1  1735 180 EARLY AND SUSTAINED EXPANSION OF ADAPTIVE NATURAL KILLER CELLS FOLLOWING HAPLOIDENTICAL TRANSPLANTATION AND CTLA4IG-PRIMED DONOR LYMPHOCYTE INFUSIONS DISSOCIATE GRAFT-VERSUS-LEUKEMIA AND GRAFT-VERSUS-HOST EFFECTS. BACKGROUND: ADAPTIVE OR MEMORY NATURAL KILLER (NK) CELLS WITH EPIGENETIC IMPRINTS SIMILAR TO MEMORY T CELLS HAVE BEEN SHOWN TO DEVELOP IN RESPONSE TO CYTOMEGALOVIRUS (CMV) INFECTION WITH UPREGULATION OF ACTIVATING RECEPTOR NKG2C. THESE CELLS HAVE BEEN SHOWN TO POSSESS STRONG ANTI-TUMOUR EFFICACY BOTH IN-VITRO AS WELL AS IN-VIVO. OBJECTIVES: TO DETERMINE IF RECONSTITUTION OF ADAPTIVE NK CELLS (CD56(DIM)NKG2C(+)NKG2A(-)) IN PATIENTS WITH ADVANCED LEUKEMIA UNDERGOING HAPLOIDENTICAL HCT HAD ANY IMPACT ON DISEASE PROGRESSION (DP). STUDY DESIGN: THE STUDY COHORT COMPRISED OF 60 PATIENTS WITH ADVANCED ACUTE LEUKEMIA, AGED 2-65 YEARS, RECEIVING MYELOABLATIVE PTCY BASED HAPLOIDENTICAL TRANSPLANTATION FROM CMV SEROPOSITIVE DONORS, FOLLOWED BY CTLA4IG-PRIMED DONOR LYMPHOCYTE INFUSIONS (DLI). THEY WERE EVALUATED FOR THE KINETICS OF RECONSTITUTION OF ADAPTIVE NK CELLS, BOTH PHENOTYPIC AND FUNCTIONAL, AT DAYS +30,+60, +90 AND AT REGULAR INTERVALS, TO 3 YEARS OF FOLLOW-UP, IN RELATION TO DP. RECONSTITUTION OF ADAPTIVE NK CELLS WAS COMPARED WITH A RETROSPECTIVE COHORT OF PATIENTS IN THE SAME PROTOCOL RECEIVING DLI WITHOUT CTLA4IG. RESULTS: NON-RELAPSE MORTALITY, ACUTE AND CHRONIC GVHD WERE 5.1%, 10.3% AND 14.5%. DP WAS 17.5% AT A MEDIAN FOLLOW-UP OF 28 MONTHS. ADAPTIVE NK CELLS WERE SIGNIFICANTLY HIGHER IN PATIENTS WITHOUT DP AT DAYS+30, +60 AND +90 (P = 0.0001), IRRESPECTIVE OF CMV REACTIVATION AND REMAINED ELEVATED UNTIL 36 MONTHS POST-HCT. THESE CELLS MAINTAINED THEIR FUNCTIONAL COMPETENCE AS MEASURED BY ROBUST INTERFERON-GAMMA PRODUCTION WITH HIGHER EXPRESSIONS OF KIR, NKG2D AND CD57, WITHOUT ANY INCREASE IN PD1 EXPRESSION. GRAFTS FROM DONORS WITH HIGHER ADAPTIVE NK CELLS WERE ASSOCIATED WITH A LOWER RISK OF DP (P = 0.0001). IN MULTIVARIATE ANALYSIS, ADAPTIVE NK CELL RECOVERY AT DAY +90 HAD THE MOST FAVORABLE IMPACT ON DP (HR-0.7). TREGS RECONSTITUTED BRISKLY ALONG WITH THE ADAPTIVE NK CELLS AND WERE SUSTAINED AS WELL, WITHOUT COMPROMISING THE GVL EFFECT. COMPARISON WITH A RETROSPECTIVE COHORT RECEIVING THE SAME PROTOCOL WITH DLI WITHOUT CTLA4IG, SHOWED A SUPERIOR RECONSTITUTION OF ADAPTIVE NK CELLS IN THOSE RECEIVING CTLA4IG-DLI (P < 0.0001). CONCLUSION: OUR STUDY SUGGESTS THAT MYELOABLATIVE TRANSPLANTATION FROM CMV SEROPOSITIVE HAPLOIDENTICAL DONORS AUGMENTED WITH CTLA4IG-PRIMED DLI MIGHT FAVOR EARLY AND SUSTAINED EXPANSION OF FUNCTIONALLY COMPETENT ADAPTIVE NK CELLS IRRESPECTIVE OF CMV REACTIVATION, WITH A FAVORABLE OUTCOME.	2021	

2  1959  43 EPIGENETIC AGING AND HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH SEVERE APLASTIC ANEMIA. CELLULAR AGING IN HEMATOPOIETIC CELL TRANSPLANTATION (HCT) IS IMPORTANT IN THE CONTEXT OF IMMUNE RECONSTITUTION AND AGE-RELATED COMPLICATIONS. RECENTLY, SEVERAL DNA-METHYLATION (DNAM)-BASED BIOMARKERS OF AGING KNOWN AS "EPIGENETIC CLOCKS" HAVE BEEN INTRODUCED AS NOVEL TOOLS TO PREDICT CELLULAR AGE. HERE, WE USED COX PROPORTIONAL HAZARDS MODELS TO ASSESS THE POSSIBLE ASSOCIATIONS OF DONOR PRE-HCT DNAM AGE, AND ITS POST-HCT CHANGES, USING THE RECENTLY PUBLISHED LIFESPAN-ASSOCIATED EPIGENETIC CLOCK KNOWN AS "DNAM-GRIMAGE," WITH OUTCOMES AMONG PATIENTS WITH SEVERE APLASTIC ANEMIA (SAA). THE STUDY INCLUDED 732 SAA PATIENTS FROM THE TRANSPLANT OUTCOMES IN APLASTIC ANEMIA PROJECT, WHO UNDERWENT UNRELATED DONOR HCT AND FOR WHOM A DONOR PRE-HCT BLOOD DNA SAMPLE WAS AVAILABLE; 41 ALSO HAD A POST-HCT SAMPLE COLLECTED AT DAY 100. IN MULTIVARIABLE ANALYSES, WE FOUND SIMILAR ASSOCIATIONS FOR DONOR CHRONOLOGICAL AGE AND PRE-HCT DNAM-GRIMAGE WITH POST-HCT SURVIVAL (HAZARD RATIO [HR] PER DECADE = 1.13; 95% CONFIDENCE INTERVAL [CI], 0.99-1.28; P = .07 AND HR = 1.14; 95% CI, 0.99-1.28; P = .06, RESPECTIVELY). IN DONORS WITH 10+ YEARS OF GRIMAGE ACCELERATION (IE, DEVIATION FROM EXPECTED DNAM AGE FOR CHRONOLOGICAL AGE), ELEVATED RISKS OF CHRONIC GRAFT VERSUS HOST DISEASE (HR = 2.4; 95% CI, 1.21-4.65; P = .01) AND POSSIBLY POST-HCT MORTALITY (HR = 1.79; 95% CI, 0.96-3.33; P = .07) WERE OBSERVED. IN THE SUBSET WITH POST-HCT SAMPLES, WE OBSERVED A SIGNIFICANT INCREASE IN DNAM-GRIMAGE IN THE FIRST 100 DAYS AFTER HCT (MEDIAN CHANGE 12.5 YEARS, RANGE 1.4 TO 26.4). HIGHER DNAM-GRIMAGE AFTER HCT WAS ASSOCIATED WITH INFERIOR SURVIVAL (HR PER YEAR = 1.11; 95% CI, 1.02-1.21; P = .01), PREDOMINANTLY WITHIN THE FIRST YEAR AFTER HCT. THIS STUDY HIGHLIGHTS THE POSSIBLE ROLE CELLULAR AGING MAY PLAY IN HCT OUTCOMES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3  3178  42 HAEMATOLOGIC MALIGNANCIES WITH UNFAVOURABLE GENE MUTATIONS BENEFIT FROM DONOR LYMPHOCYTE INFUSION WITH/WITHOUT DECITABINE FOR PROPHYLAXIS OF RELAPSE AFTER ALLOGENEIC HSCT: A PILOT STUDY. RELAPSE IS THE MAIN CAUSE OF TREATMENT FAILURE FOR LEUKAEMIA PATIENTS WITH UNFAVOURABLE GENE MUTATIONS WHO RECEIVE ALLOGENEIC HAEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT). THERE IS NO CONSENSUS ON THE INDICATION OF DONOR LYMPHOCYTE INFUSION (DLI) FOR PROPHYLAXIS OF RELAPSE AFTER ALLO-HSCT. TO EVALUATE THE TOLERANCE AND EFFICACY OF PROPHYLACTIC DLI IN PATIENTS WITH UNFAVOURABLE GENE MUTATIONS SUCH AS FLT3-ITD, TP53, ASXL1, DNMT3A OR TET2, WE PERFORMED A PROSPECTIVE, SINGLE-ARM STUDY. PROPHYLACTIC USE OF DECITABINE FOLLOWED BY DLI WAS PLANNED IN PATIENTS WITH TP53 OR EPIGENETIC MODIFIER GENE MUTATIONS. THE PROPHYLAXIS WAS PLANNED IN 46 RECIPIENTS: IT WAS ADMINISTERED IN 28 PATIENTS AND IT WAS NOT ADMINISTERED IN 18 PATIENTS DUE TO CONTRAINDICATIONS. NO DLI-ASSOCIATED PANCYTOPENIA WAS OBSERVED. THE CUMULATIVE INCIDENCES OF GRADE II-IV AND III-IV ACUTE GRAFT-VERSUS-HOST DISEASE (GVHD) AT 100 DAYS POST-DLI WERE 25.8% AND 11.0%, RESPECTIVELY. THE RATES OF CHRONIC GVHD, NON-RELAPSE MORTALITY AND RELAPSE AT 3 YEARS POST-DLI WERE 21.6%, 25.0% AND 26.1%, RESPECTIVELY. THE 3-YEAR RELAPSE-FREE SURVIVAL AND OVERALL SURVIVAL (OS) RATES WERE 48.9% AND 48.2%, RESPECTIVELY. ACUTE GVHD (HR: 2.30, P = 0.016) AND RELAPSE (HR: 2.46, P = 0.003) AFTER DLI WERE INDEPENDENTLY ASSOCIATED WITH INFERIOR OS. DATA IN THE CURRENT STUDY SHOWED THE FEASIBILITY OF PROPHYLACTIC DLI WITH/WITHOUT DECITABINE IN THE EARLY STAGE AFTER ALLO-HSCT IN PATIENTS WITH UNFAVOURABLE GENE MUTATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
4  5283  47 PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZACITIDINE AND DONOR LYMPHOCYTE INFUSION TO PREVENT DISEASE RELAPSE FOLLOWING ALLOGENEIC TRANSPLANTATION IN PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA OR MYELODYSPLASTIC SYNDROME. BECAUSE OF THE PERSISTENTLY HIGH RATES OF RELAPSE OF PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROME (MDS) FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT), POST-TRANSPLANTATION MAINTENANCE THERAPY HAS BEEN PROPOSED. WE PREVIOUSLY INITIATED A PHASE II TRIAL IN WHICH EPIGENETIC THERAPY WAS COMBINED WITH IMMUNOTHERAPY IN AN ATTEMPT TO REDUCE DISEASE RELAPSE. IN THAT STUDY, LOW-DOSE AZACITIDINE (AZA) AND ESCALATING DOSES OF DONOR LYMPHOCYTE INFUSION (DLI) WERE GIVEN AS POST-ALLO-HSCT MAINTENANCE TREATMENT. IN THE PRESENT STUDY, WE RETROSPECTIVELY ANALYZE A LARGER COHORT OF PATIENTS RECEIVING POST-TRANSPLANTATION MAINTENANCE THERAPY AND PROVIDE UPDATES ON SOME PATIENTS OF THE EARLIER STUDY. THE OBJECTIVES OF THE PRESENT STUDY WERE TO ANALYZE THE CUMULATIVE INCIDENCE OF RELAPSE (CIR), OVERALL SURVIVAL (OS), AND PROGRESSION-FREE SURVIVAL (PFS) AND THE INCIDENCE OF ACUTE AND CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) OF PATIENTS WITH HIGH-RISK AML OR MDS RECEIVING POST-TRANSPLANTATION MAINTENANCE TREATMENT WITH AZA WITH OR WITHOUT DLI. WE RETROSPECTIVELY ANALYZED 77 PATIENTS (54 WITH AML, 23 WITH MDS) CONSIDERED AT HIGH RISK BASED ON EITHER THEIR GENOMIC OR CLINICAL STATUS AT TRANSPLANTATION. FOLLOWING ALLOGENEIC TRANSPLANTATION, THEY RECEIVED AT LEAST 1 CYCLE OF PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZA WITH OR WITHOUT ESCALATING DOSES OF DLI TO PREVENT DISEASE RELAPSE. ALMOST ONE-HALF OF THE PATIENTS (47%) WERE ABLE TO RECEIVE THE FULL 12 CYCLES OF SCHEDULED AZA, AND A MAJORITY (79%) RECEIVED AT LEAST 1 DLI. WITH A MEDIAN FOLLOW-UP OF 24 MONTHS, 19 PATIENTS (25%; 16 WITH AML, 3 WITH MDS) RELAPSED, AT A MEDIAN OF 9.8 MONTHS (RANGE, 4 TO 58.6 MONTHS), GIVING A 22% CIR AT 24 MONTHS. OS AND PFS AT 24 MONTHS WERE 70.8% AND 68.3%, RESPECTIVELY. THE CUMULATIVE INCIDENCES OF GRADE II-IV ACUTE GVHD AND CHRONIC GVHD WERE 27.4% AND 45%, RESPECTIVELY. ONLY A MINORITY OF PATIENTS (11%) REQUIRED DELAYED ADMINISTRATION OF AZA. THESE FINDINGS CONFIRM THAT AZA-DLI MAINTENANCE IS BOTH TOLERABLE AND EFFECTIVE IN REDUCING THE RISK OF POST-TRANSPLANTATION RELAPSE.	2021	
                                                                                                                                                                                                                                                                                                                            
5   991  36 CHRONIC STIMULATION DRIVES HUMAN NK CELL DYSFUNCTION AND EPIGENETIC REPROGRAMING. A POPULATION OF NATURAL KILLER (NK) CELLS EXPRESSING THE ACTIVATING RECEPTOR NKG2C AND THE MATURATION MARKER CD57 EXPANDS IN RESPONSE TO HUMAN CYTOMEGALOVIRUS (HCMV) INFECTION. CD3-CD56DIMCD57+NKG2C+ NK CELLS ARE SIMILAR TO CD8+ MEMORY T CELLS WITH RAPID AND ROBUST EFFECTOR FUNCTION UPON RE-STIMULATION, PERSISTENCE, AND EPIGENETIC REMODELING OF THE IFNG LOCUS. CHRONIC ANTIGEN STIMULATION DRIVES CD8+ MEMORY T CELL PROLIFERATION WHILE ALSO INDUCING GENOME-WIDE EPIGENETIC REPROGRAMING AND DYSFUNCTION. WE HYPOTHESIZED THAT CHRONIC STIMULATION COULD SIMILARLY INDUCE EPIGENETIC REPROGRAMING AND DYSFUNCTION IN NK CELLS. HERE WE SHOW THAT CHRONIC STIMULATION OF ADAPTIVE NK CELLS THROUGH NKG2C USING PLATE-BOUND AGONISTIC ANTIBODIES IN COMBINATION WITH IL-15 DROVE ROBUST PROLIFERATION AND ACTIVATION OF CD3-CD56DIMCD57+NKG2C+ NK CELLS WHILE SIMULTANEOUSLY INDUCING HIGH EXPRESSION OF THE CHECKPOINT INHIBITORY RECEPTORS LAG-3 AND PD-1. MARKED INDUCTION OF CHECKPOINT INHIBITORY RECEPTORS WAS ALSO OBSERVED ON THE SURFACE OF ADAPTIVE NK CELLS CO-CULTURED WITH HCMV-INFECTED ENDOTHELIAL CELLS. CHRONICALLY STIMULATED ADAPTIVE NK CELLS WERE DYSFUNCTIONAL WHEN CHALLENGED WITH TUMOR TARGETS. THESE CELLS EXHIBITED A PATTERN OF EPIGENETIC REPROGRAMING, WITH GENOME-WIDE ALTERATIONS IN DNA METHYLATION. OUR STUDY HAS IMPORTANT IMPLICATIONS FOR CANCER IMMUNOTHERAPY AND SUGGEST THAT EXHAUSTED NK CELLS COULD BE TARGETED WITH INHIBITORY CHECKPOINT RECEPTOR BLOCKADE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6   765  35 CC-486 MAINTENANCE AFTER STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROMES. RELAPSE IS THE MAIN CAUSE OF TREATMENT FAILURE AFTER ALLOGENEIC STEM CELL TRANSPLANT (ALLOSCT) IN ACUTE MYELOID LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROMES (MDS). INJECTABLE AZACITIDINE CAN IMPROVE POST-TRANSPLANT OUTCOMES BUT PRESENTS CHALLENGES WITH EXPOSURE AND COMPLIANCE. ORAL CC-486 ALLOWS EXTENDED DOSING TO PROLONG AZACITIDINE ACTIVITY. WE INVESTIGATED USE OF CC-486 MAINTENANCE THERAPY AFTER ALLOSCT. ADULTS WITH MDS OR AML IN MORPHOLOGIC COMPLETE REMISSION AT CC-486 INITIATION (42 TO 84 DAYS AFTER ALLOSCT) WERE INCLUDED. PATIENTS RECEIVED 1 OF 4 CC-486 DOSING SCHEDULES PER 28-DAY CYCLE FOR UP TO 12 CYCLES. ENDPOINTS INCLUDED SAFETY, PHARMACOKINETICS, GRAFT-VERSUS-HOST DISEASE (GVHD) INCIDENCE, RELAPSE/PROGRESSION RATE, AND SURVIVAL. OF 30 PATIENTS, 7 RECEIVED CC-486 ONCE DAILY FOR 7 DAYS PER CYCLE (200 MG, N = 3; 300 MG, N = 4) AND 23 FOR 14 DAYS PER CYCLE (150 MG, N = 4; 200 MG, N = 19 [EXPANSION COHORT]). GRADES 3 TO 4 ADVERSE EVENTS WERE INFREQUENT AND OCCURRED WITH SIMILAR FREQUENCY ACROSS REGIMENS. STANDARD CONCOMITANT MEDICATIONS DID NOT ALTER CC-486 PHARMACOKINETIC PARAMETERS. THREE PATIENTS (10%) EXPERIENCED GRADE III ACUTE GVHD AND 9 EXPERIENCED CHRONIC GVHD. OF 28 EVALUABLE PATIENTS, 6 (21%) RELAPSED OR HAD PROGRESSIVE DISEASE: 3 OF 7 PATIENTS (43%) WHO HAD RECEIVED 7-DAY DOSING AND 3 OF 23 (13%) WHO HAD RECEIVED 14-DAY DOSING. TRANSPLANT-RELATED MORTALITY WAS 3%. AT 19 MONTHS OF FOLLOW-UP, MEDIAN OVERALL SURVIVAL WAS NOT REACHED. ESTIMATED 1-YEAR SURVIVAL RATES WERE 86% AND 81% IN THE 7-DAY AND 14-DAY DOSING COHORTS, RESPECTIVELY. CC-486 MAINTENANCE WAS GENERALLY WELL TOLERATED, WITH LOW RATES OF RELAPSE, DISEASE PROGRESSION, AND GVHD. CC-486 MAINTENANCE MAY PERMIT EPIGENETIC MANIPULATION OF THE ALLOREACTIVE RESPONSE POSTALLOGRAFT. FINDINGS REQUIRE CONFIRMATION IN RANDOMIZED TRIALS. (CLINICALTRIALS.GOV NCT01835587.).	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7  1286  39 DECITABINE IN COMBINATION WITH DONOR LYMPHOCYTE INFUSIONS CAN INDUCE REMISSIONS IN RELAPSED MYELOID MALIGNANCIES WITH HIGHER LEUKEMIC BURDEN AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION. THE COMBINATION OF 5-AZACYTIDINE (AZA) WITH DONOR LYMPHOCYTE INFUSIONS (DLIS) CAN INDUCE REMISSIONS IN PATIENTS WITH RELAPSED MYELOID MALIGNANCIES AFTER ALLO-HCT. AS DECITABINE (DAC) IS KNOWN TO BE EFFECTIVE ALSO IN AML/MDS WITH LEUKOCYTOSIS, WE INVESTIGATED THE COMBINATION OF DAC WITH DLIS FOR RELAPSE AFTER ALLO-HCT. BETWEEN 2006 AND 2016, 26 PATIENTS (MEDIAN AGE 59 YEARS) WITH AML (N = 18), MDS (N = 6), OR MPN (N = 2) AND OVERT HEMATOLOGICAL RELAPSE AFTER ALLO-HCT WERE TREATED. MEDIAN DURATION FROM ALLO-HCT TO RELAPSE WAS 306 DAYS (RANGE, 76-4943). EIGHTEEN PATIENTS RECEIVED DAC + DLIS, 8 DAC-ONLY (MEDIAN NUMBER CYCLES OF DAC: 2, RANGE 1-13, MEDIAN NUMBER OF DLIS: 2, RANGE 1-10). THE INCIDENCE OF ACUTE AND CHRONIC GVHD IN PATIENTS RECEIVING DLI WAS 17% (3/18) AND 6% (1/18), RESPECTIVELY. CR/CRI WAS ACHIEVED IN 15% (4/26), PR IN 4% (1/26), AND STABLE DISEASE IN 58% (15/26) OF PATIENTS. EIGHT PATIENTS RECEIVED A SECOND ALLO-HCT. MEDIAN OVERALL SURVIVAL WAS 4.7 MONTHS. ELEVATED PD-L1 PROTEIN EXPRESSION IN BONE MARROW CELLS WAS DETECTED IN 4/8 PATIENTS WITH >20% BLAST INFILTRATION PRIOR TO DAC, WITHOUT A CLEAR ASSOCIATION WITH RESPONSE. IN CONCLUSION, THE DAC + DLI REGIMEN PROVED FEASIBLE AND EFFECTIVE IN RELAPSED MYELOID MALIGNANCIES AFTER ALLO-HCT, WITH EFFICACY NOT RESTRICTED TO PATIENTS WITH LOW LEUKEMIC BURDEN.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8  2392  28 EPIGENETIC REPRESSION OF INTERLEUKIN 2 EXPRESSION IN SENESCENT CD4+ T CELLS DURING CHRONIC HIV TYPE 1 INFECTION. THE MOLECULAR MECHANISMS FOR IL2 GENE-SPECIFIC DYSREGULATION DURING CHRONIC HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 (HIV-1) INFECTION ARE UNKNOWN. HERE, WE INVESTIGATED THE ROLE OF DNA METHYLATION IN SUPPRESSING INTERLEUKIN 2 (IL-2) EXPRESSION IN MEMORY CD4(+) T CELLS DURING CHRONIC HIV-1 INFECTION. WE OBSERVED THAT CPG SITES IN THE IL2 PROMOTER OF CD4(+) T CELLS WERE FULLY METHYLATED IN NAIVE CD4(+) T CELLS AND SIGNIFICANTLY DEMETHYLATED IN THE MEMORY POPULATIONS. INTERESTINGLY, WE FOUND THAT THE MEMORY CELLS THAT HAD A TERMINALLY DIFFERENTIATED PHENOTYPE AND EXPRESSED CD57 HAD INCREASED IL2 PROMOTER METHYLATION RELATIVE TO LESS DIFFERENTIATED MEMORY CELLS IN HEALTHY INDIVIDUALS. IMPORTANTLY, EARLY EFFECTOR MEMORY SUBSETS FROM HIV-1-INFECTED SUBJECTS EXPRESSED HIGH LEVELS OF CD57 AND WERE HIGHLY METHYLATED AT THE IL2 LOCUS. FURTHERMORE, THE INCREASED CD57 EXPRESSION ON MEMORY CD4(+) T CELLS WAS INVERSELY CORRELATED WITH IL-2 PRODUCTION. THESE DATA SUGGEST THAT DNA METHYLATION AT THE IL2 LOCUS IN CD4(+) T CELLS IS COUPLED TO IMMUNOSENESCENCE AND PLAYS A CRITICAL ROLE IN THE BROAD DYSFUNCTION THAT OCCURS IN POLYCLONAL T CELLS DURING HIV-1 INFECTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
9  5478  38 RESULTS OF A RANDOMIZED STUDY OF 3 SCHEDULES OF LOW-DOSE DECITABINE IN HIGHER-RISK MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA. EPIGENETIC THERAPY WITH HYPOMETHYLATING DRUGS IS NOW THE STANDARD OF CARE IN MYELODYSPLASTIC SYNDROME (MDS). RESPONSE RATES REMAIN LOW, AND MECHANISM-BASED DOSE OPTIMIZATION HAS NOT BEEN REPORTED. WE INVESTIGATED THE CLINICAL AND PHARMACODYNAMIC RESULTS OF DIFFERENT DOSE SCHEDULES OF DECITABINE. ADULTS WITH ADVANCED MDS OR CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) WERE RANDOMIZED TO 1 OF 3 DECITABINE SCHEDULES: (1) 20 MG/M2 INTRAVENOUSLY DAILY FOR 5 DAYS; (2) 20 MG/M2 SUBCUTANEOUSLY DAILY FOR 5 DAYS; AND (3) 10 MG/M2 INTRAVENOUSLY DAILY FOR 10 DAYS. RANDOMIZATION FOLLOWED A BAYESIAN ADAPTIVE DESIGN. NINETY-FIVE PATIENTS WERE TREATED (77 WITH MDS, AND 18 WITH CMML). OVERALL, 32 PATIENTS (34%) ACHIEVED A COMPLETE RESPONSE (CR), AND 69 (73%) HAD AN OBJECTIVE RESPONSE BY THE NEW MODIFIED INTERNATIONAL WORKING GROUP CRITERIA. THE 5-DAY INTRAVENOUS SCHEDULE, WHICH HAD THE HIGHEST DOSE-INTENSITY, WAS SELECTED AS OPTIMAL; THE CR RATE IN THAT ARM WAS 39%, COMPARED WITH 21% IN THE 5-DAY SUBCUTANEOUS ARM AND 24% IN THE 10-DAY INTRAVENOUS ARM (P < .05). THE HIGH DOSE-INTENSITY ARM WAS ALSO SUPERIOR AT INDUCING HYPOMETHYLATION AT DAY 5 AND AT ACTIVATING P15 EXPRESSION AT DAYS 12 OR 28 AFTER THERAPY. WE CONCLUDE THAT A LOW-DOSE, DOSE-INTENSITY SCHEDULE OF DECITABINE OPTIMIZES EPIGENETIC MODULATION AND CLINICAL RESPONSES IN MDS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10  5246  32 PROGNOSTIC SCORE INCLUDING GENE MUTATIONS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. PURPOSE: SEVERAL PROGNOSTIC SCORING SYSTEMS HAVE BEEN PROPOSED FOR CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), A DISEASE IN WHICH SOME GENE MUTATIONS-INCLUDING ASXL1-HAVE BEEN ASSOCIATED WITH POOR PROGNOSIS IN UNIVARIABLE ANALYSES. WE DEVELOPED AND VALIDATED A PROGNOSTIC SCORE FOR OVERALL SURVIVAL (OS) BASED ON MUTATIONAL STATUS AND STANDARD CLINICAL VARIABLES. PATIENTS AND METHODS: WE GENOTYPED ASXL1 AND UP TO 18 OTHER GENES INCLUDING EPIGENETIC (TET2, EZH2, IDH1, IDH2, DNMT3A), SPLICING (SF3B1, SRSF2, ZRSF2, U2AF1), TRANSCRIPTION (RUNX1, NPM1, TP53), AND SIGNALING (NRAS, KRAS, CBL, JAK2, FLT3) REGULATORS IN 312 PATIENTS WITH CMML. GENOTYPES AND CLINICAL VARIABLES WERE INCLUDED IN A MULTIVARIABLE COX MODEL OF OS VALIDATED BY BOOTSTRAPPING. A SCORING SYSTEM WAS DEVELOPED USING REGRESSION COEFFICIENTS FROM THIS MODEL. RESULTS: ASXL1 MUTATIONS (P < .0001) AND, TO A LESSER EXTENT, SRSF2 (P = .03), CBL (P = .003), AND IDH2 (P = .03) MUTATIONS PREDICTED INFERIOR OS IN UNIVARIABLE ANALYSIS. THE RETAINED INDEPENDENT PROGNOSTIC FACTORS INCLUDED ASXL1 MUTATIONS, AGE OLDER THAN 65 YEARS, WBC COUNT GREATER THAN 15 X10(9)/L, PLATELET COUNT LESS THAN 100 X10(9)/L, AND ANEMIA (HEMOGLOBIN < 10 G/DL IN FEMALE PATIENTS, < 11G/DL IN MALE PATIENTS). THE RESULTING FIVE-PARAMETER PROGNOSTIC SCORE DELINEATED THREE GROUPS OF PATIENTS WITH MEDIAN OS NOT REACHED, 38.5 MONTHS, AND 14.4 MONTHS, RESPECTIVELY (P < .0001), AND WAS VALIDATED IN AN INDEPENDENT COHORT OF 165 PATIENTS (P < .0001). CONCLUSION: A NEW PROGNOSTIC SCORE INCLUDING ASXL1 STATUS, AGE, HEMOGLOBIN, WBC, AND PLATELET COUNTS DEFINES THREE GROUPS OF CMML PATIENTS WITH DISTINCT OUTCOMES. BASED ON CONCORDANCE ANALYSIS, THIS SCORE APPEARS MORE DISCRIMINATIVE THAN THOSE BASED SOLELY ON CLINICAL PARAMETERS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11   466  40 ARE THE HEALTHY VULNERABLE? CYTOMEGALOVIRUS SEROPOSITIVITY IN HEALTHY ADULTS IS ASSOCIATED WITH ACCELERATED EPIGENETIC AGE AND IMMUNE DYSREGULATION. BACKGROUND: EVALUATING AGE AS A RISK FACTOR FOR SUSCEPTIBILITY TO INFECTIOUS DISEASES, PARTICULARLY CORONAVIRUS DISEASE 2019 (COVID-19), IS CRITICAL. CYTOMEGALOVIRUS (CMV) SEROLOGIC PREVALENCE INCREASES WITH AGE AND ASSOCIATES WITH INFLAMMATORY-MEDIATED DISEASES IN THE ELDERLY. HOWEVER, LITTLE IS KNOWN REGARDING THE SUBCLINICAL IMPACT OF CMV AND RISK IT POSES TO HEALTHY OLDER ADULTS. PRIOR TO THE COVID-19 PANDEMIC WE CONDUCTED A STUDY TO DETERMINE THE ASSOCIATION OF CMV TO BIOLOGIC AGE AND IMMUNE DYSREGULATION. METHODS: COMMUNITY-DWELLING, HEALTHY ADULTS OLDER THAN 60 YEARS WERE EVALUATED USING DNA METHYLATION ASSAYS TO DEFINE EPIGENETIC AGE (EPIAGE) AND T-CELL IMMUNOPHENOTYPING TO ASSESS IMMUNE DYSREGULATION. RESULTS: ALL SUBJECTS WERE HEALTHY AND ASYMPTOMATIC. THOSE CMV SEROPOSITIVE HAD MORE LYMPHOCYTES, CD8 T CELLS, CD28- T CELLS, DECREASED CD4:CD8 CELL RATIOS, AND HAD HIGHER AVERAGE EPIAGE (65.34 YEARS) THAN THOSE CMV SERONEGATIVE (59.53 YEARS). DECREASED PERCENT CD4 (P = .003) AND NUMBERS OF CD4 T CELLS (P = .0199) CORRELATED WITH INCREASED EPIAGE. CONCLUSIONS: OUR NOVEL FINDINGS DISTINGUISH ALTERED IMMUNITY IN THE ELDERLY BASED ON CMV STATUS. CHRONIC CMV INFECTION IN HEALTHY, OLDER ADULTS IS ASSOCIATED WITH INDICATORS OF IMMUNE DYSREGULATION, BOTH OF WHICH CORRELATE TO DIFFERENCES IN EPIAGE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  2769  31 EXTENDED DOSING WITH CC-486 (ORAL AZACITIDINE) IN PATIENTS WITH MYELOID MALIGNANCIES. CC-486 (ORAL AZACITIDINE) IS AN EPIGENETIC MODIFIER IN CLINICAL DEVELOPMENT FOR TREATMENT OF HEMATOLOGICAL CANCERS. THIS STUDY OF EXTENDED CC-486 DOSING INCLUDED PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDSS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), OR ACUTE MYELOID LEUKEMIA (AML). AFTER A PHARMACOKINETIC ASSESSMENT PERIOD, 31 PATIENTS (MDS N = 18, CMML N = 4, AND AML N = 9) ENTERED A CLINICAL PHASE IN WHICH THEY RECEIVED CC-486 300 MG ONCE-DAILY FOR 21 DAYS OF REPEATED 28-DAY CYCLES. MEDIAN AGE WAS 71 YEARS (RANGE: 53-93); 42% OF PATIENTS WERE AGED >/=75 YEARS. A TOTAL OF 5 PATIENTS WITH AML (63%) HAD PRIOR MDS. MEDIAN NUMBER OF CC-486 TREATMENT CYCLES WAS 4 (RANGE: 1-32). THE MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) WERE GASTROINTESTINAL (84% OF PATIENTS) AND HEMATOLOGIC (81%). MOST COMMON GRADE 3-4 TEAES WERE NEUTROPENIA (N = 13, 42%) AND ANEMIA (N = 9, 29%). TEN PATIENTS EXPERIENCED GRADE 4 NEUTROPENIA. INFREQUENTLY, CC-486 DOSE WAS INTERRUPTED OR REDUCED DUE TO GASTROINTESTINAL (N = 5, 16%) OR HEMATOLOGIC (N = 6, 19%) TEAES. OVERALL RESPONSE RATE (COMPLETE REMISSION [CR], CR WITH INCOMPLETE HEMATOLOGICAL RECOVERY [CRI], PARTIAL REMISSION [PR], MARROW CR) IN THE MDS/CMML SUBGROUPS WAS 32% AND IN THE AML SUBGROUP (CR/CRI/PR) WAS 22%. RED BLOOD CELL TRANSFUSION INDEPENDENCE RATES IN THE MDS/CMML AND AML SUBGROUPS WERE 33% AND 25%, RESPECTIVELY, AND 2 MDS/CMML PATIENTS ATTAINED HEMATOLOGIC IMPROVEMENT AS A BEST RESPONSE ON-STUDY. NO BASELINE GENE MUTATION WAS PREDICTIVE OF RESPONSE/NONRESPONSE. CC-486 ALLOWS FLEXIBLE DOSING AND SCHEDULES TO IMPROVE TOLERABILITY OR RESPONSE. NEUTROPENIA IN EARLY TREATMENT CYCLES DESERVES SCRUTINY AND MAY WARRANT INITIATION OF PROPHYLACTIC ANTIBIOTICS. KEY POINTS: THE SAFETY PROFILE OF ORAL CC-486 WAS COMPARABLE TO THAT OF INJECTABLE AZACITIDINE; MOST ADVERSE EVENTS WERE HEMATOLOGICAL AND GASTROINTESTINAL. EXTENDED (21-DAY/CYCLE) CC-486 DOSING INDUCED RESPONSES IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES, MANY OF WHOM HAD PRIOR DNMTI FAILURE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13  1293  25 DECREASED ERK AND JNK SIGNALING CONTRIBUTE TO GENE OVEREXPRESSION IN "SENESCENT" CD4+CD28- T CELLS THROUGH EPIGENETIC MECHANISMS. AN INFLAMMATORY AND CYTOTOXIC CD4+CD28- T CELL SUBSET INFILTRATES ATHEROSCLEROTIC PLAQUES AND IS IMPLICATED IN PLAQUE RUPTURE AND MYOCARDIAL INFARCTIONS. THIS PATHOLOGIC SUBSET DEVELOPS WITH REPLICATIVE STRESS AND IS FOUND IN PATIENTS WITH CHRONIC INFLAMMATORY DISEASES SUCH AS RA AS WELL AS WITH AGING. CD4+CD28- CELLS OVEREXPRESS GENES NORMALLY SUPPRESSED BY DNA METHYLATION IN CD4+CD28+ T CELLS, SUCH AS KIR, PERFORIN, AND CD70. HOW THIS SUBSET OVER EXPRESSES METHYLATION-SENSITIVE GENES IS UNKNOWN. DNA METHYLATION PATTERNS ARE MAINTAINED IN PROLIFERATING CELLS BY DNMTS, WHICH ARE UP-REGULATED DURING MITOSIS BY THE ERK AND JNK SIGNALING PATHWAYS. WE HYPOTHESIZED THAT DEFECTS IN THESE SIGNALING PATHWAYS CONTRIBUTE TO ALTERED GENE EXPRESSION IN HUMAN CD4+CD28- CELLS THROUGH EFFECTS ON DNA METHYLATION. WE REPORT THAT SIGNALING THROUGH THE ERK AND JNK PATHWAYS IS DECREASED IN CD4+CD28- RELATIVE TO CD4+CD28+ CELLS FROM THE SAME INDIVIDUALS AND THAT ERK AND JNK PATHWAY INHIBITION DECREASES DNMT1 AND -3A LEVELS, WHICH IN TURN, CAUSES DEMETHYLATION AND OVEREXPRESSION OF THE TNFSF7 (CD70) GENE. WE ALSO REPORT THAT CD4+CD28- T CELLS OVEREXPRESS PP5, A STRESS-INDUCED INHIBITOR OF THE ERK AND JNK SIGNALING PATHWAYS THAT MAY CONTRIBUTE TO THE SIGNALING DEFECTS. WE CONCLUDE THAT DECREASED ERK AND JNK SIGNALING IN THE CD4+CD28- SUBSET, ARISING WITH REPLICATIVE STRESS, CAN LEAD TO THE OVEREXPRESSION OF NORMALLY SUPPRESSED GENES THROUGH EFFECTS ON DNMTS AND CONSEQUENTLY, CHROMATIN STRUCTURE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  1469  33 DISTINCT EVOLUTIONARY PATHS IN CHRONIC LYMPHOCYTIC LEUKEMIA DURING RESISTANCE TO THE GRAFT-VERSUS-LEUKEMIA EFFECT. LEUKEMIC RELAPSE REMAINS A MAJOR BARRIER TO SUCCESSFUL ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT) FOR AGGRESSIVE HEMATOLOGIC MALIGNANCIES. THE BASIS FOR RELAPSE OF ADVANCED LYMPHOID MALIGNANCIES REMAINS INCOMPLETELY UNDERSTOOD AND MAY INVOLVE ESCAPE FROM THE GRAFT-VERSUS-LEUKEMIA (GVL) EFFECT. WE HYPOTHESIZED THAT FOR PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREATED WITH ALLO-HSCT, LEUKEMIC CELL-INTRINSIC FEATURES INFLUENCE TRANSPLANT OUTCOMES BY DIRECTING THE EVOLUTIONARY TRAJECTORIES OF CLL CELLS. INTEGRATED GENETIC, TRANSCRIPTOMIC, AND EPIGENETIC ANALYSES OF CLL CELLS FROM 10 PATIENTS REVEALED THAT THE CLINICAL KINETICS OF POST-HSCT RELAPSE ARE SHAPED BY DISTINCT MOLECULAR DYNAMICS. EARLY RELAPSES AFTER ALLO-HSCT EXHIBITED NOTABLE GENETIC STABILITY; SINGLE CLL CELL TRANSCRIPTIONAL ANALYSIS DEMONSTRATED A CELLULAR HETEROGENEITY THAT WAS STATIC OVER TIME. IN CONTRAST, CLL CELLS RELAPSING LATE AFTER ALLO-HSCT DISPLAYED NOTABLE GENETIC EVOLUTION AND EVIDENCE OF NEOANTIGEN DEPLETION, CONSISTENT WITH MARKED SINGLE-CELL TRANSCRIPTIONAL SHIFTS THAT WERE UNIQUE TO EACH PATIENT. WE OBSERVED A GREATER RATE OF EPIGENETIC CHANGE FOR LATE RELAPSES NOT SEEN IN EARLY RELAPSES OR RELAPSES AFTER CHEMOTHERAPY ALONE, SUGGESTING THAT THE SELECTION PRESSURES OF THE GVL BOTTLENECK ARE UNLIKE THOSE IMPOSED BY CHEMOTHERAPY. NO SELECTIVE ADVANTAGE FOR HUMAN LEUKOCYTE ANTIGEN (HLA) LOSS WAS OBSERVED, EVEN WHEN PRESENT IN PRETRANSPLANT SUBPOPULATIONS. GAIN OF STEM CELL MODULES WAS A COMMON SIGNATURE ASSOCIATED WITH LEUKEMIA RELAPSE REGARDLESS OF POSTTRANSPLANT RELAPSE KINETICS. THESE DATA ELUCIDATE THE BIOLOGICAL PATHWAYS THAT UNDERLIE GVL RESISTANCE AND POSTTRANSPLANT RELAPSE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15  5244  30 PROGNOSTIC INTERACTION BETWEEN ASXL1 AND TET2 MUTATIONS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. MUTATIONS INVOLVING EPIGENETIC REGULATORS (TET2~60% AND ASXL1~40%) AND SPLICING COMPONENTS (SRSF2~50%) ARE FREQUENT IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). ON A 27-GENE TARGETED CAPTURE PANEL PERFORMED ON 175 CMML PATIENTS (66% MALES, MEDIAN AGE 70 YEARS), COMMON MUTATIONS INCLUDED: TET2 46%, ASXL1 47%, SRSF2 45% AND SETBP1 19%. A TOTAL OF 172 (98%) PATIENTS HAD AT LEAST ONE MUTATION, 21 (12%) HAD 2, 24 (14%) HAD 3 AND 30 (17%) HAD >3 MUTATIONS. IN A UNIVARIATE ANALYSIS, THE PRESENCE OF ASXL1 MUTATIONS (P=0.02) AND THE ABSENCE OF TET2 MUTATIONS (P=0.03), ADVERSELY IMPACTED SURVIVAL; WHILE THE NUMBER OF CONCURRENT MUTATIONS HAD NO IMPACT (P=0.3). IN A MULTIVARIABLE ANALYSIS THAT INCLUDED HEMOGLOBIN, PLATELET COUNT, ABSOLUTE MONOCYTE COUNT AND CIRCULATING IMMATURE MYELOID CELLS (MAYO MODEL), THE PRESENCE OF ASXL1 MUTATIONS (P=0.01) AND ABSENCE OF TET2 MUTATIONS (P=0.003) RETAINED PROGNOSTIC SIGNIFICANCE. PATIENTS WERE STRATIFIED INTO FOUR CATEGORIES: ASXL1WT/TET2WT (N=56), ASXL1MUT/TET2WT (N=31), ASXL1MUT/TET2MUT (N=50) AND ASXL1WT/TET2MUT (N=38). SURVIVAL DATA DEMONSTRATED A SIGNIFICANT DIFFERENCE IN FAVOR OF ASXL1WT/TET2MUT (38 MONTHS; P=0.016), COMPARED WITH THOSE WITH ASXL1WT/TET2WT (19 MONTHS), ASXL1MUT/TET2WT (21 MONTHS) AND ASXL1MUT/TET2MUT (16 MONTHS) (P=0.3). WE CONFIRM THE NEGATIVE PROGNOSTIC IMPACT IMPARTED BY ASXL1 MUTATIONS AND SUGGEST A FAVORABLE IMPACT FROM TET2 MUTATIONS IN THE ABSENCE OF ASXL1 MUTATIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16  4231  39 METHYLATION OF PROTOCADHERIN 10, A NOVEL TUMOR SUPPRESSOR, IS ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH GASTRIC CANCER. BACKGROUND & AIMS: BY USING METHYLATION-SENSITIVE REPRESENTATIONAL DIFFERENCE ANALYSIS, WE IDENTIFIED PROTOCADHERIN 10 (PCDH10), A GENE THAT ENCODES A PROTOCADHERIN AND IS SILENCED IN A TUMOR-SPECIFIC MANNER. WE ANALYZED ITS EPIGENETIC INACTIVATION, BIOLOGICAL EFFECTS, AND PROGNOSTIC SIGNIFICANCE IN GASTRIC CANCER. METHODS: METHYLATION STATUS WAS EVALUATED BY COMBINED BISULFITE RESTRICTION ANALYSIS AND BISULFITE SEQUENCING. THE EFFECTS OF PCDH10 RE-EXPRESSION WERE DETERMINED IN GROWTH, APOPTOSIS, PROLIFERATION, AND INVASION ASSAYS. PCDH10 TARGET GENES WERE IDENTIFIED BY COMPLEMENTARY DNA MICROARRAY ANALYSIS. RESULTS: PCDH10 WAS SILENCED OR DOWN-REGULATED IN 94% (16 OF 17) OF GASTRIC CANCER CELL LINES; EXPRESSION LEVELS WERE RESTORED BY EXPOSURE TO DEMETHYLATING AGENTS. RE-EXPRESSION OF PCDH10 IN MKN45 GASTRIC CANCER CELLS REDUCED COLONY FORMATION IN VITRO AND TUMOR GROWTH IN MICE; IT ALSO INHIBITED CELL PROLIFERATION (P < .01), INDUCED CELL APOPTOSIS (P < .001), AND REPRESSED CELL INVASION (P < .05), UP-REGULATING THE PRO-APOPTOSIS GENES FAS, CASPASE 8, JUN, AND CDKN1A; THE ANTIPROLIFERATION GENE FGFR; AND THE ANTI-INVASION GENE HTATIP2. PCDH10 METHYLATION WAS DETECTED IN 82% (85 OF 104) OF GASTRIC TUMORS COMPARED WITH 37% (38 OF 104) OF PAIRED NONTUMOR TISSUES (P < .0001). IN THE LATTER, PCDH10 METHYLATION WAS HIGHER IN PRECANCEROUS LESIONS (27 OF 45; 60%) THAN IN CHRONIC GASTRITIS SAMPLES (11 OF 59; 19%) (P < .0001). AFTER A MEDIAN FOLLOW-UP PERIOD OF 16.8 MONTHS, MULTIVARIATE ANALYSIS REVEALED THAT PATIENTS WITH PCDH10 METHYLATION IN ADJACENT NONTUMOR AREAS HAD A SIGNIFICANT DECREASE IN OVERALL SURVIVAL. KAPLAN-MEIER SURVIVAL CURVES SHOWED THAT PCDH10 METHYLATION WAS ASSOCIATED SIGNIFICANTLY WITH SHORTENED SURVIVAL IN STAGE I-III GASTRIC CANCER PATIENTS. CONCLUSIONS: PCDH10 IS A GASTRIC TUMOR SUPPRESSOR; ITS METHYLATION AT EARLY STAGES OF GASTRIC CARCINOGENESIS IS AN INDEPENDENT PROGNOSTIC FACTOR.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17  5044  35 PHARMACOKINETICS AND PHARMACODYNAMICS WITH EXTENDED DOSING OF CC-486 IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES. CC-486 (ORAL AZACITIDINE) IS AN EPIGENETIC MODIFIER IN DEVELOPMENT FOR PATIENTS WITH MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIA. IN PART 1 OF THIS TWO-PART STUDY, A 7-DAY CC-486 DOSING SCHEDULE SHOWED CLINICAL ACTIVITY, WAS GENERALLY WELL TOLERATED, AND REDUCED DNA METHYLATION. EXTENDING DOSING OF CC-486 BEYOND 7 DAYS WOULD INCREASE DURATION OF AZACITIDINE EXPOSURE. WE HYPOTHESIZED THAT EXTENDED DOSING WOULD THEREFORE PROVIDE MORE SUSTAINED EPIGENETIC ACTIVITY. REPORTED HERE ARE THE PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) PROFILES OF CC-486 EXTENDED DOSING SCHEDULES IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) OR ACUTE MYELOID LEUKEMIA (AML) FROM PART 2 OF THIS STUDY. PK AND/OR PD DATA WERE AVAILABLE FOR 59 PATIENTS WHO WERE SEQUENTIALLY ASSIGNED TO 1 OF 4 EXTENDED CC-486 DOSING SCHEDULES: 300MG ONCE-DAILY OR 200MG TWICE-DAILY FOR 14 OR 21 DAYS PER 28-DAY CYCLE. BOTH 300MG ONCE-DAILY SCHEDULES AND THE 200MG TWICE-DAILY 21-DAY SCHEDULE SIGNIFICANTLY (ALL P < .05) REDUCED GLOBAL DNA METHYLATION IN WHOLE BLOOD AT ALL MEASURED TIME POINTS (DAYS 15, 22, AND 28 OF THE TREATMENT CYCLE), WITH SUSTAINED HYPOMETHYLATION AT CYCLE END COMPARED WITH BASELINE. CC-486 EXPOSURES AND REDUCED DNA METHYLATION WERE SIGNIFICANTLY CORRELATED. PATIENTS WHO HAD A HEMATOLOGIC RESPONSE HAD SIGNIFICANTLY GREATER METHYLATION REDUCTIONS THAN NON-RESPONDING PATIENTS. THESE DATA DEMONSTRATE THAT EXTENDED DOSING OF CC-486 SUSTAINS EPIGENETIC EFFECTS THROUGH THE TREATMENT CYCLE. TRIAL REGISTRATION: CLINICALTRIALS.GOV NCT00528983.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18    87  42 A PHASE 1 STUDY OF AZACITIDINE WITH HIGH-DOSE CYTARABINE AND MITOXANTRONE IN HIGH-RISK ACUTE MYELOID LEUKEMIA. IN THIS PHASE 1 STUDY, AZACITIDINE (AZA) WAS GIVEN BEFORE HIGH-DOSE CYTARABINE (HIDAC) AND MITOXANTRONE (MITO) BASED ON THE HYPOTHESIS THAT EPIGENETIC PRIMING WITH A HYPOMETHYLATING AGENT BEFORE CYTOTOXIC CHEMOTHERAPY WOULD IMPROVE RESPONSE RATES IN PATIENTS WITH HIGH-RISK ACUTE MYELOID LEUKEMIA (AML), INCLUDING RELAPSED/REFRACTORY DISEASE. THE PRIMARY OBJECTIVE WAS TO ESTABLISH THE RECOMMENDED PHASE 2 DOSE OF AZA GIVEN BEFORE STANDARD HIDAC/MITO. IN A DOSE ESCALATION SCHEME, 46 PATIENTS (MEDIAN AGE, 66 YEARS) RECEIVED AZA AT 37.5, 50, OR 75 MG/M2 SUBCUTANEOUSLY OR IV ONCE DAILY ON DAYS 1 TO 5 FOLLOWED BY HIDAC (3000 MG/M2) AND MITOXANTRONE (30 MG/M2) ONCE EACH ON DAYS 6 AND 10 (THE HIDAC/MITO DOSE WAS REDUCED 33% IN ELDERLY SUBJECTS). TWO DOSE-LIMITING TOXICITIES OCCURRED (BOTH IN THE SAME PATIENT): ACUTE LIVER FAILURE AND KIDNEY INJURY AT THE 50 MG/M2 DOSE. THE 30-DAY INDUCTION DEATH RATE WAS 2.2% (1 OF 46). THE OVERALL RESPONSE RATE, INCLUDING COMPLETE REMISSION AND COMPLETE REMISSION WITH INCOMPLETE COUNT RECOVERY, WAS 61% (28 OF 46). PREVIOUSLY UNTREATED PATIENTS AGED >/=60 YEARS WITH THERAPY-RELATED AML AND DE NOVO AML WERE MORE LIKELY TO RESPOND THAN UNTREATED PATIENTS WITH AML PROGRESSING FROM AN ANTECEDENT HEMATOLOGIC DISORDER (MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA). PATIENTS WITH FAVORABLE EUROPEAN LEUKEMIA NETWORK RISK (P = .008), NPM1 MUTATIONS (P = .007), OR IDH2 MUTATIONS (P = .03) WERE MORE LIKELY TO RESPOND, AND THOSE WITH TP53 MUTATIONS (P = .03) WERE LESS LIKELY TO RESPOND. THE RECOMMENDED PHASE 2 DOSE OF AZA IS 75 MG/M2 PER DAY ON DAYS 1 TO 5 FOLLOWED BY HIDAC (3000 MG/M2) AND MITOXANTRONE (30 MG/M2) ONCE EACH ON DAYS 6 AND 10. THIS TRIAL WAS REGISTERED AT WWW.CLINICALTRIALS.GOV AS #NCT01839240.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  4601  43 NDRG2 MRNA LEVELS AND MIR-28-5P AND MIR-650 ACTIVITY IN CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: NDRG2 IS IDENTIFIED AS A TUMOR SUPPRESSOR GENE IN MANY TUMORS, AND FUNCTIONS IN CELL PROLIFERATION, DIFFERENTIATION AND APOPTOSIS. RECENT DATA INDICATE THAT NDRG2 EXPRESSION IS UP-REGULATED BY TP53. MOREOVER, PROPOSED MECHANISMS OF NDRG2 INACTIVATION INCLUDE EPIGENETIC SILENCING OF THE NDRG2 PROMOTER AND DOWN-REGULATION BY MICRORNAS (MIRNAS). HOWEVER, FEW STUDIES HAVE EVER BEEN DONE ON THE ROLE OF NDRG2 AND THE NDRG2-REGULATING MIRNAS INTERFERENCE IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). METHODS: NDRG2 AND MICRORNAS MRNA LEVELS IN CLL SUBJECTS WERE ASSESSED BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QRT-PCR). THE DUAL-LUCIFERASE REPORTER ASSAY WAS PERFORMED TO DETERMINE NDRG2-RELATED MIRNAS. LOW EXPRESSION OF MATURE EXOGENOUS MIRNAS IN CLL CELLS WAS ESTABLISHED BY TRANSIENT TRANSFECTION. NDRG2 PROTEIN LEVELS IN CLL CELLS WERE DETECTED BY WESTERN BLOT. IN ADDITION, FLOW CYTOMETRY WAS CONDUCTED TO EXAMINE THE APOPTOSIS OF CLL CELLS. RESULTS: LOWER EXPRESSION OF NDRG2 WAS FOUND IN THE B-CELLS FROM 102 CLL PATIENTS COMPARED THE 40 NORMAL SUBJECTS (P < 0.001). PATIENTS WITH ADVANCED BINET STAGE (P = 0.001), HIGH LACTATE DEHYDROGENASE (LDH) LEVEL (P = 0.036), UN-MUTATED IMMUNOGLOBULIN HEAVY CHAIN VARIABLE REGION GENE (IGHV) (P = 0.004) AND THOSE WITH P53 ABERRATIONS (P < 0.001) HAD A MARKEDLY LOWER LEVELS OF NDRG2 MRNA. THIS DECREASE WAS ASSOCIATED WITH BRIEFER TIME-TO-TREATMENT (P = 0.001) AND POORER SURVIVAL (P < 0.001). HIGH EXPRESSION OF MIR-28-5P AND MIR-650 WAS ASSOCIATED WITH BINET B/C STAGE (P = 0.044) AND IGHV UN-MUTATED (P = 0.011), AS WELL AS BINET B/C STAGE (P = 0.013) AND P53 ABERRATIONS (P = 0.037), RESPECTIVELY. INHIBITION OF MIR-28-5P OR MIR-650 COULD INDUCE MORE APOPTOSIS IN CLL CELLS WITH GERMLINE TP53. CONCLUSIONS: NDRG2 MRNA LEVELS MIGHT BE A USEFUL PROGNOSTIC VARIABLE FOR PATIENTS OF CLL AND UP-REGULATING NDRG2 TRANSCRIPTION MAY BE A THERAPY APPROACH IN CLL WITHOUT P53 ABERRATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  3294  34 HIGH INCIDENCE OF MGMT AND RARBETA PROMOTER METHYLATION IN PRIMARY GLIOBLASTOMAS: ASSOCIATION WITH HISTOPATHOLOGICAL CHARACTERISTICS, INFLAMMATORY MEDIATORS AND CLINICAL OUTCOME. GLIOBLASTOMAS, THE MOST FREQUENT PRIMARY BRAIN TUMORS IN ADULTS, ARE CHARACTERIZED BY A HIGHLY AGGRESSIVE, INFLAMMATORY AND ANGIOGENIC PHENOTYPE. METHYLATION OF CPG ISLANDS IN CANCER-RELATED GENES MAY SERVE AS AN EPIGENETIC BIOMARKER FOR GLIOBLASTOMA DIAGNOSIS AND PROGNOSIS. THE AIM OF THIS STUDY WAS TO ANALYZE THE METHYLATION STATUS OF FOUR CRITICAL TUMOR-ASSOCIATED GENES (MGMT, RARBETA, RASSF1A, CDH13), AND INVESTIGATE POSSIBLE LINKS WITH INFLAMMATORY (INTERLEUKIN [IL]-6, IL-8) AND ANGIOGENIC MEDIATORS (VASCULAR ENDOTHELIAL GROWTH FACTOR [VEGF], CYCLOOXYGENASE [COX]-2) AND CLINICAL OUTCOME IN 23 GLIOMA SAMPLES (6 GRADE II ASTROCYTOMAS, 17 GRADE IV GLIOBLASTOMAS). RARBETA AND MGMT GENES WERE MORE FREQUENTLY METHYLATED IN 70.58% AND 58.8% OF GLIOBLASTOMAS, RESPECTIVELY. RASSF1A AND CDH13 DISPLAYED A SIMILAR METHYLATION FREQUENCY (23.52%) IN GLIOBLASTOMAS. NO GENE METHYLATION WAS OBSERVED IN GRADE II ASTROCYTOMAS. TUMOR GRADE CORRELATED POSITIVELY WITH MGMT AND RARBETA METHYLATION (P = 0.005 AND P = 0.019, RESPECTIVELY) AND THE EXTENT OF NECROSIS (P = 0.001 AND P = 0.003). INTERESTINGLY, THE MARKER OF CHRONIC INFLAMMATION, IL-6, WAS POSITIVELY ASSOCIATED WITH METHYLATION OF MGMT (P = 0.004), RARBETA (P = 0.002), AND RASSF1A (P = 0.0081) AS WELL AS THE TOTAL NUMBER OF METHYLATED GENES (P < 0.0001), INDICATING THE IMPORTANT ROLE OF IL-6 IN MAINTAINING PROMOTER METHYLATION OF THESE GENES. VEGF EXPRESSION CORRELATED POSITIVELY WITH MGMT AND RARBETA METHYLATION ALTHOUGH THESE RELATIONSHIPS WERE OF MARGINAL SIGNIFICANCE (P = 0.0679 AND P = 0.0757). KAPLAN-MEIER UNIVARIATE SURVIVAL ANALYSIS INDICATED AN UNFAVORABLE SURVIVAL PERIOD IN PATIENTS WITH MGMT METHYLATION COMPARED WITH THOSE WITHOUT METHYLATION (P = 0.0474). OUR STUDY HIGHLIGHTS THE IMPLICATION OF MGMT AND RARBETA METHYLATION IN THE AGGRESSIVE PHENOTYPE OF PRIMARY GLIOBLASTOMAS. THE ASSOCIATION OF MGMT METHYLATION WITH CLINICAL OUTCOME INDICATES ITS POTENTIAL PROGNOSTIC VALUE.	2010