1 1628 140 DNMT3A AND TET2 DOMINATE CLONAL HEMATOPOIESIS AND DEMONSTRATE BENIGN PHENOTYPES AND DIFFERENT GENETIC PREDISPOSITIONS. AGE-ASSOCIATED CLONAL HEMATOPOIESIS CAUSED BY ACQUIRED MUTATIONS IN MYELOID CANCER-ASSOCIATED GENES IS HIGHLY PREVALENT IN THE NORMAL POPULATION. ITS ETIOLOGY, BIOLOGICAL IMPACT ON HEMATOPOIESIS, AND ONCOGENIC RISK IS POORLY DEFINED AT THIS TIME. TO GAIN INSIGHT INTO THIS PHENOMENON, WE ANALYZED A COHORT OF 2530 RELATED AND UNRELATED HEMATOLOGICALLY NORMAL INDIVIDUALS (AGES 55 TO 101 YEARS). WE USED A SENSITIVE GENE-TARGETED DEEP SEQUENCING APPROACH TO GAIN PRECISION ON THE EXACT PREVALENCE OF DRIVER MUTATIONS AND THE PROPORTIONS OF AFFECTED GENES. MUTATIONAL STATUS WAS CORRELATED WITH BIOLOGICAL PARAMETERS. WE REPORT A HIGHER OVERALL PREVALENCE OF DRIVER MUTATIONS (13.7%), WHICH OCCURRED MOSTLY (93%) IN DNMT3A OR TET2 AND WERE HIGHLY AGE-CORRELATED. MUTATION IN THESE 2 GENES HAD SOME DISTINCTIVE EFFECTS ON END POINTS. TET2 MUTATIONS WERE MORE AGE-DEPENDENT, ASSOCIATED WITH A MODEST NEUTROPENIC EFFECT (9%, P = .012), DEMONSTRATED FAMILIAL AGGREGATION, AND ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. MUTATIONS IN DNMT3A HAD NO IMPACT ON BLOOD COUNTS OR INDICES. MUTATIONAL BURDEN OF BOTH GENES CORRELATED WITH X-INACTIVATION SKEWING BUT NO SIGNIFICANT ASSOCIATION WITH AGE-ADJUSTED TELOMERE LENGTH REDUCTION WAS DOCUMENTED. THE DISCORDANCE BETWEEN THE HIGH PREVALENCE OF MUTATIONS IN THESE 2 GENES AND THEIR LIMITED BIOLOGICAL IMPACT RAISE THE QUESTION OF THE POTENTIAL ROLE OF DYSREGULATED EPIGENETIC MODIFIERS IN NORMAL AGING HEMATOPOIESIS, WHICH MAY INCLUDE SUPPORT TO FAILING HEMATOPOIESIS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2   59  33 A GENOME-WIDE SCREEN IDENTIFIES FREQUENTLY METHYLATED GENES IN HAEMATOLOGICAL AND EPITHELIAL CANCERS. BACKGROUND: GENETIC AS WELL AS EPIGENETIC ALTERATIONS ARE A HALLMARK OF BOTH EPITHELIAL AND HAEMATOLOGICAL MALIGNANCIES. HIGH THROUGHPUT SCREENS ARE REQUIRED TO IDENTIFY EPIGENETIC MARKERS THAT CAN BE USEFUL FOR DIAGNOSTIC AND PROGNOSTIC PURPOSES ACROSS MALIGNANCIES. RESULTS: HERE WE REPORT FOR THE FIRST TIME THE USE OF THE MIRA ASSAY (METHYLATED CPG ISLAND RECOVERY ASSAY) IN COMBINATION WITH GENOME-WIDE CPG ISLAND ARRAYS TO IDENTIFY EPIGENETIC MOLECULAR MARKERS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) ON A GENOME-WIDE SCALE. WE IDENTIFIED 30 GENES DEMONSTRATING METHYLATION FREQUENCIES OF > OR =25% IN CHILDHOOD ALL, NINE GENES SHOWED SIGNIFICANTLY DIFFERENT METHYLATION FREQUENCIES IN B VS T-ALL. FOR MAJORITY OF THE GENES EXPRESSION COULD BE RESTORED IN METHYLATED LEUKEMIA LINES AFTER TREATMENT WITH 5-AZADC. FORTY-FOUR PERCENT OF THE GENES REPRESENT TARGETS OF THE POLYCOMB COMPLEX. IN CHRONIC MYELOID LEUKEMIA (CML) TWO OF THE GENES, (TFAP2A AND EBF2), DEMONSTRATED INCREASED METHYLATION IN BLAST CRISIS COMPARED TO CHRONIC PHASE (P < 0.05). FURTHERMORE HYPERMETHYLATION OF AN AUTOPHAGY RELATED GENE ATG16L2 WAS ASSOCIATED WITH POORER PROGNOSIS IN TERMS OF MOLECULAR RESPONSE TO IMATINIB TREATMENT. LASTLY WE DEMONSTRATED THAT TEN OF THESE GENES WERE ALSO FREQUENTLY METHYLATED IN COMMON EPITHELIAL CANCERS. CONCLUSION: IN SUMMARY WE HAVE IDENTIFIED A LARGE NUMBER OF GENES SHOWING FREQUENT METHYLATION IN CHILDHOOD ALL, METHYLATION STATUS OF TWO OF THESE GENES IS ASSOCIATED WITH ADVANCED DISEASE IN CML AND METHYLATION STATUS OF ANOTHER GENE IS ASSOCIATED WITH PROGNOSIS. IN ADDITION A SUBSET OF THESE GENES MAY ACT AS EPIGENETIC MARKERS ACROSS HEMATOLOGICAL MALIGNANCIES AS WELL AS COMMON EPITHELIAL CANCERS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3 2911  36 GENE EXPRESSION PROFILING OF LOSS OF TET2 AND/OR JAK2V617F MUTANT HEMATOPOIETIC STEM CELLS FROM MOUSE MODELS OF MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLINICALLY CHARACTERIZED BY THE CHRONIC OVERPRODUCTION OF DIFFERENTIATED PERIPHERAL BLOOD CELLS AND THE GRADUAL EXPANSION OF MALIGNANT INTRAMEDULLARY/EXTRAMEDULLARY HEMATOPOIESIS. IN MPNS MUTATIONS IN JAK2 MPL OR CALR ARE DETECTED MUTUALLY EXCLUSIVE IN MORE THAN 90% OF CASES [1,2]. MUTATIONS IN THEM LEAD TO THE ABNORMAL ACTIVATION OF JAK/STAT SIGNALING AND THE AUTONOMOUS GROWTH OF DIFFERENTIATED CELLS THEREFORE THEY ARE CONSIDERED AS "DRIVER" GENE MUTATIONS. IN ADDITION TO THE ABOVE DRIVER GENE MUTATIONS MUTATIONS IN EPIGENETIC REGULATORS SUCH AS TET2 DNMT3A ASXL1 EZH2 OR IDH1/2 ARE DETECTED IN ABOUT 5%-30% OF CASES RESPECTIVELY [3]. MUTATIONS IN TET2 DNMT3A EZH2 OR IDH1/2 COMMONLY CONFER THE INCREASED SELF-RENEWAL CAPACITY ON NORMAL HEMATOPOIETIC STEM CELLS (HSCS) BUT THEY DO NOT LEAD TO THE AUTONOMOUS GROWTH OF DIFFERENTIATED CELLS AND ONLY EXHIBIT SUBTLE CLINICAL PHENOTYPES [4,6-8,5]. IT WAS UNCLEAR HOW MUTATIONS IN SUCH EPIGENETIC REGULATORS INFLUENCED ABNORMAL HSCS WITH DRIVER GENE MUTATIONS HOW THEY INFLUENCED THE DISEASE PHENOTYPE OR WHETHER A SINGLE DRIVER GENE MUTATION WAS SUFFICIENT FOR THE INITIATION OF HUMAN MPNS. THEREFORE WE FOCUSED ON JAK2V617F AND LOSS OF TET2-THE FORMER AS A REPRESENTATIVE OF DRIVER GENE MUTATIONS AND THE LATTER AS A REPRESENTATIVE OF MUTATIONS IN EPIGENETIC REGULATORS-AND EXAMINED THE INFLUENCE OF SINGLE OR DOUBLE MUTATIONS ON HSCS (LINEAGE(-)SCA-1(+)C-KIT(+) CELLS (LSKS)) BY FUNCTIONAL ANALYSES AND MICROARRAY WHOLE-GENOME EXPRESSION ANALYSES [9]. GENE EXPRESSION PROFILING SHOWED THAT THE HSC FINGERPRINT GENES [10] WAS STATISTICALLY EQUALLY ENRICHED IN TET2-KNOCKDOWN-LSKS BUT NEGATIVELY ENRICHED IN JAK2V617F-LSKS COMPARED TO THAT IN WILD-TYPE-LSKS. DOUBLE-MUTANT-LSKS SHOWED THE SAME TENDENCY AS JAK2V617F-LSKS IN TERMS OF THEIR HSC FINGERPRINT GENES BUT THE EXPRESSION OF INDIVIDUAL GENES DIFFERED BETWEEN THE TWO GROUPS. AMONG 245 HSC FINGERPRINT GENES 100 WERE MORE HIGHLY EXPRESSED IN DOUBLE-MUTANT-LSKS THAN IN JAK2V617F-LSKS. THESE ALTERED GENE EXPRESSIONS MIGHT PARTLY EXPLAIN THE MECHANISMS OF INITIATION AND PROGRESSION OF MPNS WHICH WAS OBSERVED IN THE FUNCTIONAL ANALYSES [9]. HERE WE DESCRIBE GENE EXPRESSION PROFILES DEPOSITED AT THE GENE EXPRESSION OMNIBUS (GEO) UNDER THE ACCESSION NUMBER GSE62302 INCLUDING EXPERIMENTAL METHODS AND QUALITY CONTROL ANALYSES.	2015	

4 1519  26 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5 1561  27 DNA METHYLATION OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH DIFFERENTIAL RESPONSE TO CHEMOTHERAPY. ACQUIRED RESISTANCE TO CHEMOTHERAPY IS AN IMPORTANT CLINICAL PROBLEM AND CAN ALSO OCCUR WITHOUT DETECTABLE CYTOGENETIC ABERRATIONS OR GENE MUTATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS MOLECULARLY WELL CHARACTERIZED AND HAS BEEN ELEMENTAL FOR ESTABLISHING CENTRAL PARADIGMS IN ONCOLOGY. THIS PROMPTED US TO CHECK WHETHER SPECIFIC EPIGENETIC CHANGES AT THE LEVEL OF DNA METHYLATION MIGHT UNDERLIE DEVELOPMENT OF TREATMENT RESISTANCE. WE USED ILLUMINA INFINIUM HUMANMETHYLATION450 BEADCHIPS TO OBTAIN DNA METHYLATION PROFILES OF 71 CLL PATIENTS WITH DIFFERENTIAL RESPONSES. THIRTY-SIX PATIENTS WERE CATEGORIZED AS RELAPSED/REFRACTORY AFTER TREATMENT WITH FLUDARABINE OR BENDAMUSTINE AND 21 OF THEM HAD GENETIC ABERRATIONS OF TP53. THE OTHER 35 PATIENTS WERE UNTREATED AT THE TIME OF SAMPLING AND 15 OF THEM HAD GENETIC ABERRATION OF TP53. ALTHOUGH WE COULD NOT CORRELATE CHEMORESISTANCE WITH EPIGENETIC CHANGES, THE PATIENTS WERE COMPREHENSIVELY CHARACTERIZED REGARDING RELEVANT PROGNOSTIC AND MOLECULAR MARKERS (E.G. IGHV MUTATION STATUS, CHROMOSOME ABERRATIONS, TP53 MUTATION STATUS, CLINICAL PARAMETERS), WHICH MAKES OUR DATASET A UNIQUE AND VALUABLE RESOURCE THAT CAN BE USED BY RESEARCHERS TO TEST ALTERNATIVE HYPOTHESES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6 4551  36 MUTATIONAL HIERARCHIES IN MYELODYSPLASTIC SYNDROMES DYNAMICALLY ADAPT AND EVOLVE UPON THERAPY RESPONSE AND FAILURE. CLONAL EVOLUTION IS BELIEVED TO BE A MAIN DRIVER FOR PROGRESSION OF VARIOUS TYPES OF CANCER AND IMPLICATED IN FACILITATING RESISTANCE TO DRUGS. HOWEVER, THE HIERARCHICAL ORGANIZATION OF MALIGNANT CLONES IN THE HEMATOPOIESIS OF MYELODYSPLASTIC SYNDROMES (MDS) AND ITS IMPACT ON RESPONSE TO DRUG THERAPY REMAIN POORLY UNDERSTOOD. USING HIGH-THROUGHPUT SEQUENCING OF PATIENT AND XENOGRAFTED CELLS, WE EVALUATED THE INTRATUMORAL HETEROGENEITY (N= 54) AND RECONSTRUCTED MUTATIONAL TRAJECTORIES (N = 39) IN PATIENTS SUFFERING FROM MDS (N = 52) AND CHRONIC MYELOMONOCYTIC LEUKEMIA-1 (N = 2). WE IDENTIFIED LINEAR AND ALSO BRANCHING EVOLUTION PATHS AND CONFIRMED ON A PATIENT-SPECIFIC LEVEL THAT SOMATIC MUTATIONS IN EPIGENETIC REGULATORS AND RNA SPLICING GENES FREQUENTLY CONSTITUTE ISOLATED DISEASE-INITIATING EVENTS. USING HIGH-THROUGHPUT EXOME- AND/OR DEEP-SEQUENCING, WE ANALYZED 103 CHRONOLOGICALLY ACQUIRED SAMPLES FROM 22 PATIENTS COVERING A CUMULATIVE OBSERVATION TIME OF 75 YEARS MDS DISEASE PROGRESSION. OUR DATA REVEALED HIGHLY DYNAMIC SHAPING OF COMPLEX OLIGOCLONAL ARCHITECTURES, SPECIFICALLY UPON TREATMENT WITH LENALIDOMIDE AND OTHER DRUGS. DESPITE INITIAL CLINICAL RESPONSE TO TREATMENT, PATIENTS' MARROW PERSISTENTLY REMAINED CLONAL WITH RAPID OUTGROWTH OF FOUNDER-, SUB-, OR EVEN FULLY INDEPENDENT CLONES, INDICATING AN INCREASED DYNAMIC RATE OF CLONAL TURNOVER. THE EMERGENCE AND DISAPPEARANCE OF SPECIFIC CLONES FREQUENTLY CORRELATED WITH CHANGES OF CLINICAL PARAMETERS, HIGHLIGHTING THEIR DISTINCT AND FAR-REACHING FUNCTIONAL PROPERTIES. INTRIGUINGLY, INCREASINGLY COMPLEX MUTATIONAL TRAJECTORIES ARE FREQUENTLY ACCOMPANIED BY CLINICAL PROGRESSION DURING THE COURSE OF DISEASE. THESE DATA SUBSTANTIATE A NEED FOR REGULAR BROAD MOLECULAR MONITORING TO GUIDE CLINICAL TREATMENT DECISIONS IN MDS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7 2966  23 GENETIC AND EPIGENETIC PROFILING OF CLL DISEASE PROGRESSION REVEALS LIMITED SOMATIC EVOLUTION AND SUGGESTS A RELATIONSHIP TO MEMORY-CELL DEVELOPMENT. WE EXAMINED GENETIC AND EPIGENETIC CHANGES THAT OCCUR DURING DISEASE PROGRESSION FROM INDOLENT TO AGGRESSIVE FORMS OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) USING SERIAL SAMPLES FROM 27 PATIENTS. ANALYSIS OF DNA MUTATIONS GROUPED THE LEUKEMIA CASES INTO THREE CATEGORIES: EVOLVING (26%), EXPANDING (26%) AND STATIC (47%). THUS, APPROXIMATELY THREE-QUARTERS OF THE CLL CASES HAD LITTLE TO NO GENETIC SUBCLONAL EVOLUTION. HOWEVER, WE IDENTIFIED SIGNIFICANT RECURRENT DNA METHYLATION CHANGES DURING PROGRESSION AT 4752 CPGS ENRICHED FOR REGIONS NEAR POLYCOMB 2 REPRESSIVE COMPLEX (PRC2) TARGETS. PROGRESSION-ASSOCIATED CPGS NEAR THE PRC2 TARGETS UNDERGO METHYLATION CHANGES IN THE SAME DIRECTION DURING DISEASE PROGRESSION AS DURING NORMAL DEVELOPMENT FROM NAIVE TO MEMORY B CELLS. OUR STUDY SHOWS THAT CLL PROGRESSION DOES NOT TYPICALLY OCCUR VIA SUBCLONAL EVOLUTION, BUT THAT CERTAIN CPG SITES UNDERGO RECURRENT METHYLATION CHANGES. OUR RESULTS SUGGEST CLL PROGRESSION MAY INVOLVE DEVELOPMENTAL PROCESSES SHARED IN COMMON WITH THE GENERATION OF NORMAL MEMORY B CELLS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8 1345  30 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9 2689  20 EVOLUTION OF DNA METHYLATION IS LINKED TO GENETIC ABERRATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA. ALTHOUGH CLONAL SELECTION BY GENETIC DRIVER ABERRATIONS IN CANCER IS WELL DOCUMENTED, THE ABILITY OF EPIGENETIC ALTERATIONS TO PROMOTE TUMOR EVOLUTION IS UNDEFINED. WE USED 450K ARRAYS AND NEXT-GENERATION SEQUENCING TO EVALUATE INTRATUMOR HETEROGENEITY AND EVOLUTION OF DNA METHYLATION AND GENETIC ABERRATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). CLL CASES EXHIBIT VAST INTERPATIENT DIFFERENCES IN INTRATUMOR METHYLATION HETEROGENEITY, WITH GENETICALLY CLONAL CASES MAINTAINING LOW METHYLATION HETEROGENEITY AND UP TO 10% OF TOTAL CPGS IN A MONOALLELICALLY METHYLATED STATE. INCREASING METHYLATION HETEROGENEITY CORRELATES WITH ADVANCED GENETIC SUBCLONAL COMPLEXITY. SELECTION OF NOVEL DNA METHYLATION PATTERNS IS OBSERVED ONLY IN CASES THAT UNDERGO GENETIC EVOLUTION, AND INDEPENDENT GENETIC EVOLUTION IS UNCOMMON AND IS RESTRICTED TO LOW-RISK ALTERATIONS. THESE RESULTS REVEAL THAT ALTHOUGH EVOLUTION OF DNA METHYLATION OCCURS IN HIGH-RISK, CLINICALLY PROGRESSIVE CASES, POSITIVE SELECTION OF NOVEL METHYLATION PATTERNS ENTAILS COEVOLUTION OF GENETIC ALTERATION(S) IN CLL.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10 1577  30 DNA METHYLATION PROFILE IN CHRONIC MYELOMONOCYTIC LEUKEMIA ASSOCIATES WITH DISTINCT CLINICAL, BIOLOGICAL AND GENETIC FEATURES. CHROMOSOMAL ABNORMALITIES ARE DETECTED IN 20-30% OF PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND CORRELATE WITH PROGNOSIS. ON THE MUTATION LEVEL, DISRUPTIVE ALTERATIONS ARE PARTICULARLY FREQUENT IN CHROMATIN REGULATORY GENES. HOWEVER, LITTLE IS KNOWN ABOUT THE CONSEQUENTIAL ALTERATIONS IN THE EPIGENETIC MARKING OF THE GENOME. HERE, WE REPORT THE ANALYSIS OF GENOMIC DNA METHYLATION PATTERNS OF 64 CMML PATIENTS AND 10 HEALTHY CONTROLS, USING A DNA METHYLATION MICROARRAY FOCUSED ON PROMOTER REGIONS. DIFFERENTIAL METHYLATION ANALYSIS BETWEEN PATIENTS AND CONTROLS ALLOWED US TO IDENTIFY ABNORMALITIES IN DNA METHYLATION, INCLUDING HYPERMETHYLATION OF SPECIFIC GENES AND LARGE GENOME REGIONS WITH ABERRANT DNA METHYLATION. UNSUPERVISED HIERARCHICAL CLUSTER ANALYSIS IDENTIFIED TWO MAIN CLUSTERS THAT ASSOCIATED WITH THE CLINICAL, BIOLOGICAL, AND GENETIC FEATURES OF PATIENTS. GROUP 1 WAS ENRICHED IN PATIENTS WITH ADVERSE CLINICAL AND BIOLOGICAL CHARACTERISTICS AND POORER OVERALL AND PROGRESSION-FREE SURVIVAL. IN ADDITION, SIGNIFICANT DIFFERENCES IN DNA METHYLATION WERE OBSERVED BETWEEN PATIENTS WITH LOW RISK AND INTERMEDIATE/HIGH RISK KARYOTYPES AND BETWEEN TET2 MUTANT AND WILD TYPE PATIENTS. TAKEN TOGETHER, OUR RESULTS DEMONSTRATE THAT ALTERED DNA METHYLATION PATTERNS REFLECT THE CMML DISEASE STATE AND ALLOW TO IDENTIFY PATIENT GROUPS WITH DISTINCT CLINICAL FEATURES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11 4547  23 MUTATION ALLELE BURDEN REMAINS UNCHANGED IN CHRONIC MYELOMONOCYTIC LEUKAEMIA RESPONDING TO HYPOMETHYLATING AGENTS. THE CYTIDINE ANALOGUES AZACYTIDINE AND 5-AZA-2'-DEOXYCYTIDINE (DECITABINE) ARE COMMONLY USED TO TREAT MYELODYSPLASTIC SYNDROMES, WITH OR WITHOUT A MYELOPROLIFERATIVE COMPONENT. IT REMAINS UNCLEAR WHETHER THE RESPONSE TO THESE HYPOMETHYLATING AGENTS RESULTS FROM A CYTOTOXIC OR AN EPIGENETIC EFFECT. IN THIS STUDY, WE ADDRESS THIS QUESTION IN CHRONIC MYELOMONOCYTIC LEUKAEMIA. WE DESCRIBE A COMPREHENSIVE ANALYSIS OF THE MUTATIONAL LANDSCAPE OF THESE TUMOURS, COMBINING WHOLE-EXOME AND WHOLE-GENOME SEQUENCING. WE IDENTIFY AN AVERAGE OF 14+/-5 SOMATIC MUTATIONS IN CODING SEQUENCES OF SORTED MONOCYTE DNA AND THE SIGNATURES OF THREE MUTATIONAL PROCESSES. SERIAL SEQUENCING DEMONSTRATES THAT THE RESPONSE TO HYPOMETHYLATING AGENTS IS ASSOCIATED WITH CHANGES IN DNA METHYLATION AND GENE EXPRESSION, WITHOUT ANY DECREASE IN THE MUTATION ALLELE BURDEN, NOR PREVENTION OF NEW GENETIC ALTERATION OCCURENCE. OUR FINDINGS INDICATE THAT CYTOSINE ANALOGUES RESTORE A BALANCED HAEMATOPOIESIS WITHOUT DECREASING THE SIZE OF THE MUTATED CLONE, ARGUING FOR A PREDOMINANTLY EPIGENETIC EFFECT.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
12 2653  31 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13 5894  30 T CELL EPIGENETIC REMODELING AND ACCELERATED EPIGENETIC AGING ARE LINKED TO LONG-TERM IMMUNE ALTERATIONS IN CHILDHOOD CANCER SURVIVORS. BACKGROUND: CANCER TREATMENTS HAVE SUBSTANTIALLY IMPROVED CHILDHOOD CANCER SURVIVAL BUT ARE ACCOMPANIED BY LONG-TERM COMPLICATIONS, NOTABLY CHRONIC INFLAMMATORY DISEASES. WE HYPOTHESIZE THAT CANCER TREATMENTS COULD LEAD TO LONG-TERM EPIGENETIC CHANGES IN IMMUNE CELLS, RESULTING IN INCREASED PREVALENCE OF INFLAMMATORY DISEASES IN CANCER SURVIVORS. RESULTS: TO TEST THIS HYPOTHESIS, WE ESTABLISHED THE EPIGENETIC AND TRANSCRIPTOMIC PROFILES OF IMMUNE CELLS FROM 44 CHILDHOOD CANCER SURVIVORS (CCS, > 16 YEARS OLD) ON FULL REMISSION (> 5 YEARS) WHO HAD RECEIVED CHEMOTHERAPY ALONE OR IN COMBINATION WITH TOTAL BODY IRRADIATION (TBI) AND HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). WE FOUND THAT MORE THAN 10 YEARS POST-TREATMENT, CCS TREATED WITH TBI/HSCT SHOWED AN ALTERED DNA METHYLATION SIGNATURE IN T CELL, PARTICULARLY AT GENES CONTROLLING IMMUNE AND INFLAMMATORY PROCESSES AND OXIDATIVE STRESS. DNA METHYLATION REMODELING IN T CELL WAS PARTIALLY ASSOCIATED WITH CHRONIC EXPRESSION CHANGES OF NEARBY GENES, INCREASED FREQUENCY OF TYPE 1 CYTOKINE-PRODUCING T CELL, ELEVATED SYSTEMIC LEVELS OF THESE CYTOKINES, AND OVER-ACTIVATION OF RELATED SIGNALING PATHWAYS. SURVIVORS EXPOSED TO TBI/HSCT WERE FURTHER CHARACTERIZED BY AN EPIGENETIC-AGING-SIGNATURE OF T CELL CONSISTENT WITH ACCELERATED EPIGENETIC AGING. TO INVESTIGATE THE POTENTIAL CONTRIBUTION OF IRRADIATION TO THESE CHANGES, WE ESTABLISHED TWO CELL CULTURE MODELS. WE IDENTIFIED THAT RADIATION PARTIALLY RECAPITULATED THE IMMUNE CHANGES OBSERVED IN SURVIVORS THROUGH A BYSTANDER EFFECT THAT COULD BE MEDIATED BY CIRCULATING FACTORS. CONCLUSION: CANCER TREATMENTS, IN PARTICULAR TBI/HSCT, ARE ASSOCIATED WITH LONG-TERM IMMUNE DISTURBANCES. WE PROPOSE THAT EPIGENETIC REMODELING OF IMMUNE CELLS FOLLOWING CANCER THERAPY AUGMENTS INFLAMMATORY- AND AGE-RELATED DISEASES, INCLUDING METABOLIC COMPLICATIONS, IN CHILDHOOD CANCER SURVIVORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
14 3316  27 HISTIOCYTIC SARCOMA AS A SECONDARY MALIGNANCY: PATHOBIOLOGY, DIAGNOSIS, AND TREATMENT. HISTIOCYTIC SARCOMA (HS) IS AN EXTREMELY RARE NON-LANGERHANS CELL DISORDER WITH AN AGGRESSIVE COURSE AND LIMITED TREATMENT OPTIONS. RECENT ADVANCES IN MOLECULAR/GENETIC SEQUENCING HAVE SUGGESTED A COMMON CLONAL ORIGIN BETWEEN VARIOUS HEMATOLYMPHOID DISORDERS AND CASES OF SECONDARY HS. DERIVING CONCLUSIONS FROM PREVIOUSLY REPORTED CASES OF HS ARISING SECONDARILY TO CERTAIN HEMATOLYMPHOID DISORDERS, HERE WE HAVE TRIED TO PROVIDE INSIGHT INTO THE MECHANISMS INFLUENCING THIS EVOLUTION. WE ALSO DISCUSS A CLINICAL CASE OF A 72-YEAR-OLD MAN WITH A DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA (CML), PRESENTING SUBSEQUENTLY WITH A HETEROGENEOUS LIVER MASS POSITIVE WITH A DIAGNOSIS OF HS. THE LIVER MASS SHOWED A RETAINED BCR-ABL1 TRANSLOCATION SUGGESTING CLONALITY BETWEEN THE CML AND HS. AS SEEN IN OUR CASE AND OTHER REPORTED CASES OF HS DERIVED SECONDARILY, THE CONCURRENT EXPRESSION OF IMMUNOGLOBULIN HEAVY (IGH)-/LIGHT-CHAIN REARRANGEMENTS OR CYTOGENETIC MARKERS COMMON TO THE PRIMARY MALIGNANCY SUGGESTS AN EVOLUTIONARY MECHANISM INVOLVING LINEAGE SWITCHING THAT COULD POTENTIALLY BE INFLUENCED BY GENETIC OR EPIGENETIC CUES WHICH MAY OCCUR AT THE LEVEL OF A PROGENITOR OR THE MALIGNANT CELL ITSELF.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15 5210  22 PRENEOPLASTIC ALTERATIONS DEFINE CLL DNA METHYLOME AND PERSIST THROUGH DISEASE PROGRESSION AND THERAPY. MOST HUMAN CANCERS CONVERGE TO A DEREGULATED METHYLOME WITH REDUCED GLOBAL LEVELS AND ELEVATED METHYLATION AT SELECT CPG ISLANDS. TO INVESTIGATE THE EMERGENCE AND DYNAMICS OF THE CANCER METHYLOME, WE CHARACTERIZED GENOME-WIDE DNA METHYLATION IN PRE-NEOPLASTIC MONOCLONAL B CELL LYMPHOCYTOSIS (MBL) AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), INCLUDING SERIAL SAMPLES COLLECTED ACROSS DISEASE COURSE. WE DETECTED THE ABERRANT TUMOR-ASSOCIATED METHYLATION LANDSCAPE AT CLL DIAGNOSIS AND FOUND NO SIGNIFICANTLY DIFFERENTIALLY METHYLATED REGIONS IN THE HIGH-COUNT MBL-TO-CLL TRANSITION. PATIENT METHYLOMES SHOWED REMARKABLE STABILITY WITH NATURAL DISEASE AND POST-THERAPY PROGRESSION. SINGLE CLL CELLS WERE CONSISTENTLY ABERRANTLY METHYLATED, INDICATING A HOMOGENEOUS TRANSITION TO THE ALTERED EPIGENETIC STATE, AND A DISTINCT EXPRESSION PROFILE TOGETHER WITH MBL CELLS COMPARED TO NORMAL B CELLS. OUR LONGITUDINAL ANALYSIS REVEALS THE CANCER METHYLOME TO EMERGE EARLY, WHICH MAY PROVIDE A PLATFORM FOR SUBSEQUENT GENETICALLY-DRIVEN GROWTH DYNAMICS AND TOGETHER WITH ITS PERSISTENT PRESENCE SUGGESTS A CENTRAL ROLE IN THE NORMAL-TO-CANCER TRANSITION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16 2494  24 EPIGENETICS AND CHRONIC LYMPHOCYTIC LEUKEMIA. THE DNA METHYLATION LEVEL IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IS GENERALLY LOWER THAN HEALTHY INDIVIDUALS. ALTHOUGH DNA METHYLATION IS GLOBALLY DECREASED, REGIONAL HYPERMETHYLATION OF GENE PROMOTERS LEADS TO GENE SILENCING. MANY OF THESE GENES HAVE TUMOR SUPPRESSOR PHENOTYPES. UNLIKE MUTATIONS OR DELETIONS, HYPERMETHYLATION IS POTENTIALLY REVERSIBLE AFTER INHIBITION WITH DNA METHYLATION MODULATORS. MYELODYSPLASTIC SYNDROME HAS BEEN A MODEL DISEASE IN WHICH TREATMENT OF PATIENTS RESULTS IN DEMETHYLATION OF SPECIFIC GENES. THE STORY IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IS SLOWLY UNRAVELING AS EPIGENETIC MODIFICATIONS LIKELY ALSO PLAY AN IMPORTANT ROLE. ONGOING CLINICAL TRIALS CORRELATING CLINICAL RESPONSE TO GENE EXPRESSION AFTER TREATMENT WITH DNA METHYLATION INHIBITORS WILL ULTIMATELY ALLOW US TO BETTER RISK STRATIFY AND PREDICT THE SUBGROUP OF PATIENTS WHO WILL BENEFIT FROM TREATMENT WITH THIS CLASS OF DRUGS.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17 1682  26 DRUG-MICROENVIRONMENT PERTURBATIONS REVEAL RESISTANCE MECHANISMS AND PROGNOSTIC SUBGROUPS IN CLL. THE TUMOUR MICROENVIRONMENT AND GENETIC ALTERATIONS COLLECTIVELY INFLUENCE DRUG EFFICACY IN CANCER, BUT CURRENT EVIDENCE IS LIMITED AND SYSTEMATIC ANALYSES ARE LACKING. USING CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AS A MODEL DISEASE, WE INVESTIGATED THE INFLUENCE OF 17 MICROENVIRONMENTAL STIMULI ON 12 DRUGS IN 192 GENETICALLY CHARACTERISED PATIENT SAMPLES. BASED ON MICROENVIRONMENTAL RESPONSE, WE IDENTIFIED FOUR SUBGROUPS WITH DISTINCT CLINICAL OUTCOMES BEYOND KNOWN PROGNOSTIC MARKERS. RESPONSE TO MULTIPLE MICROENVIRONMENTAL STIMULI WAS AMPLIFIED IN TRISOMY 12 SAMPLES. TRISOMY 12 WAS ASSOCIATED WITH A DISTINCT EPIGENETIC SIGNATURE. BROMODOMAIN INHIBITION REVERSED THIS EPIGENETIC PROFILE AND COULD BE USED TO TARGET MICROENVIRONMENTAL SIGNALLING IN TRISOMY 12 CLL. WE QUANTIFIED THE IMPACT OF MICROENVIRONMENTAL STIMULI ON DRUG RESPONSE AND THEIR DEPENDENCE ON GENETIC ALTERATIONS, IDENTIFYING INTERLEUKIN 4 (IL4) AND TOLL-LIKE RECEPTOR (TLR) STIMULATION AS THE STRONGEST ACTUATORS OF DRUG RESISTANCE. IL4 AND TLR SIGNALLING ACTIVITY WAS INCREASED IN CLL-INFILTRATED LYMPH NODES COMPARED WITH HEALTHY SAMPLES. HIGH IL4 ACTIVITY CORRELATED WITH FASTER DISEASE PROGRESSION. THE PUBLICLY AVAILABLE DATASET CAN FACILITATE THE INVESTIGATION OF CELL-EXTRINSIC MECHANISMS OF DRUG RESISTANCE AND DISEASE PROGRESSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18 3091  23 GENOMIC AND EPIGENOMIC HETEROGENEITY IN CHRONIC LYMPHOCYTIC LEUKEMIA. DEFINING FEATURES OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ARE NOT ONLY ITS IMMUNOPHENOTYPE OF CD19(+)CD5(+)CD23(+)SIGDIM EXPRESSING CLONAL MATURE B CELLS BUT ALSO ITS HIGHLY VARIABLE CLINICAL COURSE. IN RECENT YEARS, ADVANCES IN MASSIVELY PARALLEL SEQUENCING TECHNOLOGIES HAVE LED TO RAPID PROGRESS IN OUR UNDERSTANDING OF THE CLL GENOME AND EPIGENOME. OVERALL, THESE STUDIES HAVE CLEARLY DEMARCATED NOT ONLY THE VAST DEGREE OF GENETIC AND EPIGENETIC HETEROGENEITY AMONG INDIVIDUALS WITH CLL BUT ALSO EVEN WITHIN INDIVIDUAL PATIENT LEUKEMIAS. WE HEREIN REVIEW THE RAPIDLY GROWING SERIES OF STUDIES ASSESSING THE GENETIC AND EPIGENETIC FEATURES OF CLL WITHIN CLINICALLY DEFINED PERIODS OF ITS GROWTH. THESE STUDIES STRONGLY SUGGEST AN EVOLVING SPECTRUM OF LESIONS OVER TIME AND THAT THESE FEATURES MAY HAVE CLINICAL IMPACT.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19 4255  26 METHYLOME-WIDE ANALYSIS OF CHRONIC HIV INFECTION REVEALS FIVE-YEAR INCREASE IN BIOLOGICAL AGE AND EPIGENETIC TARGETING OF HLA. HIV-INFECTED INDIVIDUALS ARE LIVING LONGER ON ANTIRETROVIRAL THERAPY, BUT MANY PATIENTS DISPLAY SIGNS THAT IN SOME WAYS RESEMBLE PREMATURE AGING. TO INVESTIGATE AND QUANTIFY THE IMPACT OF CHRONIC HIV INFECTION ON AGING, WE REPORT A GLOBAL ANALYSIS OF THE WHOLE-BLOOD DNA METHYLOMES OF 137 HIV+ INDIVIDUALS UNDER SUSTAINED THERAPY ALONG WITH 44 MATCHED HIV- INDIVIDUALS. FIRST, WE DEVELOP AND VALIDATE EPIGENETIC MODELS OF AGING THAT ARE INDEPENDENT OF BLOOD CELL COMPOSITION. USING THESE MODELS, WE FIND THAT BOTH CHRONIC AND RECENT HIV INFECTION LEAD TO AN AVERAGE AGING ADVANCEMENT OF 4.9 YEARS, INCREASING EXPECTED MORTALITY RISK BY 19%. IN ADDITION, SUSTAINED INFECTION RESULTS IN GLOBAL DEREGULATION OF THE METHYLOME ACROSS >80,000 CPGS AND SPECIFIC HYPOMETHYLATION OF THE REGION ENCODING THE HUMAN LEUKOCYTE ANTIGEN LOCUS (HLA). WE FIND THAT DECREASED HLA METHYLATION IS PREDICTIVE OF LOWER CD4 / CD8 T CELL RATIO, LINKING MOLECULAR AGING, EPIGENETIC REGULATION, AND DISEASE PROGRESSION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20 4530  32 MULTILAYER INTRACLONAL HETEROGENEITY IN CHRONIC MYELOMONOCYTIC LEUKEMIA. THE FUNCTIONAL DIVERSITY OF CELLS THAT COMPOSE MYELOID MALIGNANCIES, I.E., THE RESPECTIVE ROLES OF GENETIC AND EPIGENETIC HETEROGENEITY IN THIS DIVERSITY, REMAINS POORLY UNDERSTOOD. THIS QUESTION IS ADDRESSED IN CHRONIC MYELOMONOCYTIC LEUKEMIA, A MYELOID NEOPLASM IN WHICH CLINICAL DIVERSITY CONTRASTS WITH LIMITED GENETIC HETEROGENEITY. TO GENERATE INDUCED PLURIPOTENT STEM CELL CLONES, WE REPROGRAMMED CD34(+) CELLS COLLECTED FROM A PATIENT WITH A CHRONIC MYELOMONOCYTIC LEUKEMIA IN WHICH WHOLE EXOME SEQUENCING OF PERIPHERAL BLOOD MONOCYTE DNA HAD IDENTIFIED 12 GENE MUTATIONS, INCLUDING A MUTATION IN KDM6A AND TWO HETEROZYGOUS MUTATIONS IN TET2 IN THE FOUNDING CLONE AND A SECONDARY KRAS(G12D) MUTATION. CD34(+) CELLS FROM AN AGE-MATCHED HEALTHY DONOR WERE ALSO REPROGRAMMED. WE CAPTURED A PART OF THE GENETIC HETEROGENEITY OBSERVED IN THE PATIENT, I.E. WE ANALYZED FIVE CLONES WITH TWO GENETIC BACKGROUNDS, WITHOUT AND WITH THE KRAS(G12D) MUTATION. HEMATOPOIETIC DIFFERENTIATION OF THESE CLONES RECAPITULATED THE MAIN FEATURES OF THE PATIENT'S DISEASE, INCLUDING OVERPRODUCTION OF GRANULOMONOCYTES AND DYSMEGAKARYOPOIESIS. THESE ANALYSES ALSO DISCLOSED SIGNIFICANT DISCREPANCIES IN THE BEHAVIOR OF HEMATOPOIETIC CELLS DERIVED FROM INDUCED PLURIPOTENT STEM CELL CLONES WITH SIMILAR GENETIC BACKGROUND, CORRELATING WITH LIMITED EPIGENETIC CHANGES. THESE ANALYSES SUGGEST THAT, BEYOND THE CODING MUTATIONS, SEVERAL LEVELS OF INTRACLONAL HETEROGENEITY MAY PARTICIPATE IN THE YET UNEXPLAINED CLINICAL HETEROGENEITY OF THE DISEASE.	2020