1  2133 95 EPIGENETIC INACTIVATION OF THE MIR-34A IN HEMATOLOGICAL MALIGNANCIES. MIR-34A IS A TRANSCRIPTIONAL TARGET OF P53 AND IMPLICATED IN CARCINOGENESIS. WE STUDIED THE ROLE OF MIR-34A METHYLATION IN A PANEL OF HEMATOLOGICAL MALIGNANCIES INCLUDING ACUTE LEUKEMIA [ACUTE MYELOID LEUKEMIA (AML) AND ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)], CHRONIC LEUKEMIA [CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND CHRONIC MYELOID LEUKEMIA (CML)], MULTIPLE MYELOMA (MM) AND NON-HODGKIN'S LYMPHOMA (NHL). THE METHYLATION STATUS OF MIR-34A PROMOTER WAS STUDIED IN 12 CELL LINES AND 188 DIAGNOSTIC SAMPLES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. MIR-34A PROMOTER WAS UNMETHYLATED IN NORMAL CONTROLS BUT METHYLATED IN 75% LYMPHOMA AND 37% MYELOMA CELL LINES. HYPOMETHYLATING TREATMENT LED TO RE-EXPRESSION OF PRI-MIR-34A TRANSCRIPT IN LYMPHOMA CELLS WITH HOMOZYGOUS MIR-34A METHYLATION. IN PRIMARY SAMPLES AT DIAGNOSIS, MIR-34A METHYLATION WAS DETECTED IN 4% CLL, 5.5% MM SAMPLES AND 18.8% OF NHL AT DIAGNOSIS BUT NONE OF ALL, AML AND CML (P = 0.011). IN MM PATIENTS WITH PAIRED SAMPLES, MIR-34A METHYLATION STATUS REMAINED UNCHANGED AT PROGRESSION. AMONGST LYMPHOID MALIGNANCIES, MIR-34A WAS PREFERENTIALLY METHYLATED IN NHL (P = 0.018), IN PARTICULAR NATURAL KILLER (NK)/T-CELL LYMPHOMA. IN CONCLUSION, AMONGST HEMATOLOGICAL MALIGNANCIES, MIR-34A METHYLATION IS PREFERENTIALLY HYPERMETHYLATED IN NHL, IN PARTICULAR NK/T-CELL LYMPHOMA, IN A TUMOR-SPECIFIC MANNER, THEREFORE THE ROLE OF MIR-34A IN LYMPHOMAGENESIS WARRANTS FURTHER STUDY.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  2131 50 EPIGENETIC INACTIVATION OF THE HSA-MIR-203 IN HAEMATOLOGICAL MALIGNANCIES. MIR-203 IS A TUMOUR SUPPRESSOR MICRORNA (MIRNA). WE STUDIED THE METHYLATION OF HSA-MIR-203 IN 150 SAMPLES INCLUDING ACUTE MYELOID LEUKAEMIA (AML), ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL), CHRONIC MYELOID LEUKAEMIA (CML), CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AND NON-HODGKIN'S LYMPHOMA (NHL) BY METHYLATION-SPECIFIC PCR, AND MIRNA EXPRESSION BY STEM-LOOP RT-QPCR. HSA-MIR-203 PROMOTER WAS UNMETHYLATED IN NORMAL CONTROLS BUT HOMOZYGOUSLY METHYLATED IN TWO AML AND FOUR LYMPHOMA CELL LINES, IN WHICH 5-AZA-2'-DEOXYCYTIDINE TREATMENT LED TO PROMOTER DEMETHYLATION AND MIR-203 RE-EXPRESSION. RESTORATION OF MIR-203 EXPRESSION IN LYMPHOMA CELLS INHIBITED CELLULAR PROLIFERATION AND INCREASED CELL DEATH, SUGGESTING AN INHERENT TUMOUR SUPPRESSOR ACTIVITY. IN PRIMARY SAMPLES, HSA-MIR-203 METHYLATION WAS ABSENT IN CML BUT DETECTED IN 5.0% ALL, 10.0% AML, 42.0% CLL AND 38.8% OF NHL (INCLUDING SIX [60.0%] NATURAL KILLER-CELL, NINE [40.9%] B-CELL AND FOUR [23.5%] T CELL NHL). MOREOVER, HSA-MIR-203 METHYLATION WAS ASSOCIATED WITH HYPERMETHYLATION OF HSA-MIR-34A, -124A AND -196B IN NHL BUT NOT CLL. IN CLL, HSA-MIR-203 METHYLATION WAS ASSOCIATED WITH A HIGHER PRESENTING HB LEVEL (P = 0.033). THE PROJECTED 10 YEAR OVERALL SURVIVAL OF THE CLL PATIENTS WAS 58.2%, WHICH WAS IMPACTED BY RAI STAGE AND HIGH-RISK KARYOTYPES BUT NOT HSA-MIR-203 METHYLATION. HSA-MIR-203 WAS MORE FREQUENTLY METHYLATED IN LYMPHOID THAN MYELOID MALIGNANCIES (P = 0.002). IN CONCLUSION, MIR-203, A TUMOUR SUPPRESSOR GENE, WAS HYPERMETHYLATED IN A TUMOUR-SPECIFIC MANNER WITH GENE SILENCING. HSA-MIR-203 WAS MORE FREQUENTLY HYPERMETHYLATED IN LYMPHOID THAN MYELOID MALIGNANCIES. IN NHL, HSA-MIR-203 METHYLATION WAS ASSOCIATED WITH CONCOMITANT METHYLATION OF OTHER TUMOUR SUPPRESSOR MIRNAS. THE FREQUENT HSA-MIR-203 METHYLATION IN LYMPHOID MALIGNANCIES SUGGESTED A PATHOGENETIC ROLE OF HSA-MIR-203 METHYLATION.	2011	
                                                                                                                                                                                                                                                
3  1433 26 DIFFERENTIAL GENOME-WIDE ARRAY-BASED METHYLATION PROFILES IN PROGNOSTIC SUBSETS OF CHRONIC LYMPHOCYTIC LEUKEMIA. GLOBAL HYPOMETHYLATION AND REGIONAL HYPERMETHYLATION ARE WELL-KNOWN EPIGENETIC FEATURES OF CANCER; HOWEVER, IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), STUDIES ON GENOME-WIDE EPIGENETIC MODIFICATIONS ARE LIMITED. HERE, WE ANALYZED THE GLOBAL METHYLATION PROFILES IN CLL, BY APPLYING HIGH-RESOLUTION METHYLATION MICROARRAYS (27,578 CPG SITES) TO 23 CLL SAMPLES, BELONGING TO THE IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE (IGHV) MUTATED (FAVORABLE) AND IGHV UNMUTATED/IGHV3-21 (POOR-PROGNOSTIC) SUBSETS. OVERALL, RESULTS DEMONSTRATED SIGNIFICANT DIFFERENCES IN METHYLATION PATTERNS BETWEEN THESE SUBGROUPS. SPECIFICALLY, IN IGHV UNMUTATED CLL, WE IDENTIFIED METHYLATION OF 7 KNOWN OR CANDIDATE TUMOR SUPPRESSOR GENES (EG, VHL, ABI3, AND IGSF4) AS WELL AS 8 UNMETHYLATED GENES INVOLVED IN CELL PROLIFERATION AND TUMOR PROGRESSION (EG, ADORA3 AND PRF1 ENHANCING THE NUCLEAR FACTOR-KAPPAB AND MITOGEN-ACTIVATED PROTEIN KINASE PATHWAYS, RESPECTIVELY). IN CONTRAST, THESE LATTER GENES WERE SILENCED BY METHYLATION IN IGHV MUTATED PATIENTS. THE ARRAY DATA WERE VALIDATED FOR SELECTED GENES USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION, QUANTITATIVE REVERSE TRANSCRIPTASE-POLYMERASE CHAIN REACTION, AND BISULFITE SEQUENCING. FINALLY, THE SIGNIFICANCE OF DNA METHYLATION IN REGULATING GENE PROMOTERS WAS SHOWN BY REINDUCING 4 METHYLATED TUMOR SUPPRESSOR GENES (EG, VHL AND ABI3) IN IGHV UNMUTATED SAMPLES USING THE METHYL-INHIBITOR 5-AZA-2'-DEOXYCYTIDINE. TAKEN TOGETHER, OUR DATA FOR THE FIRST TIME REVEAL DIFFERENCES IN GLOBAL METHYLATION PROFILES BETWEEN PROGNOSTIC SUBSETS OF CLL, WHICH MAY UNFOLD EPIGENETIC SILENCING MECHANISMS INVOLVED IN CLL PATHOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                        
4  5666 19 SF3B1-MUTATED CHRONIC LYMPHOCYTIC LEUKEMIA SHOWS EVIDENCE OF NOTCH1 PATHWAY ACTIVATION INCLUDING CD20 DOWNREGULATION. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY A LOW CD20 EXPRESSION, IN PART EXPLAINED BY AN EPIGENETIC-DRIVEN DOWNREGULATION TRIGGERED BY MUTATIONS OF THE NOTCH1 GENE. IN THE PRESENT STUDY, BY TAKING ADVANTAGE OF A WIDE AND WELL-CHARACTERIZED CLL COHORT (N=537), WE DEMONSTRATE THAT CD20 EXPRESSION IS DOWNREGULATED IN SF3B1-MUTATED CLL IN AN EXTENT SIMILAR TO NOTCH1-MUTATED CLL. IN FACT, SF3B1-MUTATED CLL CELLS SHOW COMMON FEATURES WITH NOTCH1-MUTATED CLL CELLS, INCLUDING A GENE EXPRESSION PROFILE ENRICHED OF NOTCH1-RELATED GENE SETS AND ELEVATED EXPRESSION OF THE ACTIVE INTRACYTOPLASMIC NOTCH1. ACTIVATION OF THE NOTCH1 SIGNALING AND DOWN-REGULATION OF SURFACE CD20 IN SF3B1-MUTATED CLL CELLS CORRELATE WITH OVER-EXPRESSION OF AN ALTERNATIVELY SPLICED FORM OF DVL2, A COMPONENT OF THE WNT PATHWAY AND NEGATIVE REGULATOR OF THE NOTCH1 PATHWAY. THESE FINDINGS ARE CONFIRMED BY SEPARATELY ANALYZING THE CD20-DIM AND CD20-BRIGHT CELL FRACTIONS FROM SF3B1-MUTATED CASES AS WELL AS BY DVL2 KNOCK-OUT EXPERIMENTS IN CLL-LIKE CELL MODELS. ALTOGETHER, THE CLINICAL AND BIOLOGICAL FEATURES THAT CHARACTERIZE NOTCH1-MUTATED CLL MAY ALSO BE RECAPITULATED IN SF3B1-MUTATED CLL, CONTRIBUTING TO EXPLAIN THE POOR PROGNOSIS OF THIS CLL SUBSET AND PROVIDING THE RATIONALE FOR EXPANDING NOVEL AGENTS-BASED THERAPIES TO SF3B1-MUTATED CLL.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
5  4432 20 MOLECULAR CHARACTERIZATION OF RICHTER SYNDROME IDENTIFIES DE NOVO DIFFUSE LARGE B-CELL LYMPHOMAS WITH POOR PROGNOSIS. RICHTER SYNDROME (RS) IS THE TRANSFORMATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) INTO AGGRESSIVE LYMPHOMA, MOST COMMONLY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). WE CHARACTERIZE 58 PRIMARY HUMAN RS SAMPLES BY GENOME-WIDE DNA METHYLATION AND WHOLE-TRANSCRIPTOME PROFILING. OUR COMPREHENSIVE APPROACH DETERMINES RS DNA METHYLATION PROFILE AND UNRAVELS A CLL EPIGENETIC IMPRINT, ALLOWING CLL-RS CLONAL RELATIONSHIP ASSESSMENT WITHOUT THE NEED OF THE INITIAL CLL TUMOR DNA. DNA METHYLATION- AND TRANSCRIPTOMIC-BASED CLASSIFIERS WERE DEVELOPED, AND TESTING ON LANDMARK DLBCL DATASETS IDENTIFIES A POOR-PROGNOSIS, ACTIVATED B-CELL-LIKE DLBCL SUBSET IN 111/1772 SAMPLES. THE CLASSIFICATION ROBUSTLY IDENTIFIES PHENOTYPES VERY SIMILAR TO RS WITH A SPECIFIC GENOMIC PROFILE, ACCOUNTING FOR 4.3-8.3% OF DE NOVO DLBCLS. IN THIS WORK, RS MULTI-OMICS CHARACTERIZATION DETERMINES ONCOGENIC MECHANISMS, ESTABLISHES A SURROGATE MARKER FOR CLL-RS CLONAL RELATIONSHIP, AND PROVIDES A CLINICALLY RELEVANT CLASSIFIER FOR A SUBSET OF PRIMARY "RS-TYPE DLBCL" WITH UNFAVORABLE PROGNOSIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6  6390 16 THE ROLE OF THE GENETIC ABNORMALITIES, EPIGENETIC AND MICRORNA IN THE PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS INCREASED PROLIFERATION OF B-CELLS WITH PERIPHERAL BLOOD AND BONE MARROW INVOLVEMENT, WHICH IS USUALLY OBSERVED IN OLDER PEOPLE. GENETIC MUTATIONS, EPIGENETIC CHANGES AND MIRS PLAY A ROLE IN CLL PATHOGENESIS. DEL 11Q, DEL L17Q, DEL 6Q, TRISOMY 12, P53 AND IGVH MUTATIONS ARE THE MOST IMPORTANT GENETIC CHANGES IN CLL. DELETION OF MIR-15A AND MIR-16A CAN INCREASE BCL2 GENE EXPRESSION, MIR-29 AND MIR-181 DELETIONS DECREASE THE EXPRESSION OF TCL1, AND MIR-146A DELETION PREVENTS TUMOR METASTASIS. EPIGENETIC CHANGES SUCH AS HYPO- AND HYPERMETHYLATION, UBIQUITINATION, HYPO- AND HYPERACETYLATION OF GENE PROMOTERS INVOLVED IN CLL PATHOGENESIS CAN ALSO PLAY A ROLE IN CLL. EXPRESSION OF CD38 AND ZAP70, PRESENCE OR ABSENCE OF MUTATION IN IGVH AND P53 MUTATION ARE AMONG THE FACTORS INVOLVED IN CLL PROGNOSIS. USE OF MONOCLONAL ANTIBODIES AGAINST SURFACE MARKERS OF B-CELLS LIKE ANTI-CD20 AS WELL AS TYROSINE KINASE INHIBITORS ARE THE MOST IMPORTANT THERAPEUTIC APPROACHES FOR CLL.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7  5243 22 PROGNOSTIC IMPACT OF EPIGENETIC CLASSIFICATION IN CHRONIC LYMPHOCYTIC LEUKEMIA: THE CASE OF SUBSET #2. BASED ON THE METHYLATION STATUS OF 5 SINGLE CPG SITES, A NOVEL EPIGENETIC CLASSIFICATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) WAS RECENTLY PROPOSED, CLASSIFYING CLL PATIENTS INTO 3 CLINICO-BIOLOGICAL SUBGROUPS WITH DIFFERENT OUTCOME, TERMED MEMORY LIKE CLL (M-CLL), NAIVE LIKE CLL (N-CLL), AND A THIRD INTERMEDIATE CLL SUBGROUP (I-CLL). WHILE M-CLL AND N-CLL PATIENTS AT LARGE CORRESPONDED TO PATIENTS CARRYING MUTATED AND UNMUTATED IGHV GENES, RESPECTIVELY, LIMITED INFORMATION EXISTS REGARDING THE LESS DEFINED I-CLL GROUP. USING PYROSEQUENCING, WE INVESTIGATED THE PROGNOSTIC IMPACT OF THE PROPOSED 5 CPG SIGNATURE IN A WELL-CHARACTERIZED CLL COHORT (135 CASES), INCLUDING IGHV-MUTATED AND UNMUTATED PATIENTS AS WELL AS CLINICALLY AGGRESSIVE STEREOTYPED SUBSET #2 PATIENTS. OVERALL, WE CONFIRMED THE SIGNATURE'S ASSOCIATION WITH ESTABLISHED PROGNOSTIC MARKERS. MOREOVER, IN THE PRESENCE OF THE IGHV MUTATIONAL STATUS, THE EPIGENETIC SIGNATURE REMAINED INDEPENDENTLY ASSOCIATED WITH BOTH TIME-TO-FIRST-TREATMENT AND OVERALL SURVIVAL IN MULTIVARIATE ANALYSES. AS A PRIME FINDING, WE OBSERVED THAT SUBSET #2 PATIENTS WERE PREDOMINANTLY CLASSIFIED AS I-CLL, PROBABLY REFLECTING THEIR BORDERLINE IGHV MUTATIONAL STATUS (97-99% GERMLINE IDENTITY), THOUGH HAVING A SIMILARLY POOR PROGNOSIS AS N-CLL PATIENTS. IN SUMMARY, WE VALIDATED THE EPIGENETIC CLASSIFIER AS AN INDEPENDENT FACTOR IN CLL PROGNOSTICATION AND PROVIDE FURTHER EVIDENCE THAT SUBSET #2 IS A MEMBER OF THE I-CLL GROUP, HENCE SUPPORTING THE EXISTENCE OF A THIRD, INTERMEDIATE EPIGENETIC SUBGROUP.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8  2132 59 EPIGENETIC INACTIVATION OF THE MIR-124-1 IN HAEMATOLOGICAL MALIGNANCIES. MIR-124-1 IS A TUMOUR SUPPRESSOR MICRORNA (MIR). EPIGENETIC DEREGULATION OF MIRS IS IMPLICATED IN CARCINOGENESIS. PROMOTER DNA METHYLATION AND HISTONE MODIFICATION OF MIR-124-1 WAS STUDIED IN 5 NORMAL MARROW CONTROLS, 4 LYMPHOMA, 8 MULTIPLE MYELOMA (MM) CELL LINES, 230 DIAGNOSTIC PRIMARY SAMPLES OF ACUTE MYELOID LEUKAEMIA (AML), ACUTE LYMPHOBLASTIC LEUKAEMIA (ALL), CHRONIC MYELOID LEUKAEMIA (CML), CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL), MM, AND NON-HODGKIN'S LYMPHOMA (NHL), AND 53 MM SAMPLES AT STABLE DISEASE OR RELAPSE. PROMOTER OF MIR-124-1 WAS UNMETHYLATED IN NORMAL CONTROLS BUT HOMOZYGOUSLY METHYLATED IN 4 OF 4 LYMPHOMA AND 4 OF 8 MYELOMA CELL LINES. TREATMENT OF 5-AZA-2'-DEOXYCYTIDINE LED TO MIR-124-1 DEMETHYLATION AND RE-EXPRESSION OF MATURE MIR-124, WHICH ALSO ASSOCIATED WITH EMERGENCE OF EUCHROMATIC TRIMETHYL H3K4 AND CONSEQUENT DOWNREGULATION OF CDK6 IN MYELOMA CELLS HARBORING HOMOZYGOUS MIR-124-1 METHYLATION. IN PRIMARY SAMPLES AT DIAGNOSIS, MIR-124-1 METHYLATION WAS ABSENT IN CML BUT DETECTED IN 2% EACH OF MM AT DIAGNOSIS AND RELAPSE/PROGRESSION, 5% ALL, 15% AML, 14% CLL AND 58.1% OF NHL (P<0.001). AMONGST LYMPHOID MALIGNANCIES, MIR-124-1 WAS PREFERENTIALLY METHYLATED IN NHL THAN MM, CLL OR ALL. IN PRIMARY LYMPHOMA SAMPLES, MIR-124-1 WAS PREFERENTIALLY HYPERMETHYLATED IN B- OR NK/T-CELL LYMPHOMAS AND ASSOCIATED WITH REDUCED MIR-124 EXPRESSION. IN CONCLUSION, MIR-124-1 WAS HYPERMETHYLATED IN A TUMOUR-SPECIFIC MANNER, WITH A HETEROCHROMATIC HISTONE CONFIGURATION. HYPOMETHYLATION LED TO PARTIAL RESTORATION OF EUCHROMATIC HISTONE CODE AND MIR RE-EXPRESSION. INFREQUENT MIR-124-1 METHYLATION DETECTED IN DIAGNOSTIC AND RELAPSE MM SAMPLES SHOWED AN UNIMPORTANT ROLE IN MM PATHOGENESIS, DESPITE FREQUENT METHYLATION FOUND IN CELL LINES. AMONGST HAEMATOLOGICAL CANCERS, MIR-124-1 WAS MORE FREQUENTLY HYPERMETHYLATED IN NHL, AND HENCE WARRANTS FURTHER STUDY.	2011	
                                                                                                                                                                                                                                       
9  5462 17 RESEARCH PROGRESS ON EPIGENETICS OF SMALL B-CELL LYMPHOMA. SMALL B-CELL LYMPHOMA IS THE CLASSIFICATION OF B-CELL CHRONIC LYMPHOPROLIFERATIVE DISORDERS THAT INCLUDE CHRONIC LYMPHOCYTIC LEUKAEMIA/SMALL LYMPHOCYTIC LYMPHOMA, FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA. THE CLINICAL PRESENTATION IS SOMEWHAT HETEROGENEOUS, AND ITS OCCURRENCE AND DEVELOPMENT MECHANISMS ARE NOT YET PRECISE AND MAY INVOLVE EPIGENETIC CHANGES. EPIGENETIC ALTERATIONS MAINLY INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA, WHICH ARE ESSENTIAL FOR GENETIC DETECTION, EARLY DIAGNOSIS, AND ASSESSMENT OF TREATMENT RESISTANCE IN SMALL B-CELL LYMPHOMA. AS CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA HAS ALREADY BEEN REPORTED IN THE LITERATURE, THIS ARTICLE FOCUSES ON SMALL B-CELL LYMPHOMAS SUCH AS FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, AND WALDENSTROM MACROGLOBULINEMIA. IT DISCUSSES RECENT DEVELOPMENTS IN EPIGENETIC RESEARCH TO DIAGNOSE AND TREAT THIS GROUP OF LYMPHOMAS. THIS REVIEW PROVIDES NEW IDEAS FOR THE TREATMENT AND PROGNOSIS ASSESSMENT OF SMALL B-CELL LYMPHOMA BY EXPLORING THE CONNECTION BETWEEN SMALL B-CELL LYMPHOMA AND EPIGENETICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10  3522 22 IL-10 PRODUCTION BY CLL CELLS IS ENHANCED IN THE ANERGIC IGHV MUTATED SUBSET AND ASSOCIATES WITH REDUCED DNA METHYLATION OF THE IL10 LOCUS. CHRONIC LYMPHOCYTIC LEUKEMIAS (CLLS) WITH UNMUTATED (U-CLL) OR MUTATED (M-CLL) IGHV HAVE VARIABLE FEATURES OF IMMUNOSUPPRESSION, POSSIBLY INFLUENCED BY THOSE CLL CELLS ACTIVATED TO PRODUCE INTERLEUKIN 10 (IL-10). THE TWO SUBSETS DIFFER IN THEIR LEVELS OF ANERGY, DEFINED BY LOW SURFACE IMMUNOGLOBULIN M LEVELS/SIGNALING CAPACITY, AND IN THEIR DNA METHYLATION PROFILE, PARTICULARLY VARIABLE IN M-CLL. WE HAVE NOW FOUND THAT LEVELS OF IL-10 PRODUCED BY ACTIVATED CLL CELLS WERE HIGHLY VARIABLE. LEVELS WERE HIGHER IN M-CLL THAN IN U-CLL AND CORRELATED WITH ANERGY. DNA METHYLATION ANALYSIS OF IL10 LOCUS REVEALED TWO PREVIOUSLY UNCHARACTERIZED 'VARIABLY METHYLATED REGIONS' (CLL-VMRS1/2) IN THE GENE BODY, BUT SIMILARLY LOW METHYLATION IN THE PROMOTER OF BOTH U-CLL AND M-CLL. CLL-VMR1/2 METHYLATION WAS LOWER IN M-CLL THAN IN U-CLL AND INVERSELY CORRELATED WITH IL-10 INDUCTION. A FUNCTIONAL SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) BINDING SITE IN CLL-VMR2 WAS CONFIRMED BY PROXIMITY LIGATION AND LUCIFERASE ASSAYS, WHEREAS INHIBITION OF SYK-MEDIATED STAT3 ACTIVATION RESULTED IN SUPPRESSION OF IL10. THE DATA SUGGEST EPIGENETIC CONTROL OF IL-10 PRODUCTION. HIGHER TUMOR LOAD MAY COMPENSATE THE REDUCED IL-10 PRODUCTION IN U-CLL, ACCOUNTING FOR CLINICAL IMMUNOSUPPRESSION IN BOTH SUBSETS. THE OBSERVATION THAT SYK INHIBITION ALSO SUPPRESSES IL-10 PROVIDES A POTENTIAL NEW RATIONALE FOR THERAPEUTIC TARGETING AND IMMUNOLOGICAL RESCUE BY SYK INHIBITORS IN CLL.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11  2440 39 EPIGENETIC SILENCING OF TUMOR SUPPRESSOR LONG NON-CODING RNA BM742401 IN CHRONIC LYMPHOCYTIC LEUKEMIA. BM742401 IS A TUMOR SUPPRESSOR LNCRNA DOWNREGULATED IN GASTRIC CANCER. AS THE PROMOTER REGION AND THE ENTIRE TRANSCRIPT ARE EMBEDDED IN A CPG ISLAND, WE POSTULATED THAT BM742401 IS A TUMOR SUPPRESSOR LNCRNA INACTIVATED BY DNA METHYLATION IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). THE PROMOTER OF BM742401 WAS UNMETHYLATED IN NORMAL CONTROLS INCLUDING THREE EACH OF NORMAL BONE MARROW, PERIPHERAL BLOOD BUFFY COATS, AND CD19-SORTED PERIPHERAL B-CELLS, BUT METHYLATED IN FOUR (57.1%) CLL CELL LINES. METHYLATION OF BM742401 CORRELATED INVERSELY WITH EXPRESSION. IN THE COMPLETELY METHYLATED WAC3CD5+ CLL CELLS, 5-AZA-2'-DEOXYCYTIDINE TREATMENT LED TO PROMOTER DEMETHYLATION AND RE-EXPRESSION OF BM742401 TRANSCRIPT. FUNCTIONALLY, STABLE OVEREXPRESSION OF BM742401 RESULTED IN INHIBITION OF CELLULAR PROLIFERATION AND ENHANCED APOPTOSIS THROUGH CASPASE-9-DEPENDENT INTRINSIC BUT NOT CASPASE-8-DEPENDENT EXTRINSIC APOPTOSIS PATHWAY, SUGGESTING A TUMOR SUPPRESSOR ROLE OF BM742401 IN CLL. IN PRIMARY CLL SAMPLES, METHYLATION OF BM742401 WAS DETECTED IN 43/98 (43.9%) OF PATIENTS. MOREOVER, AMONG CLL PATIENTS WITH STANDARD-RISK CYTOGENETIC ABERRATIONS, METHYLATION OF BM742401 CORRELATED WITH ADVANCED RAI STAGE (>/= STAGE 2)(P = 0.002). FURTHERMORE, BM742401 METHYLATION WAS ASSOCIATED WITH MIR-129-2 METHYLATION (P = 0.05). BM742401 IS A TUMOR SUPPRESSOR LNCRNA FREQUENTLY METHYLATED IN CLL. THE MECHANISM OF BM742401 AS A TUMOR SUPPRESSOR WARRANTS FURTHER STUDIES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
12  2126 49 EPIGENETIC INACTIVATION OF MIR-34B/C IN ADDITION TO MIR-34A AND DAPK1 IN CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: TP53 MUTATION/DELETION IS UNCOMMON IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). WE POSTULATED THAT COMPONENTS OF TP53-CENTERED TUMOR SUPPRESSOR NETWORK, MIR-34B/C, IN ADDITION TO DAPK1 AND MIR-34A MIGHT BE INACTIVATED BY DNA HYPERMETHYLATION. MOREOVER, WE TESTED IF MIR-34B/C METHYLATION MIGHT CORRELATE WITH MIR-203 OR MIR-124-1 METHYLATION IN CLL. METHODS: MIR-34B/C, MIR-34A AND DAPK1 METHYLATION WAS STUDIED IN 11 NORMAL CONTROLS, 7 CLL CELL LINES, AND 78 DIAGNOSTIC CLL SAMPLES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. MEC-1 CELLS WERE TREATED WITH 5-AZA-2'-DEOXYCYTIDINE FOR REVERSAL OF METHYLATION-ASSOCIATED MIRNA SILENCING. TUMOR SUPPRESSOR PROPERTIES OF MIR-34B WERE DEMONSTRATED BY OVER-EXPRESSION OF PRECURSOR MIR-34B IN MEC-1 CELLS. RESULTS: MIR-34B/C PROMOTER WAS UNMETHYLATED IN NORMAL CONTROLS, BUT COMPLETELY METHYLATED IN 4 CLL CELL LINES. MIR-34B/C EXPRESSION WAS INVERSELY CORRELATED WITH MIR-34B/C METHYLATION. DIFFERENT MSP STATUSES OF MIR-34B/C, INCLUDING COMPLETE METHYLATION AND COMPLETE UNMETHYLATION, WERE VERIFIED BY QUANTITATIVE BISULFITE PYROSEQUENCING. 5-AZA-2'-DEOXYCYTIDINE TREATMENT RESULTED IN PROMOTER DEMETHYLATION AND MIR-34B RE-EXPRESSION IN MEC1 CELLS. MOREOVER, OVER-EXPRESSION OF MIR-34B RESULTED IN INHIBITION OF CELLULAR PROLIFERATION AND INCREASED CELL DEATH. IN PRIMARY CLL SAMPLES, MIR-34A, MIR-34B/C AND DAPK1 METHYLATION WAS DETECTED IN 2.6%, 17.9% AND 34.6% OF PATIENTS AT DIAGNOSIS RESPECTIVELY. FURTHERMORE, 39.7%, 3.8% AND 2.6% PATIENTS HAD METHYLATION OF ONE, TWO OR ALL THREE GENES RESPECTIVELY. OVERALL, 46.2% PATIENTS HAD METHYLATION OF AT LEAST ONE OF THESE THREE GENES. BESIDES, MIR-34B/C METHYLATION WAS ASSOCIATED WITH METHYLATION OF MIR-34A (P = 0.03) AND MIR-203 (P = 0.012) IN CLL. CONCLUSIONS: TAKEN TOGETHER, MIR-34B/C IS A TUMOR SUPPRESSOR MIRNA FREQUENTLY METHYLATED, AND HENCE SILENCED IN CLL. TOGETHER WITH DAPK1 METHYLATION, MIR-34B/C METHYLATION IS IMPLICATED IN THE DISRUPTION OF THE TP53-CENTERED TUMOR SUPPRESSOR NETWORK. MOREOVER, THE ASSOCIATION OF MIRNA METHYLATION WARRANTS FURTHER STUDY.	2014	

13  1211 28 CPG ISLAND METHYLATION AND EXPRESSION OF THE SECRETED FRIZZLED-RELATED PROTEIN GENE FAMILY IN CHRONIC LYMPHOCYTIC LEUKEMIA. B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY A CLONAL ACCUMULATION OF MATURE NEOPLASTIC B CELLS INDICATING DISRUPTION OF APOPTOSIS. RESTRICTION LANDMARK GENOME SCANNING WAS DONE TO IDENTIFY NOVEL TARGET GENES SILENCED BY CPG ISLAND METHYLATION IN CLL. SECRETED FRIZZLED-RELATED PROTEIN 4 (SFRP4), A NEGATIVE REGULATOR OF THE WNT SIGNALING PATHWAY, WAS FOUND TO BE FREQUENTLY METHYLATED IN CLL SAMPLES. WNT SIGNALING HAS BEEN SHOWN TO CONTROL NORMAL APOPTOTIC BEHAVIOR AND IS REQUIRED FOR NORMAL B-CELL DEVELOPMENT WHEREAS ABERRANT ACTIVATION OF THIS PATHWAY HAS BEEN OBSERVED IN CLL. WE SHOW ABERRANT DNA METHYLATION AND SILENCING OF SFRP4, AS WELL AS OF ADDITIONAL SFRP FAMILY MEMBERS, IN PRIMARY CLL SAMPLES. INDUCTION OF THEIR EXPRESSION IN A DOSE-DEPENDENT MANNER FOLLOWING TREATMENT WITH A DEMETHYLATING AGENT, 5-AZA-2'-DEOXYCYTIDINE, WAS SHOWN. OF THE FIVE SFRP FAMILY MEMBERS STUDIED IN DETAIL, SFRP1 WAS HYPERMETHYLATED AND DOWN-REGULATED IN ALL CLL PATIENT SAMPLES STUDIED, SUGGESTING THAT THIS EPIGENETIC EVENT IS A CRITICAL STEP DURING LEUKEMOGENESIS. OUR RESULTS SUGGEST THAT SILENCING OF SFRPS BY CPG ISLAND METHYLATION IS ONE POSSIBLE MECHANISM CONTRIBUTING TO ABERRANT ACTIVATION OF WNT SIGNALING PATHWAY IN CLL.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14  1662 21 DOWNREGULATION OF DEATH-ASSOCIATED PROTEIN KINASE 1 (DAPK1) IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE HERITABILITY OF B CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS RELATIVELY HIGH; HOWEVER, NO PREDISPOSING MUTATION HAS BEEN CONVINCINGLY IDENTIFIED. WE SHOW THAT LOSS OR REDUCED EXPRESSION OF DEATH-ASSOCIATED PROTEIN KINASE 1 (DAPK1) UNDERLIES CASES OF HERITABLE PREDISPOSITION TO CLL AND THE MAJORITY OF SPORADIC CLL. EPIGENETIC SILENCING OF DAPK1 BY PROMOTER METHYLATION OCCURS IN ALMOST ALL SPORADIC CLL CASES. FURTHERMORE, WE DEFINED A DISEASE HAPLOTYPE, WHICH SEGREGATES WITH THE CLL PHENOTYPE IN A LARGE FAMILY. DAPK1 EXPRESSION OF THE CLL ALLELE IS DOWNREGULATED BY 75% IN GERMLINE CELLS DUE TO INCREASED HOXB7 BINDING. IN THE BLOOD CELLS FROM AFFECTED FAMILY MEMBERS, PROMOTER METHYLATION RESULTS IN ADDITIONAL LOSS OF DAPK1 EXPRESSION. THUS, REDUCED EXPRESSION OF DAPK1 CAN RESULT FROM GERMLINE PREDISPOSITION, AS WELL AS EPIGENETIC OR SOMATIC EVENTS CAUSING OR CONTRIBUTING TO THE CLL PHENOTYPE.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
15  2438 29 EPIGENETIC SILENCING OF THE CIRCADIAN CLOCK GENE CRY1 IS ASSOCIATED WITH AN INDOLENT CLINICAL COURSE IN CHRONIC LYMPHOCYTIC LEUKEMIA. DISRUPTION OF CIRCADIAN RHYTHM IS BELIEVED TO PLAY A CRITICAL ROLE IN CANCER DEVELOPMENT. CRYPTOCHROME 1 (CRY1) IS A CORE COMPONENT OF THE MAMMALIAN CIRCADIAN CLOCK AND WE HAVE PREVIOUSLY SHOWN ITS DEREGULATED EXPRESSION IN A SUBGROUP OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). USING REAL-TIME RT-PCR IN A COHORT OF 76 CLL PATIENTS AND 35 NORMAL BLOOD DONORS WE NOW DEMONSTRATE THAT DIFFERENTIAL CRY1 MRNA EXPRESSION IN HIGH-RISK (HR) CD38+/IMMUNOGLOBULIN VARIABLE HEAVY CHAIN GENE (IGVH) UNMUTATED PATIENTS AS COMPARED TO LOW-RISK (LR) CD38-/IGVH MUTATED PATIENTS CAN BE ATTRIBUTED TO DOWN-MODULATION OF CRY1 IN LR CLL CASES. ANALYSIS OF THE DNA METHYLATION PROFILE OF THE CRY1 PROMOTER IN A SUBGROUP OF 57 PATIENTS REVEALED THAT CRY1 EXPRESSION IN LR CLL CELLS IS SILENCED BY ABERRANT PROMOTER CPG ISLAND HYPERMETHYLATION. THE METHYLATION PATTERN OF THE CRY1 PROMOTER PROVED TO HAVE HIGH PROGNOSTIC IMPACT IN CLL WHERE ABERRANT PROMOTER METHYLATION PREDICTED A FAVOURABLE OUTCOME. CRY1 MRNA TRANSCRIPT LEVELS DID NOT CHANGE OVER TIME IN THE MAJORITY OF PATIENTS WHERE SEQUENTIAL SAMPLES WERE AVAILABLE FOR ANALYSIS. WE ALSO COMPARED THE CRY1 EXPRESSION IN CLL WITH OTHER LYMPHOID MALIGNANCIES AND OBSERVED EPIGENETIC SILENCING OF CRY1 IN A PATIENT WITH B CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL).	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  1093 20 COHESIN RAD21 GENE PROMOTER METHYLATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON TYPE OF LEUKEMIA IN ADULTS AND IS CHARACTERIZED BY THE PRESENCE OF SPECIFIC CYTOGENETIC ABNORMALITIES. CLL RESEARCH HAS BEEN FOCUSED ON EPIGENETIC PROCESSES LIKE GENE PROMOTER METHYLATION OF CPG ISLANDS. IN THE PRESENT STUDY, THE METHYLATION STATUS OF THE RAD21 GENE IS STUDIED AND ASSOCIATED WITH CYTOGENETIC FINDINGS IN CLL PATIENTS IN ORDER TO INVESTIGATE ITS POSSIBLE IMPLICATION IN CLL PATHOGENESIS AND THE FORMATION OF CLL CHROMOSOMAL ABNORMALITIES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17   494 25 ASSESSMENT OF PROMOTER METHYLATION IDENTIFIES PTCH AS A PUTATIVE TUMOR-SUPPRESSOR GENE IN HUMAN CLL. BACKGROUND: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY A CLONAL ACCUMULATION OF NEOPLASTIC LYMPHOCYTES, INDICATING DISRUPTION OF APOPTOSIS. PATIENTS AND METHODS: DIFFERENTIAL METHYLATION HYBRIDIZATION ANALYSIS WAS PERFORMED TO IDENTIFY NOVEL TARGET GENES SILENCED BY CPG ISLAND METHYLATION IN PATIENTS WITH CLL. RESULTS: PATCHED (PTCH), A TUMOR-SUPPRESSOR GENE, WAS FOUND TO BE FREQUENTLY METHYLATED IN CLL SAMPLES COMPARED TO SAMPLES DERIVED FROM HEALTHY INDIVIDUALS. DE NOVO METHYLATION OF A CPG ISLAND REGION LOCATED UPSTREAM OF PTCH EXON 1 WAS CONFIRMED BY PYROSEQUENCING IN 17/37 (46%) OF PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH CLL, BUT IN NONE ISOLATED FROM SEVEN HEALTHY INDIVIDUALS. NO ASSOCIATION WAS FOUND BETWEEN PTCH HYPERMETHYLATION AND CURRENTLY USED PROGNOSTIC CLL FACTORS. CONCLUSION: OUR INVESTIGATION SUGGESTS THAT EPIGENETIC SILENCING OF PTCH IS A MECHANISM CONTRIBUTING TO CLL TUMORIGENESIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  2090 31 EPIGENETIC DYSREGULATION OF THE WNT SIGNALLING PATHWAY IN CHRONIC LYMPHOCYTIC LEUKAEMIA. BACKGROUND: WNT SIGNALLING HAS RECENTLY BEEN IMPLICATED IN THE PATHOGENESIS OF CANCER. METHODS: THIS STUDY INVESTIGATED THE ACTIVITY OF WNT SIGNALLING IN PERIPHERAL BLOOD CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) LYMPHOCYTES, AND THE METHYLATION STATUS OF SEVEN SOLUBLE WNT ANTAGONIST GENES, INCLUDING WIF1, DKK3, APC, SFRP1, SFRP2, SFRP4 AND SFRP5, BY USING METHYLATION-SPECIFIC PCR IN THE PERIPHERAL BLOOD CLL LYMPHOCYTES AND BONE MARROW SAMPLES OF PATIENTS WITH CLL AT DIAGNOSIS. RESULTS: IN THE PERIPHERAL BLOOD CLL LYMPHOCYTES, CONSTITUTIVE ACTIVATION OF WNT SIGNALLING WAS DETECTED, ASSOCIATED WITH HYPERMETHYLATION OF THE SOLUBLE WNT INHIBITOR GENES. IN THE DIAGNOSTIC CLL MARROW SAMPLES, METHYLATION OF THE SEVEN GENES WAS DETECTED IN UP TO 36.4% OF SAMPLES. MOREOVER, 23 (52.3%) PATIENTS HAD METHYLATION OF AT LEAST ONE OF THE SEVEN GENES, OF WHOM 14 (60.8%) HAD METHYLATION OF TWO OR MORE WNT INHIBITOR GENES. APART FROM AN ASSOCIATION OF ADVANCED AGE WITH DKK3 METHYLATION, THERE WAS NO ASSOCIATION OF GENE HYPERMETHYLATION WITH EITHER CLINICAL CHARACTERISTICS (INCLUDING AGE, GENDER, LYMPHOCYTE COUNT AT DIAGNOSIS, RAI STAGE AND POOR-RISK KARYOTYPE) OR SURVIVAL. CONCLUSION: WNT SIGNALLING IS CONSTITUTIVELY ACTIVATED IN CLL B LYMPHOCYTES IN ASSOCIATION WITH METHYLATION OF MULTIPLE SOLUBLE WNT ANTAGONIST GENES. METHYLATION OF THESE SOLUBLE WNT ANTAGONIST GENES, OCCASIONALLY MULTIPLE GENES, IN PRIMARY CLL MARROW SAMPLES SUGGESTS AN IMPORTANT ROLE IN CLL PATHOGENESIS. MOREOVER, THIS STUDY UNDERSCORED THE IMPORTANCE OF STUDYING METHYLATION OF A PANEL OF, BUT NOT INDIVIDUAL, GENES REGULATING A CELLULAR PATHWAY.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19    27 21 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20   941 21 CHRONIC LYMPHOCYTIC LEUKEMIA B-CELL NORMAL CELLULAR COUNTERPART: CLUES FROM A FUNCTIONAL PERSPECTIVE. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY THE CLONAL EXPANSION OF SMALL MATURE-LOOKING CD19+ CD23+ CD5+ B-CELLS THAT ACCUMULATE IN THE BLOOD, BONE MARROW, AND LYMPHOID ORGANS. TO DATE, NO CONSENSUS HAS BEEN REACHED CONCERNING THE NORMAL CELLULAR COUNTERPART OF CLL B-CELLS AND SEVERAL B-CELL TYPES HAVE BEEN PROPOSED. CLL B-CELLS HAVE REMARKABLE PHENOTYPIC AND GENE EXPRESSION PROFILE HOMOGENEITY. IN RECENT YEARS, THE MOLECULAR AND CELLULAR BIOLOGY OF CLL HAS BEEN ENRICHED BY SEMINAL INSIGHTS THAT ARE LEADING TO A BETTER UNDERSTANDING OF THE NATURAL HISTORY OF THE DISEASE. IMMUNOPHENOTYPIC AND MOLECULAR APPROACHES (INCLUDING IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE GENE MUTATIONAL STATUS, TRANSCRIPTIONAL AND EPIGENETIC PROFILING) COMPARING THE NORMAL B-CELL SUBSET AND CLL B-CELLS PROVIDE SOME NEW INSIGHTS INTO THE NORMAL CELLULAR COUNTERPART. FUNCTIONAL CHARACTERISTICS (INCLUDING ACTIVATION REQUIREMENTS AND PROPENSITY FOR PLASMA CELL DIFFERENTIATION) OF CLL B-CELLS HAVE NOW BEEN INVESTIGATED FOR 50 YEARS. B-CELL SUBSETS DIFFER SUBSTANTIALLY IN TERMS OF THEIR FUNCTIONAL FEATURES. ANALYSIS OF SHARED FUNCTIONAL CHARACTERISTICS MAY REVEAL SIMILARITIES BETWEEN NORMAL B-CELL SUBSETS AND CLL B-CELLS, ALLOWING SPECULATIVE ASSIGNMENT OF A NORMAL CELLULAR COUNTERPART FOR CLL B-CELLS. IN THIS REVIEW, WE SUMMARIZE CURRENT DATA REGARDING PERIPHERAL B-CELL DIFFERENTIATION AND HUMAN B-CELL SUBSETS AND SUGGEST POSSIBILITIES FOR A NORMAL CELLULAR COUNTERPART BASED ON THE FUNCTIONAL CHARACTERISTICS OF CLL B-CELLS. HOWEVER, A DEFINITIVE NORMAL CELLULAR COUNTERPART CANNOT BE ATTRIBUTED ON THE BASIS OF THE AVAILABLE DATA. WE DISCUSS THE FUNCTIONAL CHARACTERISTICS REQUIRED FOR A CELL TO BE LOGICALLY CONSIDERED TO BE THE NORMAL COUNTERPART OF CLL B-CELLS.	2018