1 5665 129 SF3B1, RUNX1 AND TP53 MUTATIONS SIGNIFICANTLY IMPACT THE OUTCOME OF PATIENTS WITH LOWER-RISK MYELODYSPLASTIC SYNDROME. INTRODUCTION: PROGNOSIS OF PATIENTS WITH MYELODYSPLASTIC SYNDROME (MDS), PARTICULARLY THE GROUP WITH LOWER-RISK DISEASE (LR-MDS) IS VERY HETEROGENEOUS. SEVERAL STUDIES HAVE DESCRIBED THE PROGNOSTIC VALUE OF RECURRENT SOMATIC MUTATIONS IN MDS INCLUDING ALL RISK CATEGORIES. RECENTLY, THE INCORPORATION OF GENOMIC DATA TO CLINICAL PARAMETERS DEFINED THE NEW MOLECULAR INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS-M). MATERIALS AND METHODS: IN THIS STUDY, WE EVALUATED THE IMPACT OF MOLECULAR PROFILE IN A SERIES OF 181 PATIENTS WITH LR-MDS AND NON-PROLIFERATIVE CHRONIC MYELOMONOCYTIC LEUKEMIA. RESULTS: EPIGENETIC REGULATORS (TET2, ASXL1) AND SPLICING (SF3B1) WERE THE MOST RECURRENT MUTATED PATHWAYS. IN UNIVARIATE ANALYSIS, RUNX1 OR TP53 MUTATIONS CORRELATED WITH LOWER MEDIAN OVERALL SURVIVAL (OS). IN CONTRAST, SF3B1 MUTATION WAS ASSOCIATED WITH PROLONGED MEDIAN OS [95 MONTHS (95% IC, 32-157) VS. 33 MONTHS (95% CI, 19-46) IN UNMUTATED PATIENTS (P < 0.01)]. IN A MULTIVARIATE COX REGRESSION MODEL, RUNX1 MUTATIONS INDEPENDENTLY ASSOCIATED WITH SHORTER OS, WHILE SF3B1 MUTATION RETAINED ITS FAVORABLE IMPACT ON OUTCOME (HR: 0.24, 95% CI, 0.1-0.5; P = 0.001). IN ADDITION, TP53 OR RUNX1 MUTATIONS WERE IDENTIFIED AS PREDICTIVE COVARIATES FOR THE PROBABILITY OF LEUKEMIC PROGRESSION (P < 0.001). CONCLUSION: INCORPORATION OF MOLECULAR TESTING IN LR-MDS IDENTIFIED A SUBSET OF PATIENTS WITH EXPECTED POORER OUTCOME, EITHER DUE TO LOWER SURVIVAL OR PROBABILITY OF LEUKEMIC PROGRESSION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
2 3560  44 IMPACT OF CLINICAL, CYTOGENETIC, AND MOLECULAR PROFILES ON LONG-TERM SURVIVAL AFTER TRANSPLANTATION IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A HETEROGENEOUS GROUP OF CLONAL HEMATOPOIETIC MALIGNANCIES WITH VARIABLE CLINICAL AND MOLECULAR FEATURES. WE ANALYZED LONG-TERM RESULTS OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH CMML AND DETERMINED CLINICAL AND MOLECULAR RISK FACTORS ASSOCIATED WITH OUTCOMES. DATA FROM 129 PATIENTS, AGED 7-74 (MEDIAN 55) YEARS, AT VARIOUS STAGES OF THE DISEASE AND TRANSPLANTED FROM RELATED OR UNRELATED DONORS WERE ANALYZED. USING A PANEL OF 75 GENES SOMATIC MUTATIONS PRESENT BEFORE HEMATOPOIETIC CELL TRANSPLANTATION WERE IDENTIFIED IN 52 PATIENTS. THE PROGRESSION-FREE SURVIVAL RATE AT 10 YEARS WAS 29%. THE MAJOR CAUSE OF DEATH WAS RELAPSE (32%), WHICH WAS SIGNIFICANTLY ASSOCIATED WITH ADVERSE CYTOGENETICS (HAZARD RATIO, 3.77; P=0.0002), CMML PROGNOSTIC SCORING SYSTEM (HAZARD RATIO, 14.3, P=0.01), AND MD ANDERSON PROGNOSTIC SCORES (HAZARD RATIO, 9.4; P=0.005). MORTALITY WAS ASSOCIATED WITH HIGH-RISK CYTOGENETICS (HAZARD RATIO, 1.88; P=0.01) AND HIGH HEMATOPOIETIC CELL TRANSPLANTATION COMORBIDITY INDEX (SCORE >/=4: HAZARD RATIO, 1.99; P=0.01). HIGH OVERALL MUTATION BURDEN (>/=10 MUTATIONS: HAZARD RATIO, 3.4; P=0.02), AND >/=4 MUTATED EPIGENETIC REGULATORY GENES (HAZARD RATIO 5.4; P=0.003) WERE LINKED TO RELAPSE. UNSUPERVISED CLUSTERING OF THE CORRELATION MATRIX REVEALED DISTINCT HIGH-RISK GROUPS WITH UNIQUE ASSOCIATIONS OF MUTATIONS AND CLINICAL FEATURES. CMML WITH A HIGH MUTATION BURDEN APPEARED TO BE DISTINCT FROM HIGH-RISK GROUPS DEFINED BY COMPLEX CYTOGENETICS. NEW TRANSPLANT STRATEGIES MUST BE DEVELOPED TO TARGET SPECIFIC DISEASE SUBGROUPS, STRATIFIED BY MOLECULAR PROFILING AND CLINICAL RISK FACTORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3 4571  38 MYELOMONOCYTIC SKEWING IN CHRONIC MYELOMONOCYTIC LEUKEMIA: PHENOTYPIC, MOLECULAR AND BIOLOGIC FEATURES AND IMPACT ON SURVIVAL. BACKGROUND: MYELOMONOCYTIC SKEWING IS CONSIDERED AS A KEY PATHOPHYSIOLOGIC PHENOMENON IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), BUT ITS PREVALENCE AND POTENTIAL CORRELATION WITH PHENOTYPIC, GENOTYPIC, AND CLINICAL FEATURES ARE POORLY DEFINED. METHODS: SKEWED DIFFERENTIATION TOWARD THE MYELOMONOCYTIC OVER ERYTHROID COMMITMENT AS INDICATED BY AN INVERSE RATIO OF MYELOMONOCYTIC/ERYTHROID COLONIES WAS INVESTIGATED IN 146 PATIENTS WITH CMML BY SEMISOLID IN VITRO CULTURES. RESULTS: THERE WAS A HIGH PREVALENCE OF MYELOMONOCYTIC SKEWING IN PATIENTS WITH CMML (120/146, 82%); WHEREAS, THIS PHENOMENON WAS RARE IN NORMAL INDIVIDUALS (1/98, 1%). PATIENTS WITH CMML WITH MYELOMONOCYTIC SKEWING HAD HIGHER WHITE BLOOD CELL AND PERIPHERAL BLAST CELL COUNTS, AND LOWER PLATELET VALUES. THE NUMBER OF MUTATIONS IN GENES OF THE EPIGENETIC AND/OR SPLICING CATEGORY WAS HIGHER IN CMML PATIENTS WITH AS COMPARED WITH PATIENTS WITHOUT SKEWING. PATIENTS WITH MYELOMONOCYTIC SKEWING HAD MORE FREQUENTLY MUTATIONS IN RASOPATHY GENES AND HIGHER GROWTH FACTOR INDEPENDENT MYELOID COLONY FORMATION. INTERESTINGLY, THE LACK OF MYELOMONOCYTIC SKEWING DISCRIMINATED PATIENTS WITH CMML WITH A PARTICULARLY FAVORABLE PROGNOSIS (60 VS 19 MONTHS, P = .003) AND A MINIMAL RISK OF TRANSFORMATION. CONCLUSION: MYELOMONOCYTIC SKEWING AS DETERMINED BY SEMISOLID CULTURES CAN DISCRIMINATE SUBGROUPS OF PATIENTS WITH CMML WITH A DIFFERENT PHENOTYPE, A DIFFERENT GENOTYPE, AND A DIFFERENT PROGNOSIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4 5984  33 TET2, DNMT3A, IDH1, AND JAK2 MUTATION IN MYELOPROLIFERATIVE NEOPLASMS IN SOUTHERN IRAN. BACKGROUND: FIVE EPIGENETIC REGULATOR MUTATIONS ARE CONSIDERED IN MYELOPROLIFERATIVE NEOPLASMS (MPN) THAT HAVE PROGNOSTIC AND THERAPEUTIC VALUES. OBJECTIVE: WE AIMED TO EVALUATE THESE MUTATIONS IN MPNS AMONG THE IRANIAN POPULATION. METHODS: WE SELECTED 5 MUTATIONS IN 4 EPIGENETIC REGULATORY GENES [TET2, DNMT3A, IDH1 (RS147001633&RS121913499), AND JAK2)] AND EVALUATED 130 PATIENTS WITH MPNS INCLUDING 78 PHILADELPHIA CHROMOSOME NEGATIVE (49 ETS, 20 PVS, AND 9 PMFS) AND 52 PHILADELPHIA CHROMOSOME-POSITIVE PATIENTS AS WELL AS 51 HEALTHY CONTROLS. RESULTS: EIGHT PATIENTS (6.5%) CARRIED THE DNMT3A MUTATION, 35 (27%) WERE POSITIVE FOR TET2 MUTATION AND 64 (49.3%) HAD THE JAK2V617F MUTATION. IN THE HEALTHY CONTROLS, 16 (31.4%) CASES HAD THE TET2 MUTATION (15 HETEROZYGOTE + 1 HOMOZYGOTE) AND ONE HAD HETEROZYGOTE JAK2 MUTATION. THERE WAS NO STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN PATIENT GROUPS FOR ANY OF THESE MUTATIONS, EXCEPT FOR JAK2. THE JAK2 MUTATION RATE WAS 18 (90%), 25 (51%), 7 (77.8%), 14 (26.9%) IN POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA, PRIMARY MYELOFIBROSIS, AND CHRONIC MYELOCYTIC LEUKEMIA, RESPECTIVELY. PATIENTS AGED 60 AND OLDER WERE MORE LIKELY TO CARRY THE TET2 MUTATION (23% VS. 39% IN YOUNGER AND OLDER THAN 60 YEARS OLD INDIVIDUALS, P=0.025). IDH1 WAS NOT DETECTED AT ALL AND PV HAD THE HIGHEST TET2 MUTATION 7(35%). TWO PMF PATIENTS HAD A HISTORY OF BONE MARROW TRANSPLANTATION THAT WERE NEGATIVE FOR IDH1AND DNMT3A AND ONE WAS POSITIVE FOR TET2 MUTATION. CONCLUSION: IN THE NORMAL IRANIAN POPULATION, THE HETEROZYGOTE FORM OF TET2 MUTATION IS SIGNIFICANT, ESPECIALLY IN THE ELDERLY. NO ASSOCIATION WAS FOUND BETWEEN JAK2 AND TET2 MUTATIONS. BOTH OF THEM ARE MORE PREVALENT IN THE AGE GROUP OF 60 YEARS AND OLDER. DNMT3A MUTATION HAS A LOW PREVALENCE AND OCCURS IN BOTH POSITIVE AND NEGATIVE MPNS.	2021	
                                                                                                                                                                                                                                                                                                                                                     
5  536  33 ASXL1 MUTATIONS PREDICT INFERIOR MOLECULAR RESPONSE TO NILOTINIB TREATMENT IN CHRONIC MYELOID LEUKEMIA. GENE MUTATIONS INDEPENDENT OF BCR::ABL1 HAVE BEEN IDENTIFIED IN NEWLY DIAGNOSED PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) IN CHRONIC PHASE, WHEREBY MUTATIONS IN EPIGENETIC MODIFIER GENES WERE MOST COMMON. THESE FINDINGS PROMPTED THE SYSTEMATIC ANALYSIS OF PREVALENCE, DYNAMICS, AND PROGNOSTIC SIGNIFICANCE OF SUCH MUTATIONS, IN A CLINICALLY WELL-CHARACTERIZED PATIENT POPULATION OF 222 CML PATIENTS FROM THE TIGER STUDY (CML-V) BY TARGETED NEXT-GENERATION SEQUENCING COVERING 54 MYELOID LEUKEMIA-ASSOCIATED GENES. IN TOTAL, 53/222 CML PATIENTS (24%) CARRIED 60 MUTATIONS AT DIAGNOSIS WITH ASXL1 BEING MOST COMMONLY AFFECTED (N = 20). TO STUDY MUTATION DYNAMICS, LONGITUDINAL DEEP SEQUENCING ANALYSIS OF SERIAL SAMPLES WAS PERFORMED IN 100 PATIENTS AFTER 12, 24, AND 36 MONTHS OF THERAPY. TYPICAL PATTERNS OF CLONAL EVOLUTION INCLUDED ERADICATION, PERSISTENCE, AND EMERGENCE OF MUTATED CLONES. PATIENTS CARRYING AN ASXL1 MUTATION AT DIAGNOSIS SHOWED A LESS FAVORABLE MOLECULAR RESPONSE TO NILOTINIB TREATMENT, AS A MAJOR MOLECULAR RESPONSE (MMR) WAS ACHIEVED LESS FREQUENTLY AT MONTH 12, 18, AND 24 COMPARED TO ALL OTHER PATIENTS. PATIENTS WITH ASXL1 MUTATIONS WERE ALSO YOUNGER AND MORE FREQUENTLY FOUND IN THE HIGH RISK CATEGORY, SUGGESTING A CENTRAL ROLE OF CLONAL EVOLUTION ASSOCIATED WITH ASXL1 MUTATIONS IN CML PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6   27  34 A B-CELL EPIGENETIC SIGNATURE DEFINES THREE BIOLOGIC SUBGROUPS OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH CLINICAL IMPACT. PROSPECTIVE IDENTIFICATION OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) DESTINED TO PROGRESS WOULD GREATLY FACILITATE THEIR CLINICAL MANAGEMENT. RECENTLY, WHOLE-GENOME DNA METHYLATION ANALYSES IDENTIFIED THREE CLINICOBIOLOGIC CLL SUBGROUPS WITH AN EPIGENETIC SIGNATURE RELATED TO DIFFERENT NORMAL B-CELL COUNTERPARTS. HERE, WE DEVELOPED A CLINICALLY APPLICABLE METHOD TO IDENTIFY THESE SUBGROUPS AND TO STUDY THEIR CLINICAL RELEVANCE. USING A SUPPORT VECTOR MACHINE APPROACH, WE BUILT A PREDICTION MODEL USING FIVE EPIGENETIC BIOMARKERS THAT WAS ABLE TO CLASSIFY CLL PATIENTS ACCURATELY INTO THE THREE SUBGROUPS, NAMELY NAIVE B-CELL-LIKE, INTERMEDIATE AND MEMORY B-CELL-LIKE CLL. DNA METHYLATION WAS QUANTIFIED BY HIGHLY REPRODUCIBLE BISULFITE PYROSEQUENCING ASSAYS IN TWO INDEPENDENT CLL SERIES. IN THE INITIAL SERIES (N=211), THE THREE SUBGROUPS SHOWED DIFFERENTIAL LEVELS OF IGHV (IMMUNOGLOBULIN HEAVY-CHAIN LOCUS) MUTATION (P<0.001) AND VH USAGE (P<0.03), AS WELL AS DIFFERENT CLINICAL FEATURES AND OUTCOME IN TERMS OF TIME TO FIRST TREATMENT (TTT) AND OVERALL SURVIVAL (P<0.001). A MULTIVARIATE COX MODEL SHOWED THAT EPIGENETIC CLASSIFICATION WAS THE STRONGEST PREDICTOR OF TTT (P<0.001) ALONG WITH BINET STAGE (P<0.001). THESE FINDINGS WERE CORROBORATED IN A VALIDATION SERIES (N=97). IN THIS STUDY, WE DEVELOPED A SIMPLE AND ROBUST METHOD USING EPIGENETIC BIOMARKERS TO CATEGORIZE CLLS INTO THREE SUBGROUPS WITH DIFFERENT CLINICOBIOLOGIC FEATURES AND OUTCOME.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7 4555  35 MUTATIONAL SPECTRUM ANALYSIS OF CHRONIC MYELOMONOCYTIC LEUKEMIA INCLUDES GENES ASSOCIATED WITH EPIGENETIC REGULATION: UTX, EZH2, AND DNMT3A. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), A MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM, IS CHARACTERIZED BY MONOCYTIC PROLIFERATION, DYSPLASIA, AND PROGRESSION TO ACUTE MYELOID LEUKEMIA. CMML HAS BEEN ASSOCIATED WITH SOMATIC MUTATIONS IN DIVERSE RECENTLY IDENTIFIED GENES. WE ANALYZED 72 WELL-CHARACTERIZED PATIENTS WITH CMML (N = 52) AND CMML-DERIVED ACUTE MYELOID LEUKEMIA (N = 20) FOR RECURRENT CHROMOSOMAL ABNORMALITIES WITH THE USE OF ROUTINE CYTOGENETICS AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAYS ALONG WITH COMPREHENSIVE MUTATIONAL SCREENING. CYTOGENETIC ABERRATIONS WERE PRESENT IN 46% OF CASES, WHEREAS SINGLE NUCLEOTIDE POLYMORPHISM ARRAY INCREASED THE DIAGNOSTIC YIELD TO 60%. AT LEAST 1 MUTATION WAS FOUND IN 86% OF ALL CASES; NOVEL UTX, DNMT3A, AND EZH2 MUTATIONS WERE FOUND IN 8%, 10%, AND 5.5% OF PATIENTS, RESPECTIVELY. TET2 MUTATIONS WERE PRESENT IN 49%, ASXL1 IN 43%, CBL IN 14%, IDH1/2 IN 4%, KRAS IN 7%, NRAS IN 4%, AND JAK2 V617F IN 1% OF PATIENTS. VARIOUS MUTANT GENOTYPE COMBINATIONS WERE OBSERVED, INDICATING MOLECULAR HETEROGENEITY IN CMML. OUR RESULTS SUGGEST THAT MOLECULAR DEFECTS AFFECTING DISTINCT PATHWAYS CAN LEAD TO SIMILAR CLINICAL PHENOTYPES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8 4540  35 MULTISTEP PATHOGENESIS OF CHRONIC MYELOMONOCYTIC LEUKEMIA IN PATIENTS. BACKGROUND: A MULTISTEP PATHOGENESIS OF MYELOID LEUKEMIA INCLUDING MUTATIONS IN EPIGENETIC, SPLICEOSOME, AND SIGNALING GENES HAS BEEN RECENTLY DEMONSTRATED IN A PRECLINICAL MODEL BUT IS POORLY VALIDATED IN PATIENTS. METHODS: CLINICAL, PHENOTYPIC, AND BIOLOGIC FEATURES WERE COMPARED BETWEEN THREE DISTINCT MOLECULARLY DEFINED CMML COHORTS INCLUDING TET2 MONOMUTATED PATIENTS (T, N = 10), TET2/SRSF2 BIMUTATED PATIENTS (TS, N = 19), AND PATIENTS WHO HAD NRAS MUTATIONS IN ADDITION TO TET2/SRSF2 COMUTATIONS (TSN, N = 14). RESULTS: MEDIAN SURVIVAL WAS 90, 45, AND 9 MONTHS, RESPECTIVELY (P = .001). WHEREAS NO PATIENT IN THE T AND TS GROUP TRANSFORMED INTO ACUTE MYELOID LEUKEMIA (AML), 6/14 PATIENTS IN THE TSN GROUP HAD AML AT STUDY ENTRY OR TRANSFORMED DURING FOLLOW-UP. LEUKOCYTE COUNTS, BLAST CELL COUNTS, AND LDH LEVELS WERE SIGNIFICANTLY HIGHER IN TSN VS. TS AND T, RESPECTIVELY, WHEREAS HEMOGLOBIN AND PLATELET VALUES WERE NOT SIGNIFICANTLY DIFFERENT. INCREASED GROWTH FACTOR-INDEPENDENT MYELOID COLONY FORMATION WAS RESTRICTED TO TSN BUT NOT FOUND IN T AND TS, RESPECTIVELY. THE PROPORTION OF PATIENTS SHOWING IN VITRO MYELOMONOCYTIC SKEWING IN T, TS, AND TSN WAS 0%, 56%, AND 100%, RESPECTIVELY (P = .010). CONCLUSION: OUR RESULTS DEMONSTRATE THAT THE MODEL OF MULTISTEP PATHOGENESIS IN CMML CAN BE RECAPITULATED IN PATIENTS REGARDING CLINICAL, PHENOTYPIC, AND BIOLOGIC FEATURES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
9 4549  28 MUTATION ANALYSIS OF THERAPY-RELATED MYELOID NEOPLASMS. WE ANALYZED THE GENETIC MUTATION STATUS OF 13 PATIENTS WITH THERAPY-RELATED MYELOID NEOPLASMS (T-MN). CONSISTENT WITH PREVIOUS REPORTS, T-MN CELLS PREFERENTIALLY ACQUIRED MUTATIONS IN TP53 AND EPIGENETIC MODIFYING GENES, INSTEAD OF MUTATIONS IN TYROSINE KINASE AND SPLICEOSOME GENES. FURTHERMORE, WE COMPARED THE MUTATION STATUS OF THREE T-MN CELLS WITH EACH OF THE INITIAL LYMPHOID MALIGNANT CELLS, AND IDENTIFIED COMMON MUTATIONS AMONG T-MN AND THE INITIAL MALIGNANT CELLS IN TWO PATIENTS. IN A PATIENT WHO DEVELOPED CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AFTER FOLLICULAR LYMPHOMA (FL), TET2 MUTATION WAS IDENTIFIED IN BOTH CMML AND FL CELLS. NOTABLY, THE TET2 MUTATION WAS ALSO IDENTIFIED IN PERIPHERAL BLOOD CELLS IN THE DISEASE-FREE PERIOD WITH THE SAME ALLELIC FREQUENCY AS CMML AND FL CELLS, BUT NOT IN A GERM-LINE CONTROL, INDICATING THAT THE TET2 MUTATION OCCURRED SOMATICALLY IN THE INITIATING CLONE FOR BOTH MALIGNANT CELLS. ON THE OTHER HAND, A GERM-LINE MYB MUTATION WAS IDENTIFIED IN A PATIENT WHO DEVELOPED MYELODYSPLASTIC SYNDROMES (MDS) AFTER FL. THESE RESULTS SUGGEST THAT GERM-LINE DEPOSITION AND CLONAL HEMATOPOIESIS ARE CLOSELY ASSOCIATED WITH T-MN SUSCEPTIBILITY; HOWEVER, FURTHER ANALYSIS IS NECESSARY TO CLARIFY THE MECHANISM REQUIRED TO PROVIDE THE INITIATING CLONE WITH LINEAGE COMMITMENT AND CLONAL EXPANSION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10 5246  55 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 4907  34 P53 ABERRATIONS DO NOT PREDICT INDIVIDUAL RESPONSE TO FLUDARABINE IN PATIENTS WITH B-CELL CHRONIC LYMPHOCYTIC LEUKAEMIA IN ADVANCED STAGES RAI III/IV. ABNORMALITIES OF P53 HAVE BEEN ASSOCIATED WITH SHORT SURVIVAL AND NON-RESPONSE TO THERAPY IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). WE HAVE EVALUATED THE RATE OF RESPONSE TO FLUDARABINE AS FIRST-LINE THERAPY IN 54 PATIENTS WITH ADVANCED STAGE CLL, ANALYSING THE CYTOGENETIC PROFILE, ABERRATIONS IN P53, INCLUDING THE METHYLATION STATUS OF ITS PROMOTER, AND THE IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE-REGION (IGVH) MUTATION STATUS. ACCORDING TO THE ADVANCED STAGE OF THE DISEASE IN THIS SERIES, 75% OF PATIENTS PRESENTED GENETIC ABERRATIONS ASSOCIATED WITH POOR PROGNOSIS: DEL(17P) AND/OR DEL(11Q), AND NO-MUTATED IGVH GENES. TEN PATIENTS (18.5%) HAD METHYLATION IN THE PROMOTER REGION OF P53. EIGHTY-THREE PER CENT OF PATIENTS TREATED ACHIEVED A RESPONSE, WITH A HIGH RATE OF COMPLETE REMISSION (47.6%). ALTHOUGH WE FOUND A SIGNIFICANT CORRELATION BETWEEN FAILURES AND THE PRESENCE OF P53 ABERRATIONS (P = 0.0065), EITHER WITH METHYLATION (P = 0.018) OR DELETION (P = 0.015), 64% OF THE PATIENTS WITH ABERRATIONS IN THIS GENE RESPONDED TO TREATMENT (11/17), SUGGESTING THAT FLUDARABINE INDUCES HIGH REMISSION RATES, EVEN IN THESE PATIENTS. THIS IS THE FIRST TIME THAT THE SIGNIFICANCE OF P53 PROMOTER METHYLATION STATUS IS DESCRIBED IN THIS PATHOLOGY, AND OUR DATA SUPPORT THAT THIS EPIGENETIC PHENOMENON COULD BE INVOLVED IN THE PATHOGENESIS AND CLINICAL EVOLUTION OF CLL.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12 3071  48 GENOME-WIDE DNA METHYLATION PROFILING INTEGRATED WITH GENE EXPRESSION PROFILING IDENTIFIES PAX9 AS A NOVEL PROGNOSTIC MARKER IN CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), EPIGENOMIC AND GENOMIC STUDIES HAVE EXPANDED THE EXISTING KNOWLEDGE ABOUT THE DISEASE BIOLOGY AND LED TO THE IDENTIFICATION OF POTENTIAL BIOMARKERS RELEVANT FOR IMPLEMENTATION OF PERSONALIZED MEDICINE. IN THIS STUDY, AN ATTEMPT HAS BEEN MADE TO EXAMINE AND INTEGRATE THE GLOBAL DNA METHYLATION CHANGES WITH GENE EXPRESSION PROFILE AND THEIR IMPACT ON CLINICAL OUTCOME IN EARLY STAGE CLL PATIENTS. RESULTS: THE INTEGRATION OF DNA METHYLATION PROFILE (N = 14) WITH THE GENE EXPRESSION PROFILE (N = 21) REVEALED 142 GENES AS HYPERMETHYLATED-DOWNREGULATED AND; 62 GENES AS HYPOMETHYLATED-UPREGULATED IN EARLY STAGE CLL PATIENTS COMPARED TO CD19+ B-CELLS FROM HEALTHY INDIVIDUALS. THE MRNA EXPRESSION LEVELS OF 17 GENES IDENTIFIED TO BE DIFFERENTIALLY METHYLATED AND/OR DIFFERENTIALLY EXPRESSED WAS FURTHER EXAMINED IN EARLY STAGE CLL PATIENTS (N = 93) BY QUANTITATIVE REAL TIME PCR (RQ-PCR). SIGNIFICANT DIFFERENCES WERE OBSERVED IN THE MRNA EXPRESSION OF MEIS1, PMEPA1, SOX7, SPRY1, CDK6, TBX2, AND SPRY2 GENES IN CLL CELLS AS COMPARED TO B-CELLS FROM HEALTHY INDIVIDUALS. THE ANALYSIS IN THE IGHV MUTATION BASED CATEGORIES (UNMUTATED = 39, MUTATED = 54) REVEALED SIGNIFICANTLY HIGHER MRNA EXPRESSION OF CRY1 AND PAX9 GENES IN THE IGHV UNMUTATED SUBGROUP (P < 0.001). THE RELATIVE RISK OF TREATMENT INITIATION WAS SIGNIFICANTLY HIGHER AMONG PATIENTS WITH HIGH EXPRESSION OF CRY1 (RR = 1.91, P = 0.005) OR PAX9 (RR = 1.87, P = 0.001). HIGH EXPRESSION OF CRY1 (HR: 3.53, P < 0.001) OR PAX9 (HR: 3.14, P < 0.001) GENE WAS SIGNIFICANTLY ASSOCIATED WITH SHORTER TIME TO FIRST TREATMENT. THE HIGH EXPRESSION OF PAX9 GENE (HR: 3.29, 95% CI 1.172-9.272, P = 0.016) WAS ALSO PREDICTIVE OF SHORTER OVERALL SURVIVAL IN CLL. CONCLUSIONS: THE DNA METHYLATION CHANGES ASSOCIATED WITH MRNA EXPRESSION OF CRY1 AND PAX9 GENES ALLOW RISK STRATIFICATION OF EARLY STAGE CLL PATIENTS. THIS COMPREHENSIVE ANALYSIS SUPPORTS THE CONCEPT THAT THE EPIGENETIC CHANGES ALONG WITH THE ALTERED EXPRESSION OF GENES HAVE THE POTENTIAL TO PREDICT CLINICAL OUTCOME IN EARLY STAGE CLL PATIENTS.	2017	

13 1083  36 CNL AND ACML SHOULD BE CONSIDERED AS A SINGLE ENTITY BASED ON MOLECULAR PROFILES AND OUTCOMES. CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) ARE RARE MYELOID DISORDERS THAT ARE CHALLENGING WITH REGARD TO DIAGNOSIS AND CLINICAL MANAGEMENT. TO STUDY THE SIMILARITIES AND DIFFERENCES BETWEEN THESE DISORDERS, WE UNDERTOOK A MULTICENTER INTERNATIONAL STUDY OF ONE OF THE LARGEST CASE SERIES (CNL, N = 24; ACML, N = 37 CASES, RESPECTIVELY), FOCUSING ON THE CLINICAL AND MUTATIONAL PROFILES (N = 53 WITH MOLECULAR DATA) OF THESE DISEASES. WE FOUND NO DIFFERENCES IN CLINICAL PRESENTATIONS OR OUTCOMES OF BOTH ENTITIES. AS PREVIOUSLY DESCRIBED, BOTH CNL AND ACML SHARE A COMPLEX MUTATIONAL PROFILE WITH MUTATIONS IN GENES INVOLVED IN EPIGENETIC REGULATION, SPLICING, AND SIGNALING PATHWAYS. APART FROM CSF3R, ONLY EZH2 AND TET2 WERE DIFFERENTIALLY MUTATED BETWEEN THEM. THE MOLECULAR PROFILES SUPPORT THE NOTION OF CNL AND ACML BEING A CONTINUUM OF THE SAME DISEASE THAT MAY FIT BEST WITHIN THE MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS. WE IDENTIFIED 4 HIGH-RISK MUTATED GENES, SPECIFICALLY CEBPA (BETA = 2.26, HAZARD RATIO [HR] = 9.54, P = .003), EZH2 (BETA = 1.12, HR = 3.062, P = .009), NRAS (BETA = 1.29, HR = 3.63, P = .048), AND U2AF1 (BETA = 1.75, HR = 5.74, P = .013) USING MULTIVARIATE ANALYSIS. OUR FINDINGS UNDERSCORE THE RELEVANCE OF MOLECULAR-RISK CLASSIFICATION IN CNL/ACML AS WELL AS THE IMPORTANCE OF CSF3R MUTATIONS IN THESE DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  831  39 CHARACTERIZATION OF TET AND IDH GENE EXPRESSION IN CHRONIC LYMPHOCYTIC LEUKEMIA: COMPARISON WITH NORMAL B CELLS AND PROGNOSTIC SIGNIFICANCE. BACKGROUND: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON HEMATOLOGICAL MALIGNANCY IN WESTERN COUNTRIES, CHARACTERIZED BY A HETEROGENEOUS CLINICAL COURSE. ALTHOUGH GENETIC STUDIES HAVE IDENTIFIED CHROMOSOMAL ABERRATIONS OR SPECIFIC MUTATIONS, EPIGENETIC CHANGES HAVE BEEN POORLY CHARACTERIZED IN CLL. METHODS: WE ASSESSED TEN-ELEVEN TRANSLOCATIONS (TET) 1, 2, AND 3, ISOCITRATE DEHYDROGENASE (IDH) 1, AND 2 MESSENGER RNA (MRNA) EXPRESSION USING REAL-TIME PCR ON PURIFIED LEUKEMIC B CELLS FROM 214 CLL PATIENTS (MEDIAN FOLLOW-UP = 75 MONTHS, RANGE 1-380), NORMAL PERIPHERAL BLOOD B CELLS (N = 20), AND UMBILICAL CORD BLOOD B CELLS (N = 21). THE MICROENVIRONMENT INFLUENCE WAS ASSESSED AFTER 24 H CO-CULTURE OF CLL CELLS WITH BONE MARROW MESENCHYMAL STROMAL CELLS (BMSC). FINALLY, 5-HYDROXYMETHYLCYTOSINE LEVEL (%5-HMC) WAS ASSESSED BY ELISA IN CLL CELLS ALONE OR WITH MICROENVIRONMENT STIMULI. RESULTS: TET 1 AND 3 AND IDH2 WERE DECREASED IN CLL CELLS COMPARED WITH HEALTHY B CELLS (P = 0.0221, 0.0013, <0.0001, RESPECTIVELY), WHILE IDH1 WAS OVEREXPRESSED (P = 0.0037). TET2 AND IDH1 WERE SIGNIFICANTLY CORRELATED WITH TREATMENT-FREE SURVIVAL (TFS); PATIENTS WITH HIGH TET2/IDH1 EXPRESSION HAD A HIGHER MEDIAN TFS (111 MONTHS) THAN PATIENTS WITH LOW EXPRESSION (78 MONTHS, P = 0.0071/0.0123). MOREOVER, TET1 EXPRESSION DECREASED (P = 0.0371), WHILE TET3 AND IDH2 EXPRESSION INCREASED (P = 0.0273/0.0039) IN CO-CULTURES. HOWEVER, %5-HMC WAS NOT CORRELATED WITH CLINICAL DATA AND WAS UNCHANGED FOLLOWING MICROENVIRONMENT STIMULI. CONCLUSIONS: DESPITE A SLIGHT DEREGULATION IN CLL CELLS COMPARED WITH NORMAL B CELLS, WE IDENTIFIED A SIGNIFICANT ASSOCIATION BETWEEN TET/IDH GENE EXPRESSION AND PROGNOSIS, SUGGESTING THAT EPIGENETIC CHANGES COULD POTENTIALLY BE ASSOCIATED WITH DISEASE PROGRESSION. MOREOVER, DESPITE AN IDENTICAL %5-HMC, TET GENE EXPRESSION WAS INFLUENCED BY CONTACT WITH BMSC CONFIRMING THE CRUCIAL ROLE OF THE MICROENVIRONMENT IN CLL PATHOGENESIS.	2016	
                                                                                                                                                            
15 1100  31 COMBINATION OF MYELOPROLIFERATIVE NEOPLASM DRIVER GENE ACTIVATION WITH MUTATIONS OF SPLICE FACTOR OR EPIGENETIC MODIFIER GENES INCREASES RISK OF RAPID BLASTIC PROGRESSION. OBJECTIVES: MYELOPROLIFERATIVE NEOPLASMS (MPN) COMPRISING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF) FOLLOW A BI-PHASIC COURSE OF DISEASE WITH FIBROTIC AND/OR BLASTIC PROGRESSION. AT PRESENTATION IN THE CHRONIC PHASE, CURRENTLY THERE ARE ONLY INSUFFICIENT TOOLS TO PREDICT THE RISK OF PROGRESSION IN INDIVIDUAL CASES. METHODS: IN THIS STUDY, CHRONIC PHASE MPN (16 PMF, 11 PV, AND 11 MPN UNCLASSIFIED) WITH BLASTIC TRANSFORMATION DURING COURSE OF DISEASE (N = 38, MEDIAN FOLLOW-UP 5.3 YEARS) WERE ANALYZED BY HIGH-THROUGHPUT SEQUENCING. MPN CASES WITH A COMPARABLE FOLLOW-UP PERIOD AND WITHOUT EVIDENCE OF BLAST INCREASE SERVED AS CONTROL (N = 63, MEDIAN FOLLOW-UP 5.8 YEARS). RESULTS: FREQUENT ARCH/CHIP-ASSOCIATED MUTATIONS (TET2, ASXL1, DNMT3A) FOUND AT PRESENTATION WERE NOT SIGNIFICANTLY ASSOCIATED WITH BLASTIC TRANSFORMATION. BY CONTRAST, MUTATIONS OF SRSF2, U2AF1, AND IDH1/2 AT FIRST PRESENTATION WERE FREQUENTLY OBSERVED IN THE PROGRESSION COHORT (13/38, 34.2%) AND WERE COMPLETELY MISSING IN THE CONTROL GROUP WITHOUT BLAST TRANSFORMATION DURING FOLLOW-UP (P = .0007 FOR SRSF2; P = .0063 FOR U2AF1 AND IDH1/2). CONCLUSION: UNLIKE FREQUENT ARCH/CHIP ALTERATIONS (TET2, ASXL1, DNMT3A), MUTATIONS IN SRSF2, IDH1/2, AND U2AF1 WHEN MANIFEST ALREADY AT FIRST PRESENTATION PROVIDE AN INDEPENDENT RISK FACTOR FOR RAPID BLAST TRANSFORMATION OF MPN.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16 5270  35 PROMOTER DNA METHYLATION FREQUENCY AND CLINICOPATHOLOGICAL ROLE OF MIR-129-2 GENE IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. OBJECTIVES: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY THE ACCUMULATION OF APPARENTLY MATURE B-TYPE LYMPHOCYTES IN THE LYMPHOHEMATOPOIETIC ORGANS. METHYLATION IN PROMOTERS OF TUMOR SUPPRESSOR GENES IS ONE OF THE MECHANISMS THAT CAUSES BLOOD MALIGNANCY. IN THIS STUDY, WE EVALUATED THE PROMOTER DNA METHYLATION STATUS OF MIR-129-2 TUMOR SUPPRESSOR GENE AND ITS ASSOCIATION WITH CLINICAL AND LABORATORY PARAMETERS OF PATIENTS WITH CLL. METHODS: WE STUDIED THE PROMOTER DNA METHYLATION FREQUENCY OF THE MIR-129-2 GENE IN 50 PATIENTS WITH CLL AND 50 HEALTHY CONTROLS USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION METHODS. STATISTICAL ANALYSIS WAS PERFORMED USING SPSS-18 SOFTWARE, AND A P-VALUE < 0.050 WAS CONSIDERED STATISTICALLY SIGNIFICANT. RESULTS: THE FREQUENCY OF PROMOTER DNA METHYLATION OF THE MIR-129-2 GENE WAS SIGNIFICANTLY HIGHER IN THE CLL GROUP COMPARED WITH CONTROL GROUP (38.0% VS. 0.0%, P < 0.001; CHI(2) = 23.457). THE PROMOTER DNA METHYLATION FREQUENCY OF MIR-129-2 GENE WAS NOT SIGNIFICANTLY DIFFERENT BETWEEN THE TWO SEXES (P = 0.236). A SIGNIFICANT BUT WEAK CORRELATION WAS SEEN BETWEEN THE METHYLATED STATE OF THE MIR-129-2 GENE AND ORGANOMEGALY (P = 0.019, R = 0.330) AS WELL AS HEMOGLOBIN LEVELS (P = 0.020, R = -0.233). HOWEVER, BINARY LOGISTIC REGRESSION ANALYSIS INDICATED ORGANOMEGALY AS THE ONLY CLINICAL BIOMARKER WITH A STATISTICALLY SIGNIFICANT ASSOCIATION WITH THE HYPERMETHYLATED MIR-129-2 GENE STATE (P = 0.046). CONCLUSIONS: THE HIGH FREQUENCY OF PROMOTER DNA METHYLATION OF THE MIR-129-2 GENE IN THE CLL GROUP COMPARED TO THE CONTROL GROUP, AS WELL AS ITS SIGNIFICANT ASSOCIATION WITH ORGANOMEGALY, SUGGESTS THE IMPORTANCE OF THIS EPIGENETIC BIOMARKER IN THE PATHOGENESIS AND PROGNOSIS OF CLL DISEASE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                             
17 1044  42 CLINICAL CHARACTERISTICS OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH NON-HODGKIN B-CELL LYMPHOMA: A MULTICENTER RETROSPECTIVE STUDY. BACKGROUND: HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ASSOCIATED WITH B-CELL LYMPHOMA IS A HIGHLY AGGRESSIVE DISEASE WITH UNCLEAR CLINICAL FEATURES AND HAS NO STANDARD TREATMENT. PATIENTS AND METHODS: WE ANALYZED THE CLINICAL CHARACTERISTICS OF 31 PATIENTS FROM TWO INDIVIDUAL CENTERS. RESULTS: THE MEDIAN OVERALL SURVIVAL WAS ONLY 1.5 MONTHS. BOTH UNIVARIATE AND MULTIVARIATE ANALYSES, BASED ON LYMPHOMA OR HLH-RELATED CHARACTERISTICS, REVEALED THAT PATIENTS WITH HIGH EPSTEIN-BARR VIRUS (EBV) DNA LOAD AND >/= 2 EXTRANODAL LESIONS, OR HYPOFIBRINOGENEMIA, RESPECTIVELY, SHOWED SIGNIFICANTLY POORER OVERALL SURVIVAL. INTERESTINGLY, SOME PATIENTS WITH HIGH EBV DNA LOAD HAD EBV-POSITIVE NATURAL KILLER (NK) AND/OR T CELLS, WHICH MAY BE RELATED TO THE COEXISTENCE OF IMMUNODEFICIENCY AND/OR CHRONIC ACTIVE EBV INFECTION. MOLECULAR GENETICS EXAMINATION CONFIRMED THAT 47.4% (9/19) OF PATIENTS HAD COMPLEX KARYOTYPES, 37.5% (3/8) OF PATIENTS HAD TP53 DELETIONS, AND 21.34% (3/14) OF PATIENTS HAD TP53 MUTATION OR ALTERATION OF MALIGNANCY-RELATED PATHWAYS, INCLUDING BCR/NF-KAPPAB, JAK-STAT, AND EPIGENETIC REGULATORY PATHWAYS, WHICH MAY PROVIDE CLUES TO CHOOSE TARGETS FOR THERAPY. TREATMENT REGIMENS CONTAINING ETOPOSIDE, ANTI-CD20 MONOCLONAL ANTIBODIES, OR ANTHRACYCLINES IMPROVED PATIENT PROGNOSIS (P = .0183, .025, AND .0436, RESPECTIVELY). PATIENTS WITH INFECTIONS HAD SIGNIFICANTLY SHORTER SURVIVAL THAN THOSE WITHOUT INFECTIONS (P = .00019). CONCLUSION: THE PATIENTS' PERFORMANCE STATUS, NUMBER OF EXTRANODAL LESIONS, HIGH EBV DNA LOAD, AND HYPOFIBRINOGENEMIA ARE POOR PROGNOSTIC FACTORS FOR HLH ASSOCIATED WITH B-CELL LYMPHOMA. MOLECULAR GENETIC HIGH-RISK FACTORS ARE OF PARTICULAR IMPORTANCE BECAUSE THESE FACTORS CAN PROVIDE INFORMATION FOR PROGNOSIS PREDICTION, TREATMENT DECISIONS, AND DISEASE SURVEILLANCE.	2021	
                                                                                                                                                                                                                                                                                                                    
18 5911  27 TARGETED NEXT-GENERATION SEQUENCING IN MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA AIDS DIAGNOSIS IN CHALLENGING CASES AND IDENTIFIES FREQUENT SPLICEOSOME MUTATIONS IN TRANSFORMED ACUTE MYELOID LEUKEMIA. OBJECTIVES: OPTIMAL INTEGRATION OF NEXT-GENERATION SEQUENCING (NGS) INTO CLINICAL PRACTICE IN HEMATOLOGIC MALIGNANCIES REMAINS UNCLEAR. WE EVALUATE THE UTILITY OF NGS IN MYELOID MALIGNANCIES. METHODS: A 42-GENE PANEL WAS USED TO SEQUENCE 109 CASES OF MYELODYSPLASTIC SYNDROME (MDS, N = 38), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML, N = 14), MYELOPROLIFERATIVE NEOPLASM (MPN, N = 24), AND MDS AND/OR MPN TRANSFORMED TO ACUTE MYELOID LEUKEMIA (AML, N = 33). RESULTS: AT LEAST ONE PATHOGENIC MUTATION WAS IDENTIFIED IN 74% OF CASES OF MDS, 100% OF CMMLS, AND 96% OF MPNS. IN CONTRAST, ONLY 47% OF CASES OF MDS (18/38) AND 7% (1/14) OF CMMLS EXHIBITED ABNORMAL CYTOGENETICS. IN DIAGNOSTICALLY DIFFICULT CASES OF MDS OR CMML WITH NORMAL CYTOGENETICS, NGS IDENTIFIED A PATHOGENIC MUTATION AND WAS CRITICAL IN ESTABLISHING THE CORRECT DIAGNOSIS. SPLICEOSOMAL GENES AND EPIGENETIC MODIFIERS WERE FREQUENTLY MUTATED. SPLICEOSOME MUTATIONS WERE ALSO FREQUENTLY DETECTED IN AML ARISING FROM MDS, CMML, OR MPN (39%) COMPARED WITH THE REPORTED RATE IN DE NOVO AML (7%-14%). CONCLUSIONS: IN DIFFICULT CASES OF MDS OR MPN, NGS FACILITATES DIAGNOSIS BY DETECTION OF GENE MUTATIONS TO CONFIRM CLONALITY, AND AMLS EVOLVING FROM MDS OR MPN CARRY FREQUENT MUTATIONS IN SPLICEOSOMAL GENES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19 1070  30 CLONAL ARCHITECTURE OF CHRONIC MYELOMONOCYTIC LEUKEMIAS. GENOMIC STUDIES IN CHRONIC MYELOID MALIGNANCIES, INCLUDING MYELOPROLIFERATIVE NEOPLASMS (MPN), MYELODYSPLASTIC SYNDROMES (MDS), AND MPN/MDS, HAVE IDENTIFIED COMMON MUTATIONS IN GENES ENCODING SIGNALING, EPIGENETIC, TRANSCRIPTION, AND SPLICING FACTORS. IN THE PRESENT STUDY, WE INTERROGATED THE CLONAL ARCHITECTURE BY MUTATION-SPECIFIC DISCRIMINATION ANALYSIS OF SINGLE-CELL-DERIVED COLONIES IN 28 PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIAS (CMML), THE MOST FREQUENT MPN/MDS. THIS ANALYSIS REVEALS A LINEAR ACQUISITION OF THE STUDIED MUTATIONS WITH LIMITED BRANCHING THROUGH LOSS OF HETEROZYGOSITY. SERIAL ANALYSIS OF UNTREATED AND TREATED SAMPLES DEMONSTRATES A DYNAMIC ARCHITECTURE ON WHICH MOST CURRENT THERAPEUTIC APPROACHES HAVE LIMITED EFFECTS. THE MAIN DISEASE CHARACTERISTICS ARE EARLY CLONAL DOMINANCE, ARISING AT THE CD34(+)/CD38(-) STAGE OF HEMATOPOIESIS, AND GRANULOMONOCYTIC DIFFERENTIATION SKEWING OF MULTIPOTENT AND COMMON MYELOID PROGENITORS. COMPARISON OF CLONAL EXPANSIONS OF TET2 MUTATIONS IN MDS, MPN, AND CMML, TOGETHER WITH FUNCTIONAL INVALIDATION OF TET2 IN SORTED PROGENITORS, SUGGESTS A CAUSATIVE LINK BETWEEN EARLY CLONAL DOMINANCE AND SKEWED GRANULOMONOCYTIC DIFFERENTIATION. ALTOGETHER, EARLY CLONAL DOMINANCE MAY DISTINGUISH CMML FROM OTHER CHRONIC MYELOID NEOPLASMS WITH SIMILAR GENE MUTATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20 5980  41 TET2 MUTATIONS WERE PREDICTIVE OF INFERIOR PROGNOSIS IN THE PRESENCE OF ASXL1 MUTATIONS IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. BACKGROUND: SOMATIC MUTATIONS INVOLVING EPIGENETIC REGULATORS, HISTONE MODIFICATION AND CHROMATIN REGULATION, SPLICING COMPONENTS, TRANSCRIPTION FACTORS AND SIGNALING REGULATOR GENES ARE COMMON IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) PATIENTS. IT HAS BEEN CONSENSUS THAT ASXL1 MUTATIONS HAVE ADVERSELY IMPACT ON OVERALL SURVIVAL (OS), WHILE THE EFFECT OF TET2 MUTATIONS REMAINS CONTROVERSIAL AND UNDEFINED. METHODS: ASXL1 AND TET2 MUTATIONS WERE ANALYZED IN 141 PATIENTS WITH CMML USING SANGER SEQUENCING, WITH THE AIM TO IDENTIFY THE INTERPLAY OF ASXL1 AND TET2 MUTATIONS IN THE PROGNOSIS OF CMML. RESULTS: SIXTY-FIVE (46.1%) OF THE CMML PATIENTS HARBORED ASXL1 MUTATIONS (FRAMESHIFT AND NONSENSE), AND 46 (32.6%) HAD TET2 MUTATIONS (FRAME SHIFT, NONSENSE AND MISSENSE). IN A SEPARATE MULTIVARIABLE ANALYSIS THAT INCLUDED THE MAYO PROGNOSTIC MODEL AS A SINGLE VARIABLE ALONG WITH ASXL1WT/TET2WT, THE RESPECTIVE HAZARD RATIOS OF ASXL1MUT/TET2MUT, ASXL1MUT/TET2WT AND ASXL1WT/TET2MUT WERE 4.7 (95% CI, 2.2-10.3; P<0.001), 2.2 (95% CI, 1.1-4.2; P=0.025) AND 1.3 (95% CI, 0.6-2.5; P=0.521). CONCLUSIONS: OUR STUDY SHOWED THAT ASXL1 MUTATIONS PREDICT INFERIOR OS, AND ADDITIONAL TET2 MUTATIONS WERE ASSOCIATED WITH POOR SURVIVAL IN THE PRESENCE OF ASXL1 MUTATIONS OF CMML PATIENTS.	2016