DLX4-TV2 AND BP1 MRNA WERE SIGNIFICANTLY INCREASED AFTER 5-AZA-DC TREATMENT IN K562 CELL LINE (P < 0.001). OUR STUDY INDICATED THAT HYPERMETHYLATION OF DLX4 CORRELATED WITH DISEASE PROGRESSION OF CML. MOREOVER, DLX4 EXPRESSION WAS REGULATED BY ITS METHYLATION IN CML.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  829  28 CHARACTERIZATION OF P190-BCR-ABL CHRONIC MYELOID LEUKEMIA REVEALS SPECIFIC SIGNALING PATHWAYS AND THERAPEUTIC TARGETS. THE ONCOGENIC PROTEIN BCR-ABL HAS TWO MAJOR ISOFORMS, P190(BCR-ABL) AND P210(BCR-ABL). WHILE P210(BCR-ABL) IS THE HALLMARK OF CHRONIC MYELOID LEUKEMIA (CML), P190(BCR-ABL) OCCURS IN THE MAJORITY OF PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (PH + ALL) PATIENTS. IN CML, P190(BCR-ABL) OCCURS IN A MINORITY OF PATIENTS ASSOCIATING WITH DISTINCT HEMATOLOGICAL FEATURES AND INFERIOR OUTCOMES, YET THE PATHOGENIC ROLE OF P190(BCR-ABL) AND POTENTIAL TARGETING THERAPIES ARE LARGELY UNCHARACTERIZED. WE EMPLOYED NEXT GENERATION SEQUENCING, PHOSPHO-PROTEOMIC PROFILING, AND DRUG SENSITIVITY TESTING TO CHARACTERIZE P190(BCR-ABL) IN CML AND HEMATOPOIETIC PROGENITOR CELL LINE MODELS (BA/F3 AND HPC-LSK). P190(BCR-ABL) CML PATIENTS DEMONSTRATED POOR RESPONSE TO IMATINIB AND FREQUENT MUTATIONS IN EPIGENETIC MODIFIERS GENES. IN CONTRAST WITH P210(BCR-ABL), P190(BCR-ABL) EXHIBITED SPECIFIC TRANSCRIPTIONAL UPREGULATION OF INTERFERON, INTERLEUKIN-1 RECEPTOR, AND P53 SIGNALING PATHWAYS, ASSOCIATED WITH HYPERPHOSPHORYLATION OF RELEVANT SIGNALING MOLECULES INCLUDING JAK1/STAT1 AND PAK1 IN ADDITION TO SRC HYPERPHOSPHORYLATION. COMPARABLE TO P190(BCR-ABL) CML PATIENTS, P190(BCR-ABL) CELL LINES DEMONSTRATED SIMILAR TRANSCRIPTIONAL AND PHOSPHO-SIGNALING SIGNATURES. WITH THE DRUG SENSITIVITY SCREENING WE IDENTIFIED TARGETED DRUGS WITH SPECIFIC ACTIVITY IN P190(BCR-ABL) CELL LINES INCLUDING IAP-, PAK1-, AND SRC INHIBITORS AND GLUCOCORTICOIDS. OUR RESULTS PROVIDE NOVEL INSIGHTS INTO THE MECHANISMS UNDERLYING THE DISTINCT FEATURES OF P190(BCR-ABL) CML AND PROMISING THERAPEUTIC TARGETS FOR THIS HIGH-RISK PATIENT GROUP.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5 2127  33 EPIGENETIC INACTIVATION OF MIR-9 FAMILY MICRORNAS IN CHRONIC LYMPHOCYTIC LEUKEMIA--IMPLICATIONS ON CONSTITUTIVE ACTIVATION OF NFKAPPAB PATHWAY. BACKGROUND: THE MIR-9 FAMILY MICRORNAS HAVE BEEN IDENTIFIED AS A TUMOR SUPPRESSOR MIRNA IN CANCERS. WE POSTULATED THAT MIR-9-1, MIR-9-2 AND MIR-9-3 MIGHT BE INACTIVATED BY DNA HYPERMETHYLATION IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). METHODS: METHYLATION OF MIR-9-1, MIR-9-2 AND MIR-9-3 WAS STUDIED IN EIGHT NORMAL CONTROLS INCLUDING NORMAL BONE MARROW, BUFFY COAT, AND CD19-SORTED PERIPHERAL BLOOD B-CELLS FROM HEALTHY INDIVIDUALS, SEVEN CLL CELL LINES, AND SEVENTY-EIGHT DIAGNOSTIC CLL SAMPLES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. RESULTS: THE PROMOTERS OF MIR-9-3 AND MIR-9-1 WERE BOTH UNMETHYLATED IN NORMAL CONTROLS, BUT METHYLATED IN FIVE (71.4%) AND ONE OF SEVEN CLL CELL LINES RESPECTIVELY. HOWEVER, MIR-9-2 PROMOTER WAS METHYLATED IN NORMAL CONTROLS INCLUDING CD19 + VE B-CELLS, HENCE SUGGESTIVE OF A TISSUE-SPECIFIC BUT NOT TUMOR-SPECIFIC METHYLATION, AND THUS NOT FURTHER STUDIED. DIFFERENT MSP STATUSES OF MIR-9-3, INCLUDING COMPLETE METHYLATION, PARTIAL METHYLATION, AND COMPLETE UNMETHYLATION, WERE VERIFIED BY QUANTITATIVE BISULFITE METHYLATION ANALYSIS. 5-AZA-2'-DEOXYCYTIDINE TREATMENT RESULTED IN MIR-9-3 PROMOTER DEMETHYLATION AND RE-EXPRESSION OF PRI-MIR-9-3 IN I83-E95 AND WAC3CD5+ CELLS, WHICH WERE HOMOZYGOUSLY METHYLATED FOR MIR-9-3. MOREOVER, OVEREXPRESSION OF MIR-9 LED TO SUPPRESSED CELL PROLIFERATION AND ENHANCED APOPTOSIS TOGETHER WITH DOWNREGULATION OF NFKAPPAB1 IN I83-E95 CELLS, SUPPORTING A TUMOR SUPPRESSOR ROLE OF MIR-9-3 IN CLL. IN PRIMARY CLL SAMPLES, MIR-9-3 WAS DETECTED IN 17% AND MIR-9-1 METHYLATION IN NONE OF THE PATIENTS AT DIAGNOSIS. MOREOVER, MIR-9-3 METHYLATION WAS ASSOCIATED WITH ADVANCED RAI STAGE (>/= STAGE 2) (P = 0.04). CONCLUSIONS: OF THE MIR-9 FAMILY, MIR-9-3 IS A TUMOR SUPPRESSOR MIRNA RELATIVELY FREQUENTLY METHYLATED, AND HENCE SILENCED IN CLL; WHEREAS MIR-9-1 METHYLATION IS RARE IN CLL. THE ROLE OF MIR-9-3 METHYLATION IN THE CONSTITUTIVE ACTIVATION OF NFKAPPAB SIGNALING PATHWAY IN CLL WARRANTS FURTHER STUDY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6 3484  33 IDENTIFICATION OF CHROMATIN REMODELING GENES ARID4A AND ARID4B AS LEUKEMIA SUPPRESSOR GENES. BACKGROUND: LEUKEMIA EVOLVES THROUGH A MULTISTEP PROCESS FROM PREMALIGNANCY TO MALIGNANCY. EPIGENETIC ALTERATIONS, INCLUDING HISTONE MODIFICATIONS, HAVE BEEN PROPOSED TO PLAY AN IMPORTANT ROLE IN TUMORIGENESIS. THE INVOLVEMENT OF TWO CHROMATIN REMODELING GENES, RETINOBLASTOMA-BINDING PROTEIN 1 (RBBP1/ARID4A) AND RBBP1-LIKE 1 (RBBP1L1/ARID4B), IN LEUKEMOGENESIS WAS NOT CHARACTERIZED. METHODS: THE LEUKEMIC PHENOTYPE OF MICE DEFICIENT FOR ARID4A WITH OR WITHOUT HAPLOINSUFFICIENCY FOR ARID4B WAS INVESTIGATED BY SERIALLY MONITORING COMPLETE BLOOD COUNTS TOGETHER WITH MICROSCOPIC HISTOLOGIC ANALYSIS AND FLOW CYTOMETRIC ANALYSIS OF BONE MARROW AND SPLEEN FROM THE ARID4A(-/-) MICE OR ARID4A(-/-)ARID4B(+/-) MICE. REGULATION IN BONE MARROW CELLS OF DOWNSTREAM GENES IMPORTANT FOR NORMAL HEMATOPOIESIS WAS ANALYZED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION. GENOTYPIC EFFECTS ON HISTONE MODIFICATIONS WERE EXAMINED BY WESTERN BLOTTING AND IMMUNOFLUORESCENCE ANALYSIS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: YOUNG (2-5 MONTHS OLD) ARID4A-DEFICIENT MICE HAD INEFFECTIVE BLOOD CELL PRODUCTION IN ALL HEMATOPOIETIC LINEAGES. BEYOND 5 MONTHS OF AGE, THE ARID4A(-/-) MICE MANIFESTED MONOCYTOSIS, ACCOMPANIED BY SEVERE ANEMIA AND THROMBOCYTOPENIA. THESE SICK ARID4A(-/-) MICE SHOWED BONE MARROW FAILURE WITH MYELOFIBROSIS ASSOCIATED WITH SPLENOMEGALY AND HEPATOMEGALY. FIVE OF 42 ARID4A(-/-) MICE AND 10 OF 12 ARID4A(-/-)ARID4B(+/-) MICE PROGRESSED TO ACUTE MYELOID LEUKEMIA (AML) AND HAD RAPID FURTHER INCREASES OF LEUKOCYTE COUNTS. EXPRESSION OF HOX GENES (HOXB3, HOXB5, HOXB6, AND HOXB8) WAS DECREASED IN ARID4A-DEFICIENT BONE MARROW CELLS WITH OR WITHOUT ARID4B HAPLOINSUFFICIENCY, AND FOXP3 EXPRESSION WAS REDUCED IN ARID4A(-/-)ARID4B(+/-) BONE MARROW. INCREASES OF HISTONE TRIMETHYLATION OF H3K4, H3K9, AND H4K20 (FOLD INCREASES IN TRIMETHYLATION = 32, 95% CONFIDENCE INTERVAL [CI] = 27 TO 32; 45, 95% CI = 41 TO 49; AND 2.2, 95% CI = 1.7 TO 2.7, RESPECTIVELY) WERE OBSERVED IN THE BONE MARROW OF ARID4A-DEFICIENT MICE. CONCLUSIONS: ARID4A-DEFICIENT MICE INITIALLY DISPLAY INEFFECTIVE HEMATOPOIESIS, FOLLOWED BY TRANSITION TO CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)-LIKE MYELODYSPLASTIC/MYELOPROLIFERATIVE DISORDER, AND THEN TRANSFORMATION TO AML. THE DISEASE PROCESSES IN THE ARID4A-DEFICIENT MICE ARE VERY SIMILAR TO THE COURSE OF EVENTS IN HUMANS WITH CMML AND AML. THIS MOUSE MODEL HAS THE POTENTIAL TO FURNISH ADDITIONAL INSIGHTS INTO THE ROLE OF EPIGENETIC ALTERATIONS IN LEUKEMOGENESIS, AND IT MAY BE USEFUL IN DEVELOPING NOVEL PHARMACOLOGICAL APPROACHES TO TREATMENT OF PRELEUKEMIC AND LEUKEMIC STATES.	2008	

7  145  30 ABERRANT DNA METHYLATION STATUS AND MRNA EXPRESSION LEVEL OF SMG1 GENE IN CHRONIC MYELOID LEUKEMIA: A CASE-CONTROL STUDY. OOBJECTIVE: CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE MALIGNANCY WITH DIFFERENT STAGES. ABERRANT EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, HAVE BEEN INTRODUCED AS A SIGNATURE FOR DIVERSE CANCERS WHICH ALSO PLAYS A CRUCIAL ROLE IN CML PATHOGENESIS AND DEVELOPMENT. SUPPRESSOR WITH MORPHOGENETIC EFFECT ON GENITALIA (SMG1) GENE RECENTLY HAS BEEN BROUGHT TO THE SPOTLIGHT AS A POTENT TUMOR SUPPRESSOR GENE THAT CAN BE SUPPRESSED BY TUMORS FOR FURTHER PROGRESS. THE PRESENT STUDY AIMS TO INVESTIGATE SMG1 STATUS IN CML PATIENTS. MATERIALS AND METHODS: IN THIS CASE-CONTROL STUDY, PERIPHERAL BLOOD FROM 30 PATIENTS WITH DIFFERENT PHASES OF CML [NEW CASE (N)=10, COMPLETE MOLECULAR REMISSION (CMR)=10, BLASTIC PHASE (BP)=10] AND 10 HEALTHY SUBJECTS WERE COLLECTED. METHYLATION STATUS AND EXPRESSION LEVEL OF SMG1 GENE PROMOTER WAS ASSESSED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) AND QUANTITATIVE REVERSE-TRANSCRIPTION PCR, RESPECTIVELY. RESULTS: MSP RESULTS OF SMG1 GENE PROMOTOR IN THE NEW CASE GROUP WERE METHYLATED (60% METHYLATED, 30% HEMIMETHYLATED AND 10% UNMETHYLATED). ALL CMR AND CONTROL GROUP PATIENTS WERE UNMETHYLATED IN THE SMG1 GENE PROMOTER. IN THE BP GROUP, METHYLATED SMG1 PROMOTER WAS SEEN (50% OF PATIENTS HAD A METHYLATED STATUS AND 50% HAD HEMIMETHYLATED STATUS). IN COMPARISON WITH THE HEALTHY SUBJECTS, EXPRESSION LEVEL OF SMG1 IN THE NEW CASE GROUP WAS DECREASED (P<0.01); IN THE CMR GROUP AND BP-CML GROUPS, IT WAS INCREASED (P<0.05). NO SIGNIFICANT CORRELATION BETWEEN PATIENTS' HEMATOLOGICAL FEATURES AND SMG1 METHYLATION WAS SEEN. CONCLUSION: OUR RESULTS DEMONSTRATED THAT ABERRANT METHYLATION OF SMG1 OCCURRED IN CML PATIENTS AND IT HAD A SIGNIFICANT ASSOCIATION WITH SMG1 EXPRESSION. SMG1 GENE PROMOTER SHOWED DIVERSE METHYLATED STATUS AND SUBSEQUENT EXPRESSION LEVELS IN DIFFERENT PHASES OF CML. THESE FINDINGS SUGGESTED POSSIBLE PARTICIPATION OF SMG1 SUPPRESSION IN THE CML PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8 5775  29 SPERMIDINE/SPERMINE N(1)-ACETYLTRANSFERASE ACTIVITY ASSOCIATES WITH WHITE BLOOD CELL COUNT IN MYELOID LEUKEMIAS. THE METABOLISM OF POLYAMINES, THE CATIONIC SMALL MOLECULES ESSENTIAL FOR CELL PROLIFERATION AND DIFFERENTIATION, IS ALTERED IN CANCER CELLS AND CAN BE EXPLOITED IN CANCER DIAGNOSIS AND THERAPY. SPERMIDINE/SPERMINE N(1)-ACETYLTRANSFERASE (SSAT), WHICH REGULATES INTRACELLULAR LEVELS OF POLYAMINES BY CATABOLIZING SPERMIDINE AND SPERMINE, HAS A CONTROVERSIAL ROLE IN THE DEVELOPMENT OF CANCERS. IN THIS STUDY, THE POLYAMINE METABOLISM AND FUNCTION OF SSAT WERE CHARACTERIZED IN ACUTE MYELOID LEUKEMIA (AML), CHRONIC MYELOID LEUKEMIA (CML), AND ACUTE LYMPHOID LEUKEMIA PATIENT SAMPLES. ALSO, MICE OVEREXPRESSING SSAT AND HAVING A MYELOPROLIFERATIVE PHENOTYPE WERE ANALYZED FOR THEIR RESPONSE TO DECITABINE AND HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A. THE PRESENCE OF EPIGENETIC FACTORS IN THE BONE MARROW CELLS OF SSAT MICE WAS ANALYZED. ELEVATED LEVELS OF SPERMIDINE AND SPERMINE, AS WELL AS INCREASED ACTIVITY OF SSAT, WERE DETECTED IN AML, CML, AND ACUTE LYMPHOID LEUKEMIA PATIENTS COMPARED WITH THE CONTROLS. HOWEVER, WE FOUND SSAT ACTIVITY TO BE ASSOCIATED WITH WHITE BLOOD CELL COUNT ONLY IN AML AND CML PATIENTS. DECITABINE TREATMENT BROUGHT THE PERIPHERAL BLOOD AND BONE MARROW CELL COUNTS OF SSAT MICE TO THE LEVEL OF WILD-TYPE MICE. SPERMIDINE/SPERMINE N(1)-ACETYLTRANSFERASE MICE HAD INCREASED HISTONE METHYLATION AND AN INCREASED LEVEL OF HISTONE DEACETYLASE 1 IN THEIR BONE MARROW CELLS. THE STUDY SUGGESTS THAT SSAT INFLUENCES THE DEVELOPMENT OF MYELOID MALIGNANCIES, AND EPIGENETIC FACTORS PARTLY CONTRIBUTE TO THE SSAT OVEREXPRESSION-INDUCED MYELOPROLIFERATIVE DISEASE IN MICE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
9 1843  26 EFFECTS OF TELOMERASE INHIBITOR ON EPIGENETIC CHROMATIN MODIFICATION ENZYMES IN MALIGNANCIES. TELOMERASE HAS A CRITICAL ROLE IN CELL PROLIFERATION, TUMOR MAINTAINING, AND THERAPY RESISTANCE, WHICH ACT BY MODIFYING MANY SIGNALING PATHWAYS. 2-[(E)-3-NAPHTALEN-2-YL-BUT-2-ENOYLAMINO]-BENZOIC ACID (BIBR1532) IS ONE OF THE MOST STUDIED TELOMERASE INHIBITORS, AND IT TARGETS TELOMERASE COMPONENTS TERC AND TERT. IN THIS NOVEL STUDY, WE AIMED TO INVESTIGATE THE EPIGENETIC EFFECTS OF BIBR1532 ON BOTH HEMATOLOGIC MALIGNANCIES AND SOLID TUMORS. K-562 HUMAN CHRONIC MYELOID LEUKEMIA CELL LINE AND U87MG GLIOBLASTOMA CELL LINE WERE COMPARED WITH CONTROL GROUPS WITHOUT BIBR1532 TREATMENT. CYTOTOXIC EFFECTS OF BIBR1532 WERE DETERMINED BY USING WST-1 ASSAY. APOPTOTIC EFFECTS OF BIBR1532 WERE DETECTED BY USING ANNEXIN V METHOD. TO ASSESS EXPRESSION CHANGES IN THE HUMAN EPIGENETIC CHROMATIN MODIFICATION ENZYME GENES, TOTAL RNA WAS ISOLATED FROM K-562 AND U87MG CELLS TREATED WITH BIBR1532 AND UNTREATED CONTROL CELLS. BIBR1532 INDUCED 2.41-FOLD APOPTOTIC CELL DEATH IN U87MG CELL LINES COMPARED WITH CONTROL GROUPS. APOPTOSIS WAS SLIGHTLY INDUCED IN K-562 CELLS WITH BIBR1532 TREATMENT COMPARED WITH CONTROL CELLS. WE OBSERVED THAT BIBR1532 ALSO REGULATES SIMILAR GENES IN BOTH CELL LINES, AND IT IS USEFUL ON EPIGENETIC MECHANISMS. AS A RESULT, TELOMERASE INHIBITOR BIBR1532 HAS A SIGNIFICANT EFFECT ON BOTH HEMATOLOGICAL MALIGNANCIES AND SOLID TUMORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10 2431  34 EPIGENETIC SILENCING OF MIR-26A1 IN CHRONIC LYMPHOCYTIC LEUKEMIA AND MANTLE CELL LYMPHOMA: IMPACT ON EZH2 EXPRESSION. DOWNREGULATION OF MIR26A1 HAS BEEN REPORTED IN VARIOUS B-CELL MALIGNANCIES; HOWEVER, THE MECHANISM BEHIND ITS DEREGULATION REMAINS LARGELY UNKNOWN. WE INVESTIGATED MIR26A1 METHYLATION AND EXPRESSION LEVELS IN A WELL-CHARACTERIZED SERIES OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND MANTLE CELL LYMPHOMA (MCL). FROM 450K METHYLATION ARRAYS, WE FIRST OBSERVED MIR26A1 (CG26054057) AS UNIFORMLY HYPERMETHYLATED IN MCL (N = 24) (ALL >75%), WHILE CLL (N = 18) SHOWED DIFFERENTIAL METHYLATION BETWEEN PROGNOSTIC SUBGROUPS. EXTENDED ANALYSIS USING PYROSEQUENCING CONFIRMED OUR FINDINGS AND REAL-TIME QUANTITATIVE PCR VERIFIED LOW MIR26A1 EXPRESSION IN BOTH CLL (N = 70) AND MCL (N = 38) COMPARED TO NORMAL B-CELLS. NOTABLY, THE LEVEL OF MIR26A1 METHYLATION PREDICTED OUTCOME IN CLL, WITH HIGHER LEVELS SEEN IN POOR-PROGNOSTIC, IGHV-UNMUTATED CLL. SINCE EZH2 WAS RECENTLY REPORTED AS A TARGET FOR MIR26A1, WE ANALYZED THE EXPRESSION LEVELS OF BOTH MIR26A1 AND EZH2 IN PRIMARY CLL SAMPLES AND OBSERVED AN INVERSE CORRELATION. BY OVEREXPRESSION OF MIR26A1 IN CLL AND MCL CELL LINES, REDUCED EZH2 PROTEIN LEVELS WERE OBSERVED USING BOTH WESTERN BLOT AND FLOW CYTOMETRY. IN CONTRAST, METHYL-INHIBITOR TREATMENT LED TO UPREGULATED MIR26A1 EXPRESSION WITH A PARALLEL DECREASE OF EZH2 EXPRESSION. FINALLY, INCREASED LEVELS OF APOPTOSIS WERE OBSERVED IN MIR26A1-OVEREXPRESSING CELL LINES, FURTHER UNDERSCORING THE FUNCTIONAL RELEVANCE OF MIR26A1. IN SUMMARY, WE PROPOSE THAT EPIGENETIC SILENCING OF MIR26A1 IS REQUIRED FOR THE MAINTENANCE OF INCREASED LEVELS OF EZH2, WHICH IN TURN TRANSLATE INTO A WORSE OUTCOME, AS SHOWN IN CLL, HIGHLIGHTING MIR26A1 AS A TUMOR SUPPRESSOR MIRNA.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11 1062  39 CLINICAL SIGNIFICANCE OF DNA METHYLATION IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS: RESULTS FROM 3 UK CLINICAL TRIALS. CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS WITH MUTATED IMMUNOGLOBULIN HEAVY-CHAIN GENES (IGHV-M), PARTICULARLY THOSE LACKING POOR-RISK GENOMIC LESIONS, OFTEN RESPOND WELL TO CHEMOIMMUNOTHERAPY (CIT). DNA METHYLATION PROFILING CAN SUBDIVIDE EARLY-STAGE PATIENTS INTO NAIVE B-CELL-LIKE CLL (N-CLL), MEMORY B-CELL-LIKE CLL (M-CLL), AND INTERMEDIATE CLL (I-CLL), WITH DIFFERING TIMES TO FIRST TREATMENT AND OVERALL SURVIVAL. HOWEVER, WHETHER DNA METHYLATION CAN IDENTIFY PATIENTS DESTINED TO RESPOND FAVORABLY TO CIT HAS NOT BEEN ASCERTAINED. WE CLASSIFIED TREATMENT-NAIVE PATIENTS (N = 605) FROM 3 UK CHEMO AND CIT CLINICAL TRIALS INTO THE 3 EPIGENETIC SUBGROUPS, USING PYROSEQUENCING AND MICROARRAY ANALYSIS, AND PERFORMED EXPANSIVE SURVIVAL ANALYSIS. THE N-CLL, I-CLL, AND M-CLL SIGNATURES WERE FOUND IN 80% (N = 245/305), 17% (53/305), AND 2% (7/305) OF IGHV-UNMUTATED (IGHV-U) CASES, RESPECTIVELY, AND IN 9%, (19/216), 50% (108/216), AND 41% (89/216) OF IGHV-M CASES, RESPECTIVELY. MULTIVARIATE COX PROPORTIONAL ANALYSIS IDENTIFIED M-CLL AS AN INDEPENDENT PROGNOSTIC FACTOR FOR OVERALL SURVIVAL (HAZARD RATIO [HR], 0.46; 95% CONFIDENCE INTERVAL [CI], 0.24-0.87; P = .018) IN CLL4, AND FOR PROGRESSION-FREE SURVIVAL (HR, 0.25; 95% CI, 0.10-0.57; P = .002) IN ARCTIC AND ADMIRE PATIENTS. THE ANALYSIS OF EPIGENETIC SUBGROUPS IN PATIENTS ENTERED INTO 3 FIRST-LINE UK CLL TRIALS IDENTIFIES M-CLL AS AN INDEPENDENT MARKER OF PROLONGED SURVIVAL AND MAY AID IN THE IDENTIFICATION OF PATIENTS DESTINED TO DEMONSTRATE PROLONGED SURVIVAL AFTER CIT.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12 1457  30 DISEASE PROGRESSION FROM CHRONIC HEPATITIS C TO CIRRHOSIS AND HEPATOCELLULAR CARCINOMA IS ASSOCIATED WITH INCREASING DNA PROMOTER METHYLATION. BACKGROUND: CHANGES IN DNA METHYLATION PATTERNS ARE BELIEVED TO BE EARLY EVENTS IN HEPATOCARCINOGENESIS. A BETTER UNDERSTANDING OF METHYLATION STATES AND HOW THEY CORRELATE WITH DISEASE PROGRESSION WILL AID IN FINDING POTENTIAL STRATEGIES FOR EARLY DETECTION OF HCC. THE AIM OF OUR STUDY WAS TO ANALYZE THE METHYLATION FREQUENCY OF TUMOR SUPPRESSOR GENES, P14, P15, AND P73, AND A MISMATCH REPAIR GENE (O6MGMT) IN HCV RELATED CHRONIC LIVER DISEASE AND HCC TO IDENTIFY CANDIDATE EPIGENETIC BIOMARKERS FOR HCC PREDICTION. MATERIALS AND METHODS: 516 EGYPTIAN PATIENTS WITH HCV-RELATED LIVER DISEASE WERE RECRUITED FROM KASR ALAINI MULTIDISCIPLINARY HCC CLINIC FROM APRIL 2010 TO JANUARY 2012. SUBJECTS WERE DIVIDED INTO 4 DIFFERENT CLINICALLY DEFINED GROUPS - HCC GROUP (N=208), LIVER CIRRHOSIS GROUP (N=108), CHRONIC HEPATITIS C GROUP (N=100), AND CONTROL GROUP (N=100) - TO ANALYZE THE METHYLATION STATUS OF THE TARGET GENES IN PATIENT PLASMA USING EPITECT METHYL QPCR ARRAY TECHNOLOGY. METHYLATION WAS CONSIDERED TO BE HYPERMETHYLATED IF >10% AND/OR INTERMEDIATELY METHYLATED IF >60%. RESULTS: IN OUR SERIES, A SIGNIFICANT DIFFERENCE IN THE HYPERMETHYLATION STATUS OF ALL STUDIED GENES WAS NOTED WITHIN THE DIFFERENT STAGES OF CHRONIC LIVER DISEASE AND ULTIMATELY HCC. HYPERMETHYLATION OF THE P14 GENE WAS DETECTED IN 100/208 (48.1%), 52/108 (48.1%), 16/100 (16%) AND 8/100 (8%) AMONG HCC, LIVER CIRRHOSIS, CHRONIC HEPATITIS AND CONTROL GROUPS, RESPECTIVELY, WITH A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN THE STUDIED GROUPS (P-VALUE 0.008). WE ALSO DETECTED P15 HYPERMETHYLATION IN 92/208 (44.2%), 36/108 (33.3%), 20/100 (20%) AND 4/100 (4%) , RESPECTIVELY (P-VALUE 0.006). IN ADDITION, HYPERMETHYLATION OF P73 WAS DETECTED IN 136/208 (65.4%), 72/108 (66.7%), 32/100 (32%) AND 4/100 (4%) (P-VALUE <0.001). ALSO, WE DETECTED O6MGMT HYPERMETHYLATION IN 84/208 (40.4%), 60/108 (55.3%), 20/100 (20%) AND 4/100 (4%), RESPECTIVELY (P VALUE <0.001. CONCLUSIONS: THE EPIGENETIC CHANGES OBSERVED IN THIS STUDY INDICATE THAT HCC TUMORS EXHIBIT SPECIFIC DNA METHYLATION SIGNATURES WITH POTENTIAL CLINICAL APPLICATIONS IN DIAGNOSIS AND PROGNOSIS. IN ADDITION, METHYLATION FREQUENCY COULD BE USED TO MONITOR WHETHER A PATIENT WITH CHRONIC HEPATITIS C IS LIKELY TO PROGRESS TO LIVER CIRRHOSIS OR EVEN HCC. WE CAN CONCLUDE THAT METHYLATION PROCESSES ARE NOT JUST EARLY EVENTS IN HEPATOCARCINOGENESIS BUT ACCUMULATE WITH PROGRESSION TO CANCER.	2014	
                                                                                                                                            
13 2763  32 EXPRESSION OF THE LEUKEMIC PROGNOSTIC MARKER CD7 IS LINKED TO EPIGENETIC MODIFICATIONS IN CHRONIC MYELOID LEUKEMIA. BACKGROUND: EXPRESSION LEVELS OF THE CELL SURFACE GLYCOPROTEIN, CD7, AND THE SERINE PROTEASE, ELASTASE 2 (ELA2), IN THE LEUKEMIC CELLS OF PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) HAVE BEEN ASSOCIATED WITH CLINICAL OUTCOME. HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISMS THAT UNDERLIE THE VARIABLE EXPRESSION OF THESE GENES IN THE LEUKEMIC CELLS. RESULTS: TO ADDRESS THIS QUESTION, WE COMPARED THE LEVEL OF THEIR EXPRESSION WITH THE DNA METHYLATION AND HISTONE ACETYLATION STATUS OF 5' SEQUENCES OF BOTH GENES IN LEUKEMIC CELL LINES AND PRIMITIVE (LIN-CD34+) LEUKEMIC CELLS FROM CHRONIC PHASE CML PATIENTS. DNA METHYLATION OF THE ELA2 GENE PROMOTER DID NOT CORRELATE WITH ITS EXPRESSION PATTERN IN LIN-CD34+ CELLS FROM CHRONIC PHASE CML PATIENT SAMPLES EVEN THOUGH THERE WAS CLEAR DIFFERENTIAL DNA METHYLATION OF THIS LOCUS IN ELA2-EXPRESSING AND NON-EXPRESSING CELL LINES. IN CONTRAST, WE FOUND A STRONG RELATION BETWEEN CD7 EXPRESSION AND TRANSCRIPTION-PERMISSIVE CHROMATIN MODIFICATIONS, BOTH AT THE LEVEL OF DNA METHYLATION AND HISTONE ACETYLATION WITH EVIDENCE OF HYPOMETHYLATION OF THE CD7 PROMOTER REGION IN THE LIN-CD34+ CELLS FROM CML PATIENTS WITH HIGH CD7 EXPRESSION. CONCLUSION: THESE FINDINGS INDICATE A LINK BETWEEN EPIGENETIC MODIFICATIONS AND CD7 EXPRESSION IN PRIMITIVE CML CELLS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14 6248  24 THE METHYLATION STATUS OF THE DDX43 PROMOTER IN CHINESE PATIENTS WITH CHRONIC MYELOID LEUKEMIA. ABERRANT DNA METHYLATION IS A COMMON EPIGENETIC ALTERATION AND AN IMPORTANT FEATURE IN HUMAN CANCERS. THE DEAD BOX POLYPEPTIDE 43 (DDX43) HAS BEEN FOUND TO BE OVEREXPRESSED IN VARIOUS SOLID TUMORS AND SOME HEMATOLOGIC MALIGNANCIES. IN THE PRESENT STUDY, WE INVESTIGATED THE METHYLATION STATUS OF THE DDX43 PROMOTER IN 87 CHINESE PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) USING REAL-TIME QUANTITATIVE METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION AND EXAMINED THE DDX43 TRANSCRIPT IN 35 PATIENTS USING REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION. DDX43 PROMOTER HYPOMETHYLATION WAS OBSERVED IN 22 (25.3%) CML PATIENTS. NO SIGNIFICANT CORRELATION WAS FOUND BETWEEN THE HYPOMETHYLATION OF THE DDX43 PROMOTER WITH THE AGE, SEX, WHITE BLOOD CELL COUNTS, HEMOGLOBIN CONCENTRATION, PLATELET COUNTS, AND CHROMOSOMAL ABNORMALITIES OF CML PATIENTS (P>0.05). THE FREQUENCY OF DDX43 HYPOMETHYLATION IN PATIENTS IN THE CHRONIC PHASE, IN THE ACCELERATED PHASE, AND IN BLAST CRISIS WAS 23.4% (15/64), 25.0% (2/8), AND 33.3% (5/15), RESPECTIVELY (P>0.05). THERE WAS A SIGNIFICANT CORRELATION BETWEEN DDX43 HYPOMETHYLATION AND DDX43 TRANSCRIPT (R=0.469, P=0.004). OUR DATA SUGGEST THAT HYPOMETHYLATION OF THE DDX43 PROMOTER MAY BE AN EARLY AND FREQUENT MOLECULAR EVENT IN THE DEVELOPMENT OF CML IN CHINESE PATIENTS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15 5934  27 TARGETING FEATURES OF CURAXIN CBL0137 ON HEMATOLOGICAL MALIGNANCIES IN VITRO AND IN VIVO. THE ANTICANCER ACTIVITY OF CURAXIN CBL0137, A DNA-BINDING SMALL MOLECULE WITH CHROMATIN REMODULATING EFFECT, HAS BEEN DEMONSTRATED IN DIFFERENT CANCERS. HEREIN, A COMPARATIVE EVALUATION OF CBL0137 ACTIVITY WAS PERFORMED IN RESPECT TO ACUTE MYELOID LEUKEMIA (AML), ACUTE LYMPHOBLASTIC LEUKEMIA (ALL), CHRONIC MYELOID LEUKEMIA AND MULTIPLE MYELOMA (MM) CULTURED IN VITRO. MTT ASSAY SHOWED AML AND MM HIGHER SENSITIVITY TO CBL0137'S CYTOSTATIC EFFECT COMPARATIVELY TO OTHER HEMATOLOGICAL MALIGNANCY CELLS. FLOW CYTOMETRY CELL CYCLE ANALYSIS REVEALED AN INCREASE IN SUBG1 AND G2/M POPULATIONS AFTER CBL0137 CELL TREATMENT, BUT THE PREVALENT TYPE OF ARREST VARIED. APOPTOSIS ACTIVATION BY CBL0137 MEASURED BY ANNEXIN-V/PI DUAL STAINING WAS MORE ACTIVE IN AML AND MM CELLS. RT2 PCR ARRAY SHOWED THAT CHANGES CAUSED BY CBL0137 IN SIGNALING PATHWAYS INVOLVED IN CANCER PATHOGENESIS WERE MORE INTENSIVE IN AML AND MM CELLS. ON THE MURINE MODEL OF AML WEHI-3, CBL0137 SHOWED SIGNIFICANT ANTICANCER EFFECTS IN VIVO, WHICH WERE EVALUATED BY CORRESPONDING CHANGES IN SPLEEN AND LIVER. THUS, MORE PRONOUNCED ANTICANCER EFFECTS OF CBL0137 IN VITRO WERE OBSERVED IN RESPECT TO AML AND MM. EXPERIMENTS IN VIVO ALSO INDICATED THE PERSPECTIVE OF CBL0137 USE FOR AML TREATMENT. THIS IN ACCORDANCE WITH THE FRONTLINE TREATMENT APPROACH IN AML USING EPIGENETIC DRUGS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16 2134  31 EPIGENETIC INACTIVATION OF THE MIR129-2 IN HEMATOLOGICAL MALIGNANCIES. BACKGROUND: MIR129-2 HAS BEEN SHOWN TO BE A TUMOR SUPPRESSOR MICRORNA HYPERMETHYLATED IN EPITHELIAL CANCERS. PATIENTS AND METHODS: EPIGENETIC INACTIVATION OF MIR129-2 WAS STUDIED BY METHYLATION-SPECIFIC PCR (MSP) IN 13 CELL LINES (EIGHT MYELOMA AND FIVE LYMPHOMA), 15 NORMAL CONTROLS AND 344 PRIMARY SAMPLES INCLUDING ACUTE MYELOID LEUKEMIA (AML), ACUTE LYMPHOBLASTIC LEUKEMIA (ALL), CHRONIC MYELOID LEUKEMIA (CML), CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), NON-HODGKIN'S LYMPHOMA (NHL), MULTIPLE MYELOMA (MM) AT DIAGNOSIS, MM AT RELAPSE/PROGRESSION, AND MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS). EXPRESSION OF MIR129 AND ITS TARGET, SOX4, IN CELL LINES WAS MEASURED BEFORE AND AFTER HYPOMETHYLATING TREATMENT AND MIR129 OVEREXPRESSION. MIR129 EXPRESSION WAS CORRELATED WITH MIR129-2 METHYLATION STATUS IN PRIMARY LYMPHOMA SAMPLES. TUMOR SUPPRESSOR FUNCTION OF MIR129 WAS DEMONSTRATED BY MTT AND TRYPAN BLUE EXCLUSION ASSAY AFTER MIR129 OVEREXPRESSION. RESULTS: THE SENSITIVITY OF THE METHYLATED-MSP WAS ONE IN 10(3). DIFFERENT MSP STATUSES, INCLUDING COMPLETE METHYLATION, PARTIAL METHYLATION, AND COMPLETE UNMETHYLATION, WERE VERIFIED BY QUANTITATIVE BISULFITE PYROSEQUENCING. ALL FIVE LYMPHOMA AND SEVEN OF EIGHT MYELOMA CELL LINES SHOWED COMPLETE AND PARTIAL MIR129-2 METHYLATION. IN PRIMARY SAMPLES, MIR129-2 METHYLATION WAS ABSENT IN AML AND CML, BUT DETECTED IN 5% ALL, 45.9% CLL, 49.5% MM AT DIAGNOSIS, AND 59.1% NHL. IN CLL, MIR129-2 METHYLATION ADVERSELY IMPACTED ON SURVIVAL (P=0.004). IN MM, MIR129-2 METHYLATION INCREASED FROM 27.5% MGUS TO 49.5% MM AT DIAGNOSIS AND 41.5% AT RELAPSE/PROGRESSION (P=0.023). IN NHL, MIR129-2 METHYLATION WAS ASSOCIATED WITH MIR124-1 AND MIR203 METHYLATION (P<0.001), AND LOWER MIR129 EXPRESSION (P=0.009). HYPOMETHYLATION TREATMENT OF JEKO-1, HOMOZYGOUSLY METHYLATED FOR MIR129-2, LED TO MIR129-2 DEMETHYLATION AND MIR129 RE-EXPRESSION, WITH DOWNREGULATION OF SOX4 MRNA. MOREOVER, MIR129 OVEREXPRESSION IN BOTH MANTLE CELL LINES, JEKO-1 AND GRANTA-519, INHIBITED CELLULAR PROLIFERATION AND ENHANCED CELL DEATH, WITH CONCOMITANT SOX4 MRNA DOWNREGULATION. CONCLUSIONS: MIR129-2 IS A TUMOR SUPPRESSIVE MICRORNA FREQUENTLY METHYLATED IN LYMPHOID BUT NOT MYELOID MALIGNANCIES, LEADING TO REVERSIBLE MIR129-2 SILENCING. IN CLL, MIR129-2 METHYLATION WAS ASSOCIATED WITH AN INFERIOR SURVIVAL. IN MM, MIR129-2 METHYLATION MIGHT BE ACQUIRED DURING PROGRESSION FROM MGUS TO SYMPTOMATIC MM. IN NHL, MIR129-2 METHYLATION MIGHT COLLABORATE WITH MIR124-1 AND MIR203 METHYLATION IN LYMPHOMAGENESIS.	2013	
                                                                                                           
17 1067  37 CLINICAL UTILITY OF PDSS2 EXPRESSION TO STRATIFY PATIENTS AT RISK FOR RECURRENCE OF HEPATOCELLULAR CARCINOMA. IDENTIFICATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS IS REQUIRED FOR OPTIMAL STRATIFICATION OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) AT RISK FOR RECURRENCE AND ADVERSE PROGNOSIS. COENZYME Q10 (COQ10), WHICH MEDIATES APOPTOSIS, IS SYNTHESIZED BY PRENYL DIPHOSPHATE SYNTHASE SUBUNIT 2 (PDSS2). IN THE PRESENT STUDY WE EVALUATED THE CLINICAL SIGNIFICANCE AND REGULATORY MECHANISMS OF PDSS2 EXPRESSION IN HCC. PDSS2 EXPRESSION LEVELS AND THOSE OF GENES ENCODING POTENTIALLY INTERACTING PROTEINS AS WELL AS THE METHYLATION STATUS OF THE PDSS2 PROMOTER REGION WERE ANALYZED IN HCC CELL LINES. PDSS2 MRNA LEVELS IN 151 PAIRS OF RESECTED SPECIMENS WERE DETERMINED TO EVALUATE THE ASSOCIATION OF PDSS2 EXPRESSION AND CLINICOPATHOLOGICAL FACTORS. THE EXPRESSION AND DISTRIBUTION OF PDSS2 WERE DETERMINED USING IMMUNOHISTOCHEMISTRY. PDSS2 MRNA EXPRESSION WAS DECREASED IN SIX OF NINE HCC CELL LINES AND SIGNIFICANTLY CORRELATED WITH THOSE OF HEPATOCYTE NUCLEAR FACTOR 4ALPHA. PDSS2 TRANSCRIPTION IN HCC CELLS WITH DECREASED PDSS2 EXPRESSION ACCOMPANYING HYPERMETHYLATION WAS REACTIVATED AFTER TREATING THESE CELLS WITH A METHYLATION INHIBITOR. MEAN EXPRESSION LEVELS OF PDSS2 MRNA RELATIVE TO THAT OF UNINVOLVED LIVER DIMINISHED GRADUALLY IN THE ORDER OF CHRONIC HEPATITIS TO CIRRHOSIS, AND EACH WAS SIGNIFICANTLY HIGHER THAN THOSE OF HCCS. PDSS2 AND PDSS2 MRNA LEVELS WERE CONSISTENT. DECREASED PDSS2 MRNA LEVELS WERE DETECTED IN HCC TISSUES OF 56 PATIENTS, CORRELATED WITH SHORTER DISEASE-SPECIFIC SURVIVAL, AND WAS IDENTIFIED AS AN INDEPENDENT PROGNOSTIC FACTOR. PDSS2 IS A PUTATIVE TUMOR SUPPRESSOR, AND PROMOTER HYPERMETHYLATION IS A KEY REGULATORY MECHANISM IN HCC. DECREASED LEVELS OF PDSS2 MRNA EXPRESSION MAY REPRESENT A NOVEL BIOMARKER OF HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18 5640  36 SERUM TUMOR MARKERS AND MOLECULAR BIOLOGICAL DIAGNOSIS IN PANCREATIC CANCER. RECENT STUDIES ON GENETIC ABNORMALITIES IN PANCREATIC DUCTAL CANCER HAVE LED TO THE INVESTIGATION OF TUMOR MARKERS AND GENETIC MARKERS IN BOTH SERUM AND PANCREATIC JUICE (PJ). SERUM TYPE 1 CHAIN CARBOHYDRATE ANTIGENS SUCH AS CA19-9 ARE POSITIVE IN NEARLY 80% OF PATIENTS WITH PANCREATIC CANCER (PCA), OF WHICH MOST ARE IN ADVANCED STAGE, WHEREAS FALSE-POSITIVE RATES ARE RELATIVELY HIGH AT 20%-30% IN BENIGN HEPATOBILIARY AND PANCREATIC DISEASES. ALTHOUGH THE PREVALENCE OF TYPE 2 CHAIN CARBOHYDRATE ANTIGENS, SUCH AS SLX, IS RELATIVELY LOW, CANCER SPECIFICITY OF THESE ANTIGENS IS HIGH. HOWEVER, SERUM TUMOR MARKERS HAVE LIMITED DIAGNOSTIC VALUE FOR EARLY DETECTION OF PCA. IN PJ COLLECTED ENDOSCOPICALLY FROM PATIENTS WITH PCA, K-RAS MUTATIONS (KRM) ARE DETECTABLE IN > 80%, WHEREAS KRM ARE OBSERVED IN 20%-30% OF PJ FROM PATIENTS WITH CHRONIC PANCREATITIS (CP), REFLECTING BENIGN MUCOUS CELL HYPERPLASIA HARBORING KRM. THUS, A QUALITATIVE ANALYSIS OF KRM IN PJ IS UNSUITABLE FOR DIAGNOSIS OF PCA. ON THE OTHER HAND, USING AN HYBRIDIZATION PROTECTION ASSAY THAT CAN QUANTITATIVELY DETERMINE KRM, KRM WERE POSITIVE IN 66% OF PCA BUT ONLY IN 40% OF CP CASES, INDICATING THAT QUALITATIVE ANALYSIS OF KRM IN PJ MAY BE USEFUL FOR DIFFERENTIATING PCA FROM CP. P53 MUTATIONS ARE FOUND IN 4%-50% IN PJ FROM PATIENTS WITH PCA BUT ARE NOT DETECTABLE IN PJ FROM CP, SUGGESTING THAT THE SPECIFICITY OF P53 MUTATIONS IS VERY HIGH FOR PCA. FURTHERMORE, P53 MUTATIONS WERE DETECTED IN 7 OF 15 (47%) PATIENTS WITH PCA IN WHICH THE PJ CYTOLOGIC DIAGNOSIS WAS NEGATIVE. TELOMERASE (TE) ACTIVITY OR ITS CATALYTIC SUBUNIT, H-TERT, WAS REPORTEDLY POSITIVE >80% IN PJ FROM PCA BUT WAS DETECTED IN <20% OF PJ FROM CP. TE ACTIVITY IN PJ FROM CP ORIGINATES FROM LYMPHOCYTES. THE DEVELOPMENT AND APPLICATION OF THESE NEW GENETIC AND EPIGENETIC MARKERS WITH HIGH SPECIFICITY AND SENSITIVITY FOR PCA IN SERUM AND PJ WILL SIGNIFICANTLY IMPROVE OUR DIAGNOSTIC ACCURACY.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19 4556  24 MUTATIONAL SPECTRUM OF MYELOID MALIGNANCIES WITH INV(3)/T(3;3) REVEALS A PREDOMINANT INVOLVEMENT OF RAS/RTK SIGNALING PATHWAYS. MYELOID MALIGNANCIES BEARING CHROMOSOMAL INV(3)/T(3;3) ABNORMALITIES ARE AMONG THE MOST THERAPY-RESISTANT LEUKEMIAS. DEREGULATED EXPRESSION OF EVI1 IS THE MOLECULAR HALLMARK OF THIS DISEASE; HOWEVER, THE GENOME-WIDE SPECTRUM OF COOPERATING MUTATIONS IN THIS DISEASE SUBSET HAS NOT BEEN SYSTEMATICALLY ELUCIDATED. HERE, WE SHOW THAT 98% OF INV(3)/T(3;3) MYELOID MALIGNANCIES HARBOR MUTATIONS IN GENES ACTIVATING RAS/RECEPTOR TYROSINE KINASE (RTK) SIGNALING PATHWAYS. IN ADDITION, HEMIZYGOUS MUTATIONS IN GATA2, AS WELL AS HETEROZYGOUS ALTERATIONS IN RUNX1, SF3B1, AND GENES ENCODING EPIGENETIC MODIFIERS, FREQUENTLY CO-OCCUR WITH THE INV(3)/T(3;3) ABERRATION. NOTABLY, NEITHER MUTATIONAL PATTERNS NOR GENE EXPRESSION PROFILES DIFFER ACROSS INV(3)/T(3;3) ACUTE MYELOID LEUKEMIA, CHRONIC MYELOID LEUKEMIA, AND MYELODYSPLASTIC SYNDROME CASES, SUGGESTING RECOGNITION OF INV(3)/T(3;3) MYELOID MALIGNANCIES AS A SINGLE DISEASE ENTITY IRRESPECTIVE OF BLAST COUNT. THE HIGH INCIDENCE OF ACTIVATING RAS/RTK SIGNALING MUTATIONS MAY PROVIDE A TARGET FOR A RATIONAL TREATMENT STRATEGY IN THIS HIGH-RISK PATIENT GROUP.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  511  32 ASSOCIATION OF RASSF1A HYPERMETHYLATION WITH RISK OF HBV/HCV-INDUCED HEPATOCELLULAR CARCINOMA: A META-ANALYSIS. BACKGROUND: RESEARCHERS HAVE DISCOVERED A LARGE NUMBER OF DNA METHYLATION PATTERNS IN HUMAN CANCER. THESE CANCER-SPECIFIC METHYLATION PATTERNS CAN PROVIDE INFORMATION FOR THE DIAGNOSIS, TREATMENT, AND PROGNOSIS OF CANCER. METHYLATION STUDIES CAN FIND NEW BIOMARKERS BASED ON EPIGENETIC ANALYSIS AND APPLY THESE BIOMARKERS TO CLINICAL ONCOLOGY. MANY STUDIES ON THE ASSOCIATION BETWEEN RAASF1A METHYLATION STATUS AND SUSCEPTIBILITY TO HEPATITIS B VIRUS (HBV)/HEPATITIS C VIRUS (HCV)-INDUCED HEPATOCELLULAR CARCINOMA (HCC) HAVE REACHED CONTROVERSIAL CONCLUSIONS. HENCE, THE CURRENT REVIEW COMPREHENSIVELY ASSESSED THE CORRELATION BETWEEN RAS ASSOCIATION DOMAIN FAMILY 1A (RASSF1A) METHYLATION AND THE RISK OF THE HCV/HBV-INDUCED HCC. METHODS: THE APPROPRIATED PUBLICATIONS WERE EXTRACTED IN EMBASE, PUBMED, WEB OF SCIENCE, COCHRANE LIBRARY, AND CHINA NATIONAL KNOWLEDGE INFRASTRUCTURE DATABASES USING STATA 5.0 SOFTWARE. THE ODDS RATIOS (ORS) WITH 95 % CONFIDENCE INTERVAL (95 % CI) OF RASSF1A METHYLATION WERE COMPUTED. RESULTS: A TOTAL OF 1015 HBV/HCV-RELATED HCC SAMPLES, 124 NON-HBV/HCV-RELATED HCC (NBNC-HCC) SAMPLES, AND 1225 NONTUMOROUS CONTROLS WERE EXTRACTED AND EXAMINED IN THIS RESEARCH. THE FREQUENCY OF THE METHYLATED RASSF1A IN THE HBV/HCV-RELATED TUMOR CASES DISPLAYED A SIGNIFICANTLY INCREASED OR COMPARED WITH THE OVERALL NONTUMOR SAMPLES (OR = 19.372, 95 % CI = 11.060-33.931, P = 0.000). THE FREQUENCY OF THE METHYLATED RASSF1A IN HBV/HCV-RELATED NEOPLASM CASES DISPLAYED A SIGNIFICANTLY INCREASED OR COMPARED WITH THE NON-HBV/HCV-RELATED NEOPLASM (NBNC-NEOPLASM) SAMPLES (OR = 2.150, 95 % CI = 1.398-3.308, P = 0.000). COMPARED WITH NORMAL, CHRONIC HEPATITIS B OR C, CIRRHOSIS, AND PARACANCEROUS SAMPLES, THE POOLED OR OF THE RASSF1A PROMOTER METHYLATION IN THE HBV/HCV-INDUCED HCC SAMPLES WAS 62.785(95 % CI = 35.224-111.909), 25.07 (95 % CI = 13.85-45.36), 6.89 (95 % CI = 3.33-14.264) AND 9.02 (95 % CI = 0.91-89.80), RESPECTIVELY. THE RATE OF RASSF1A HYPERMETHYLATION WAS ROBUSTLY CORRELATED WITH TUMOR SIZE AND VASCULAR INVASION, AND THE POOLED OR WAS 0.346 (95 % CI = 0.210 - 0.569) AND 0.081 (95 % CI = 0.022 - 0.303), RESPECTIVELY. CONCLUSION: RESULTS SHOWED ROBUST ASSOCIATIONS BETWEEN RASSF1A GENE METHYLATION IN PROMOTER REGION AND ENHANCED HBV/HCV-RELATED HCC SUSCEPTIBILITY, THEREBY REVEALING THAT RASSF1A METHYLATION STATUS MAY SERVE AS AN IMPORTANT INDICATOR FOR HCC ONCOGENESIS.	2020