1 2129 109 EPIGENETIC INACTIVATION OF SUPPRESSORS OF CYTOKINE SIGNALLING IN PHILADELPHIA-NEGATIVE CHRONIC MYELOPROLIFERATIVE DISORDERS. PH-NEGATIVE CHRONIC MYELOPROLIFERATIVE DISORDERS (CMPD) ARE CHARACTERIZED BY CONSTITUTIVE JANUS KINASE-SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (JAK-STAT) ACTIVATION. SOCS3, SOCS1 AND PTPN6 (SHP1) ARE NEGATIVE REGULATORS OF THE JAK-STAT PATHWAY. WE INVESTIGATED EPIGENETIC AND GENETIC INACTIVATION OF SOCS3, SOCS1 AND PTPN6 IN 112 CMPD AND 20 ACUTE MYELOID LEUKAEMIA (AML) POST-CMPD. SOCS3 METHYLATION OCCURRED AT HIGH FREQUENCY IN BOTH CMPD (46/112; 41.1%) AND AML POST-CMPD (10/17; 58.8%) AND WAS ASSOCIATED WITH TRANSCRIPTIONAL SILENCING. IN CONTRAST, METHYLATION OF SOCS1 AND PTPN6 WAS OBSERVED IN ONLY A FRACTION OF CMPD (15/112, 13.4% FOR SOCS1; AND 8/112, 7.1% FOR PTPN6) AND AML POST-CMPD (3/20, 15% FOR SOCS1; AND 1/20, 5% FOR PTPN6). NO SOMATIC MUTATIONS OF SOCS1 WERE FOUND IN CMPD. SOCS3, SOCS1 AND PTPN6 METHYLATION OCCURRED IN BOTH JAK2V617F-POSITIVE (35.1% FOR SOCS3; 14.9% FOR SOCS1; 8.1% FOR PTPN6) AND JAK2V617F-NEGATIVE (57.1% FOR SOCS3; 14.3% FOR SOCS1; AND 9.5% FOR PTPN6) CMPD. THESE DATA INDICATE THAT METHYLATION OF SOCS3 AND, TO A LESSER EXTENT, SOCS1 AND PTPN6 IS A FREQUENT EVENT IN BOTH JAK2V617F-POSITIVE AND -NEGATIVE CMPD AND MAY ACT AS AN ALTERNATIVE OR COMPLEMENTARY MECHANISM TO JAK2 MUTATIONS, ENHANCING CYTOKINE SIGNAL TRANSDUCTION. THE FREQUENT INACTIVATION OF SOCS3 IS A NOVEL FINDING IN CMPD WITH POTENTIAL IMPLICATIONS FOR THE MOLECULAR PATHOLOGY OF THESE DISORDERS.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
2 2088  42 EPIGENETIC DYSREGULATION OF SECRETED FRIZZLED-RELATED PROTEINS IN MYELOPROLIFERATIVE NEOPLASMS COMPLEMENTS THE JAK2V617F-MUTATION. BACKGROUND: SECRETED FRIZZLED-RELATED PROTEINS (SFRPS) ARE ANTAGONISTS OF THE WNT SIGNALING PATHWAY, WHICH PLAYS A CENTRAL ROLE IN STEM CELL MAINTENANCE AND DIFFERENTIATION OF STEM CELLS AND HEMATOPOIETIC PROGENITORS. EPIGENETIC DOWNREGULATION OF SFRPS BY PROMOTER HYPERMETHYLATION HAS BEEN DESCRIBED TO BE INVOLVED IN THE PATHOGENESIS OF HEMATOPOIETIC MALIGNANCIES. THERE IS AN ASSOCIATION BETWEEN ABERRANT WNT SIGNALING AND THE ESTABLISHED CANCER STEM CELL CONCEPT. IN CONTRAST TO BCR-ABL1-POSITIVE CHRONIC MYELOID LEUKEMIA CML, BCR-ABL1-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS (PH-MPN) ARE CHARACTERIZED BY THE FREQUENT OCCURRENCE OF AN AUTOACTIVATING MUTATION IN THE JAK2 TYROSINE KINASE (JAK2V617F) OR OTHER MUTATIONS IN THE JAK-STAT PATHWAY. HOWEVER, PATHOGENETIC MECHANISMS OF JAK2 MUTATED OR UNMUTATED PH-MPN REMAIN NOT COMPLETELY UNDERSTOOD. WE DETERMINED THE PROMOTER METHYLATION STATUS OF SFRP-1, -2, -4, AND -5 IN 57 MPN PATIENT SAMPLES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) (MSP). JAK2V617F WAS ASSESSED BY ALLELE-SPECIFIC PCR. RESULTS: ABERRANT METHYLATION AMONG PRIMARY MPN SAMPLES WAS 4% FOR SFRP-1, 25% FOR SFRP-2, 2% FOR SFRP-4, AND 0% FOR SFRP-5. HYPERMETHYLATION OF SFRP-2, WHICH WAS THE MOST FREQUENTLY HYPERMETHYLATED GENE IN OUR STUDY, COULD NOT BE CORRELATED TO ANY SPECIFIC MPN SUBTYPE. HOWEVER, WE DETECTED A SIGNIFICANT CORRELATION BETWEEN SFRP-2 METHYLATION AND PRESENCE OF A JAK2V617F MUTATION (P = 0.008). NONE OF THE 10 CML SAMPLES SHOWED ANY SFRP-METHYLATION. CONCLUSIONS: OUR DATA INDICATE THAT EPIGENETIC DYSREGULATION OF THE WNT SIGNALING PATHWAY IS A COMMON EVENT IN MPN WITH ABERRANT METHYLATION OF AT LEAST ONE SFRP BEING DETECTED IN 25% OF THE PRIMARY PATIENT SAMPLES AND IN 30% IF ONLY ACCOUNTING FOR PH-MPN. A SIGNIFICANT CORRELATION BETWEEN SFRP-2 METHYLATION AND PRESENCE OF JAK2V617F IN OUR DATA SUPPORTS THE HYPOTHESIS THAT EPIGENETIC DYSREGULATION MAY BE A COMPLEMENTARY MECHANISM TO GENETIC ABERRATIONS. ABERRANT METHYLATION OF CRUCIAL STEM CELL MAINTENANCE GENES SEEMS TO CONTRIBUTE TO DISEASE PATHOGENESIS IN PH-MPN.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
3 1629  21 DNMT3A ARG882 MUTATION DRIVES CHRONIC MYELOMONOCYTIC LEUKEMIA THROUGH DISTURBING GENE EXPRESSION/DNA METHYLATION IN HEMATOPOIETIC CELLS. THE GENE ENCODING DNA METHYLTRANSFERASE 3A (DNMT3A) IS MUTATED IN APPROXIMATELY 20% OF ACUTE MYELOID LEUKEMIA CASES, WITH ARG882 (R882) AS THE HOTSPOT. HERE, WE ADDRESSED THE TRANSFORMATION ABILITY OF THE DNMT3A-ARG882HIS (R882H) MUTANT BY USING A RETROVIRAL TRANSDUCTION AND BONE MARROW TRANSPLANTATION (BMT) APPROACH AND FOUND THAT THE MUTANT GENE CAN INDUCE ABERRANT PROLIFERATION OF HEMATOPOIETIC STEM/PROGENITOR CELLS. AT 12 MO POST-BMT, ALL MICE DEVELOPED CHRONIC MYELOMONOCYTIC LEUKEMIA WITH THROMBOCYTOSIS. RNA MICROARRAY ANALYSIS REVEALED ABNORMAL EXPRESSIONS OF SOME HEMATOPOIESIS-RELATED GENES, AND THE DNA METHYLATION ASSAY IDENTIFIED CORRESPONDING CHANGES IN METHYLATION PATTERNS IN GENE BODY REGIONS. MOREOVER, DNMT3A-R882H INCREASED THE CDK1 PROTEIN LEVEL AND ENHANCED CELL-CYCLE ACTIVITY, THEREBY CONTRIBUTING TO LEUKEMOGENESIS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4 3168  32 GTPASE REGULATOR ASSOCIATED WITH THE FOCAL ADHESION KINASE (GRAF) TRANSCRIPT WAS DOWN-REGULATED IN PATIENTS WITH MYELOID MALIGNANCIES. BACKGROUND: GTPASE REGULATOR ASSOCIATED WITH THE FOCAL ADHESION KINASE (GRAF), A PUTATIVE TUMOR SUPPRESSOR GENE, IS FOUND INACTIVATED IN HEMATOPOIETIC MALIGNANCIES BY EITHER GENETIC OR EPIGENETIC ABNORMALITIES. HOWEVER, THE EXPRESSION LEVEL OF GRAF GENE HAS NOT YET BEEN STUDIED IN LEUKEMIA. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EXPRESSION LEVEL OF GRAF GENE IN THOSE PATIENTS WITH MYELOID MALIGNANCIES INCLUDING ACUTE MYELOID LEUKEMIA (AML), MYELODYSPLASTIC SYNDROME (MDS) AND CHRONIC MYELOID LEUKEMIA (CML). METHODS: THE EXPRESSION LEVELS OF GRAF TRANSCRIPT WERE DETERMINED IN 94 PATIENTS USING REAL-TIME QUANTITATIVE PCR (RQ-PCR). CLINICAL AND LABORATORY DATA OF THESE PATIENTS WERE COLLECTED AND ANALYZED. RESULTS: THE SIGNIFICANTLY DECREASED LEVEL OF GRAF TRANSCRIPT WAS OBSERVED IN THREE MYELOID MALIGNANCIES COMPARED TO CONTROLS. WITHIN AML, THERE WAS NO DIFFERENCE IN THE LEVEL OF GRAF TRANSCRIPT AMONG DIFFERENT FAB SUBTYPES (P > 0.05). DIFFERENCE WAS NOT OBSERVED IN THE AMOUNT OF GRAF MRNA BETWEEN CML AT CHRONIC PHASE AND CONTROLS. AS CML PROGRESSED, GRAF TRANSCRIPT SIGNIFICANTLY DECREASED. IN MDS, THREE CASES WITH 5Q DELETION HAD LOWER GRAF TRANSCRIPT THAN FOUR WITHOUT 5Q DELETION (MEDIAN 0.76 VS 2.99) (P > 0.05). CONCLUSION: OUR RESULTS DEMONSTRATE THAT THE GRAF TRANSCRIPT IS DECREASED IN MYELOID MALIGNANCIES.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
5 2128  27 EPIGENETIC INACTIVATION OF PLCD1 IN CHRONIC MYELOID LEUKEMIA. PHOSPHOLIPASE C DELTA1 (PLCD1), IS LOCATED AT THE IMPORTANT TUMOR SUPPRESSOR LOCUS 3P22. IT ENCODES AN ENZYME THAT MEDIATES REGULATORY SIGNALING OF ENERGY METABOLISM, CALCIUM HOMEOSTASIS AND INTRACELLULAR MOVEMENTS. PLCD1 HAS BEEN STUDIED IN SOME HUMAN SOLID TUMORS RELATING TO THE CPG ISLAND METHYLATION OF THE GENE PROMOTER AS A FUNCTIONAL TUMOR SUPPRESSOR. HOWEVER, NO SUCH INFORMATION IS AVAILABLE IN CHRONIC MYELOID LEUKEMIA (CML). IN THIS STUDY, WE INVESTIGATED PLCD1 EXPRESSION IN THE CML K562 CELL LINE (0/1) AND 15% (2/13) OF BONE MARROW MONONUCLEAR CELLS WITH CML BY USING SEMI-QUANTITATIVE PCR. THE CPG ISLAND (CGI) METHYLATION STATUS OF THE PLCD1 PROMOTER WAS DETECTED IN K562 (0/1) AND 56% (23/41) OF CML PATIENTS BY METHYLATION-SPECIFIC PCR (MSP), BUT NOT IN THE NORMAL ADULT BONE MARROW MONONUCLEAR CELLS. FURTHERMORE, THE DNA DEMETHYLATION AGENT 5'-AZA-2'DEOXYCYTIDINE RESTORED THE EXPRESSION OF PLCD1 IN K562 CELLS. FUNCTIONAL STUDIES SHOWED THAT ECTOPIC EXPRESSION OF PLCD1 IN K562 CELLS WAS ABLE TO DRAMATICALLY INHIBIT THEIR COLONY FORMATION AND INDUCE CELL CYCLE G1 ARREST, SUGGESTING THAT PLCD1 ACTS AS A FUNCTIONAL TUMOR SUPPRESSOR AND MAY SERVE AS A BIOMARKER FOR POSSIBLE EARLY DETECTION AND PROGNOSIS OF CML.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6 2888  33 GAIN-OF-FUNCTION MUTATION OF GATA-2 IN ACUTE MYELOID TRANSFORMATION OF CHRONIC MYELOID LEUKEMIA. ACQUISITION OF ADDITIONAL GENETIC AND/OR EPIGENETIC ABNORMALITIES OTHER THAN THE BCR/ABL FUSION GENE IS BELIEVED TO CAUSE DISEASE PROGRESSION IN CHRONIC MYELOID LEUKEMIA (CML) FROM CHRONIC PHASE TO BLAST CRISIS (BC). TO GAIN INSIGHTS INTO THE UNDERLYING MECHANISMS OF PROGRESSION TO BC, WE SCREENED DNA SAMPLES FROM CML PATIENTS DURING BLAST TRANSFORMATION FOR MUTATIONS IN A NUMBER OF TRANSCRIPTION FACTOR GENES THAT ARE CRITICAL FOR MYELOID-LYMPHOID DEVELOPMENT. IN 85 CASES OF CML BLAST TRANSFORMATION, WE IDENTIFIED TWO NEW MUTATIONS IN THE CODING REGION OF GATA-2, A NEGATIVE REGULATOR OF HEMATOPOIETIC STEM/PROGENITOR CELL DIFFERENTIATION. A L359V SUBSTITUTION WITHIN ZINC FINGER DOMAIN (ZF) 2 OF GATA-2 WAS FOUND IN EIGHT CASES WITH MYELOMONOBLASTIC FEATURES, WHEREAS AN IN-FRAME DELETION OF 6 AA (DELTA341-346) SPANNING THE C-TERMINAL BORDER OF ZF1 WAS DETECTED IN ONE PATIENT AT MYELOID BC WITH EOSINOPHILIA. FURTHER STUDIES INDICATED THAT L359V NOT ONLY INCREASED TRANSACTIVATION ACTIVITY OF GATA-2 BUT ALSO ENHANCED ITS INHIBITORY EFFECTS ON THE ACTIVITY OF PU.1, A MAJOR REGULATOR OF MYELOPOIESIS. CONSISTENT WITH THE MYELOMONOBLASTIC FEATURES OF CML TRANSFORMATION WITH THE GATA-2 L359V MUTANT, TRANSDUCTION OF THE GATA-2 L359V MUTANT INTO HL-60 CELLS OR BCR/ABL-HARBORING MURINE CELLS DISTURBED MYELOMONOCYTIC DIFFERENTIATION/PROLIFERATION IN VITRO AND IN VIVO, RESPECTIVELY. THESE DATA STRONGLY SUGGEST THAT GATA-2 MUTATIONS MAY PLAY A ROLE IN ACUTE MYELOID TRANSFORMATION IN A SUBSET OF CML PATIENTS.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7 2327  27 EPIGENETIC REGULATION OF HUMAN CANCER/TESTIS ANTIGEN GENE, HAGE, IN CHRONIC MYELOID LEUKEMIA. BACKGROUND AND OBJECTIVES: CANCER TESTIS ANTIGENS (CTA) PROVIDE ATTRACTIVE TARGETS FOR CANCER-SPECIFIC IMMUNOTHERAPY. ALTHOUGH CTA GENES ARE EXPRESSED IN SOME NORMAL TISSUES, SUCH AS THE TESTIS, THIS IMMUNOLOGICALLY PROTECTED SITE LACKS MHC I EXPRESSION AND AS SUCH, DOES NOT PRESENT SELF ANTIGENS TO T CELLS. TO DATE, CTA GENES HAVE BEEN SHOWN TO BE EXPRESSED IN A RANGE OF SOLID TUMORS VIA DEMETHYLATION OF THEIR PROMOTER CPG ISLANDS, BUT RARELY IN CHRONIC MYELOID LEUKEMIA (CML) OR OTHER HEMATOLOGIC MALIGNANCIES. DESIGN AND METHODS: IN THIS STUDY, THE METHYLATION STATUS OF THE HAGE CTA GENE PROMOTER WAS ANALYZED BY QUANTITATIVE METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) AND SEQUENCING IN FOUR PHILADELPHIA-POSITIVE CELL LINES (TCC-S, K562, KU812 AND KYO-1) AND IN CML SAMPLES TAKEN FROM PATIENTS IN CHRONIC PHASE (CP N=215) OR BLAST CRISIS (BC N=47). HAGE EXPRESSION WAS ASSESSED BY QUANTITATIVE REVERSE TRANSCRIPTASE-POLYMERASE CHAIN REACTION. RESULTS: THE TCC-S CELL LINE SHOWED DEMETHYLATION OF HAGE THAT WAS ASSOCIATED WITH OVER-EXPRESSION OF THIS GENE. HAGE HYPOMETHYLATION WAS SIGNIFICANTLY MORE FREQUENT IN BC (46%) THAN IN CP (22%) (P=0.01) AND WAS CORRELATED WITH HIGH EXPRESSION LEVELS OF HAGE TRANSCRIPTS (P<0.0001). OF NOTE, IN CP-CML, EXTENSIVE HAGE HYPOMETHYLATION WAS ASSOCIATED WITH POORER PROGNOSIS IN TERMS OF CYTOGENETIC RESPONSE TO INTERFERON (P=0.01) OR IMATINIB (P=0.01), MOLECULAR RESPONSE TO IMATINIB (P=0.003) AND PROGRESSION-FREE SURVIVAL (P=0.05). INTERPRETATIONS AND CONCLUSION: THE METHYLATION STATUS OF THE HAGE PROMOTER DIRECTLY CORRELATES WITH ITS EXPRESSION IN BOTH CML CELL LINES AND PATIENTS AND IS ASSOCIATED WITH ADVANCED DISEASE AND POOR OUTCOME.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8 4388  33 MLL2/KMT2D AND MLL3/KMT2C EXPRESSION CORRELATES WITH DISEASE PROGRESSION AND RESPONSE TO IMATINIB MESYLATE IN CHRONIC MYELOID LEUKEMIA. BACKGROUND: CHRONIC MYELOID LEUKEMIA (CML) IS A CLONAL MYELOPROLIFERATIVE NEOPLASM WHOSE PATHOGENESIS IS LINKED TO THE PHILADELPHIA CHROMOSOME PRESENCE THAT GENERATES THE BCR-ABL1 FUSION ONCOGENE. TYROSINE KINASE INHIBITORS (TKI) SUCH AS IMATINIB MESYLATE (IM) DRAMATICALLY IMPROVED THE TREATMENT EFFICIENCY AND SURVIVAL OF CML PATIENTS BY TARGETING BCR-ABL TYROSINE KINASE. THE DISEASE SHOWS THREE DISTINCT CLINICAL-LABORATORY STAGES: CHRONIC PHASE, ACCELERATED PHASE AND BLAST CRISIS. ALTHOUGH PATIENTS IN THE CHRONIC PHASE RESPOND WELL TO TREATMENT, PATIENTS IN THE ACCELERATED PHASE OR BLAST CRISIS USUALLY SHOW THERAPY RESISTANCE AND CML RELAPSE. IT IS CRUCIAL, THEREFORE, TO IDENTIFY BIOMARKERS TO PREDICT CML GENETIC EVOLUTION AND RESISTANCE TO TKI THERAPY, CONSIDERING NOT ONLY THE EFFECTS OF GENETIC ABERRATIONS BUT ALSO THE ROLE OF EPIGENETIC ALTERATIONS DURING THE DISEASE. ALTHOUGH DYSREGULATIONS IN EPIGENETIC MODULATORS SUCH AS HISTONE METHYLTRASNFERASES HAVE ALREADY BEEN DESCRIBED FOR SOME HEMATOLOGIC MALIGNANCIES, TO DATE VERY LIMITED DATA IS AVAILABLE FOR CML, ESPECIALLY WHEN CONSIDERING THE LYSINE METHYLTRANSFERASE MLL2/KMT2D AND MLL3/KMT2C. METHODS: HERE WE INVESTIGATED THE EXPRESSION PROFILE OF BOTH GENES IN CML PATIENTS IN DIFFERENT STAGES OF THE DISEASE, IN PATIENTS SHOWING DIFFERENT RESPONSES TO THERAPY WITH IM AND IN NON-NEOPLASTIC CONTROL SAMPLES. IMATINIB SENSITIVE AND RESISTANT CML CELL LINES WERE ALSO USED TO INVESTIGATE WHETHER TREATMENT WITH OTHER TYROSINE KINASE INHIBITORS INTERFERED IN THEIR EXPRESSION. RESULTS: IN PATIENTS, BOTH METHYLTRANSFERASES WERE EITHER UPREGULATED OR WITH BASAL EXPRESSION LEVEL DURING THE CHRONIC PHASE COMPARED TO CONTROLS. INTERESTINGLY, MLL3/KMT2C AND SPECIALLY MLL2/KMT2D LEVELS DECREASED DURING DISEASE PROGRESSION CORRELATING WITH DISTINCT CLINICAL STAGES. FURTHERMORE, MLL2/KMT2D WAS DECREASED IN PATIENTS RESISTANT TO IM TREATMENT. A RESCUE IN THE EXPRESSION OF BOTH MLL GENES WAS OBSERVED IN KCL22S, A CML CELL LINE SENSITIVE TO IM, AFTER TREATMENT WITH DASATINIB OR NILOTINIB WHICH WAS ASSOCIATED WITH A HIGHER RATE OF APOPTOSIS, AN ENHANCED EXPRESSION OF P21 (CDKN1A) AND A CONCOMITANT DECREASE IN THE EXPRESSION OF CDK2, CDK4 AND CYCLIN B1 (CCNB1) IN COMPARISON TO UNTREATED KCL22S CONTROL OR IM RESISTANT KCL22R CELL LINE, WHICH SUGGESTS INVOLVEMENT OF P53 REGULATED PATHWAY. CONCLUSION: OUR RESULTS ESTABLISHED A NEW ASSOCIATION BETWEEN MLL2/KMT2D AND MLL3/KMT2C GENES WITH CML AND SUGGEST THAT MLL2/KMT2D IS ASSOCIATED WITH DISEASE EVOLUTION AND MAY BE A POTENTIAL MARKER TO PREDICT THE DEVELOPMENT OF THERAPY RESISTANCE.	2018	

9 4221  26 METHYLATION AND SILENCING OF PROTEIN TYROSINE PHOSPHATASE RECEPTOR TYPE O IN CHRONIC LYMPHOCYTIC LEUKEMIA. PURPOSE: PREVIOUS STUDIES IN OUR LABORATORY HAVE SHOWN THE PROGRESSIVE METHYLATION AND SUPPRESSION OF THE GENE ENCODING PROTEIN TYROSINE PHOSPHATASE, PTPRO, IN THE LIVERS OF RATS FED A METHYL-DEFICIENT DIET THAT INDUCES HEPATOCARCINOGENESIS. SUBSEQUENTLY, WE OBSERVED THE METHYLATION OF PTPRO IN PRIMARY HUMAN LUNG TUMORS AND ALSO SHOWED ITS POTENTIAL TUMOR SUPPRESSOR CHARACTERISTICS. THE PRESENT STUDY WAS UNDERTAKEN TO INVESTIGATE WHETHER THE TRUNCATED FORM OF PTPRO (PTPROT), SPECIFICALLY EXPRESSED IN NAIVE B LYMPHOCYTES, WAS ALSO METHYLATED AND SUPPRESSED IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), A DISEASE GENERALLY AFFECTING B LYMPHOCYTES. EXPERIMENTAL DESIGN AND RESULTS: INITIAL SCREENING SHOWED THAT 60% OF THE 52 CLL SAMPLES ANALYZED USING METHYLATION-SPECIFIC PCR ASSAY WERE METHYLATED COMPARED WITH B LYMPHOCYTES FROM NORMAL INDIVIDUALS, WHICH WERE NOT METHYLATED. THE EXPRESSION OF PTPROT, AS MEASURED BY SEMIQUANTITATIVE REVERSE TRANSCRIPTION-PCR, INVERSELY CORRELATED WITH METHYLATION IN THE FEW SAMPLES TESTED. ANALYSIS OF ADDITIONAL SAMPLES (N = 50) BY COMBINED BISULFITE RESTRICTION ANALYSIS SHOWED THAT THE PTPRO CPG ISLAND WAS METHYLATED IN 82% OF PATIENTS WITH CLL COMPARED WITH B LYMPHOCYTES FROM NORMAL INDIVIDUALS. FURTHERMORE, OVERALL EXPRESSION OF PTPRO WAS REDUCED IN CLL RELATIVE TO NORMAL LYMPHOCYTES. THE PTPRO GENE WAS ALSO SUPPRESSED BY METHYLATION IN THE CLL CELL LINE WAC3CD5, WHERE IT COULD BE REACTIVATED UPON TREATMENT WITH THE DNA HYPOMETHYLATING AGENT 5-AZAC. ECTOPIC EXPRESSION OF PTPROT IN A NONEXPRESSING CELL LINE INCREASED GROWTH INHIBITION WITH FLUDARABINE TREATMENT, A THERAPY COMMONLY USED FOR CLL. CONCLUSION: THIS STUDY REVEALS THE POTENTIAL ROLE OF PTPRO METHYLATION AND SILENCING IN CLL TUMORIGENESIS AND ALSO PROVIDES A NOVEL MOLECULAR TARGET IN THE EPIGENETIC THERAPY.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
10 3352  27 HISTONE DEMETHYLASE RBP2 MEDIATES THE BLAST CRISIS OF CHRONIC MYELOID LEUKEMIA THROUGH AN RBP2/PTEN/BCR-ABL CASCADE. EPIGENETIC DISORDERS PLAY A KEY ROLE IN TUMORIGENESIS AND DEVELOPMENT, AMONG WHICH HISTONE METHYLATION ABNORMALITIES ARE COMMON. WHILE PATIENTS LIVING WITH CHRONIC MYELOID LEUKEMIA IN THE CHRONIC PHASE (CML-CP) HAVE A GOOD RESPONSE TO TKI, BLASTIC PHASE (CML-BP) PATIENTS DEMONSTRATE POOR EFFICACY AND HIGH FATALITY RATES. HOWEVER, WHILE THE MECHANISM OF BLAST CRISIS OF CHRONIC MYELOID LEUKEMIA REMAINS UNCLEAR, HIGH EXPRESSION AND ACTIVATION OF BCR-ABL ARE USUALLY RELATED TO CML BLAST CRISIS TRANSITION. WE FOUND THAT HISTONE H3 LYSINE 4 (H3K4) DEMETHYLASE RBP2 EXPRESSION IS NEGATIVELY CORRELATED WITH BCR-ABL EXPRESSION, WHICH SUGGESTS A REGULATORY LINK BETWEEN THESE TWO GENES. WE ALSO DISCOVERED THAT RBP2 MEDIATES THE DEPHOSPHORYLATION OF BCR-ABL BY DIRECTLY DOWNREGULATING PTEN EXPRESSION, DEPENDING ON HISTONE DEMETHYLASE ACTIVITY, WHILE PTEN TARGETS PROTEIN PHOSPHATASE ACTIVITY OF BCR-ABL, A PHOSPHATASE WHICH DIRECTLY DEPHOSPHORYLATES BCR-ABL. IN CLINICAL SPECIMENS, THE MRNA EXPRESSION OF RBP2 WAS FOUND TO BE POSITIVELY CORRELATED WITH THAT OF PTEN. THESE DATA SUGGEST THAT THE UNDER-EXPRESSION OF RBP2 PROMOTES BLAST CRISIS TRANSITION BY ACTIVATING AN RBP2/PTEN/BCR-ABL CASCADE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11 5669  29 SFRP1 PROMOTER METHYLATION IS ASSOCIATED WITH PERSISTENT PHILADELPHIA CHROMOSOME IN CHRONIC MYELOID LEUKEMIA. EPIGENETIC SILENCING OF SFRP GENES HAS BEEN SHOWN TO LEAD TO CONSTITUTIVE ACTIVATION OF THE CANONICAL WNT-SIGNALING PATHWAY. THE FIRST DESCRIPTION OF DEREGULATED WNT-SIGNALING ACTIVATION IN A HEMATOLOGICAL MALIGNANCY WAS REPORTED IN CHRONIC MYELOID LEUKEMIA (CML). TO INVESTIGATE WHETHER EPIGENETIC SILENCING OF SFRP IS RESPONSIBLE FOR THE OBSERVED WNT ACTIVATION IN CML, WE STUDIED THE METHYLATION AND MUTATIONAL STATUS OF THE SFRP1 PROMOTER IN 48 CHRONIC PHASE CML PATIENTS. OF THE 48 CML PATIENTS 41 WERE SHOWN TO BE UNMETHYLATED, 6 PATIENTS HEMI-METHYLATED AND 1 PATIENT FULLY METHYLATED AT THE SFRP1 PROMOTER. ALBEIT OBSERVED INFREQUENTLY IN CHRONIC PHASE CML, SFRP1 PROMOTER METHYLATION CORRELATED WITH PRIMARY CYTOGENETIC RESISTANCE TO IMATINIB MESYLATE. SFRP1 PROMOTER METHYLATION MAY INDICATE A GENETICALLY MORE UNSTABLE FORM OF DISEASE RESISTANT TO THERAPY AND PROVIDE A KEY BIOLOGICAL DIFFERENCE IN THERAPY RESISTANT PATIENTS, IN ADDITION TO A POSSIBLE MECHANISM FOR THE OBSERVED ACTIVATION OF CANONICAL WNT SIGNALING IN CML.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
12  388  31 AN INTEGRATED ANALYSIS OF SOCS1 DOWN-REGULATION IN HBV INFECTION-RELATED HEPATOCELLULAR CARCINOMA. PERSISTENT INFLAMMATION TOGETHER WITH GENETIC/EPIGENETIC ABERRATIONS IS STRONGLY ASSOCIATED WITH CHRONIC HEPATITIS B VIRUS (HBV) INFECTION-RELATED HEPATOCARCINOGENESIS. HERE, WE INVESTIGATED THE ALTERATIONS OF THE SUPPRESSOR OF CYTOKINE SIGNALLING (SOCS) FAMILY GENES IN HBV-RELATED HEPATOCELLULAR CARCINOMA (HCC). A TOTAL OF 116 PATIENTS WITH HCC WERE ENROLLED IN THIS STUDY. THE METHYLATION STATUSES OF SOCS1-7 AND CISH GENES WERE QUANTITATIVELY MEASURED AND CLINICOPATHOLOGICAL SIGNIFICANCE OF SOCS1 METHYLATION WAS STATISTICALLY ANALYSED. THE GENE COPY NUMBER VARIATION WAS ASSAYED BY ACGH. LUCIFERASE REPORTER ASSAY AND WESTERN BLOT WERE USED TO DETECT THE INVOLVEMENT OF SOCS1 IN P53 SIGNALLING. WE FOUND HIGH FREQUENCIES OF SOCS1 GENE HYPERMETHYLATION IN BOTH TUMOUR (56.03%) AND ADJACENT NONTUMOUR TISSUES (54.31%), BUT TUMOUR TISSUES EXHIBITED INCREASED METHYLATION INTENSITY (24.01% VS 13.11%, P < 0.0001), PARTICULARLY IN PATIENTS WITH LARGER TUMOUR SIZE OR CIRRHOSIS BACKGROUND (P < 0.0001). IN ADDITION, THE FREQUENCY AND INTENSITY OF SOCS1 HYPERMETHYLATION IN TUMOUR TISSUES WERE BOTH SIGNIFICANTLY HIGHER THAN THOSE IN NONTUMOUR TISSUES IN MALE GENDER PATIENTS AND IN PATIENTS >/=45 YEARS OLD (P = 0.0214 AND P < 0.0001, P = 0.0232 AND P < 0.0001, RESPECTIVELY). SOCS1 GENE DELETION WAS FOUND IN 8 OF 25 ACGH ASSAYED TUMOUR SPECIMENS, WHICH WAS ASSOCIATED WITH LOWER SOCS1 MRNA EXPRESSION (P = 0.0448). FURTHERMORE, ECTOPIC SOCS1 OVEREXPRESSION COULD ACTIVATE THE P53 SIGNALLING PATHWAY IN HCC CELL LINES. HYPERMETHYLATION OF SOCS2-7 AND CISH GENES WAS SELDOM FOUND IN HCC. OUR RESULTS SUGGESTED THAT THE GENE LOSS AND EPIGENETIC SILENCING OF SOCS1 WERE STRONGLY ASSOCIATED WITH HBV-RELATED HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13 5924  23 TARGETING DNMT1 BY DEMETHYLATING AGENT OR-2100 INCREASES TYROSINE KINASE INHIBITORS-SENSITIVITY AND DEPLETES LEUKEMIC STEM CELLS IN CHRONIC MYELOID LEUKEMIA. ABL1 TYROSINE KINASE INHIBITORS (TKIS) DRAMATICALLY IMPROVE THE PROGNOSIS OF CHRONIC MYELOID LEUKEMIA (CML), BUT 10-20% OF PATIENTS ACHIEVE SUBOPTIMAL RESPONSES WITH LOW TKIS SENSITIVITY. FURTHERMORE, RESIDUAL LEUKEMIC STEM CELLS (LSCS) ARE INVOLVED IN THE MOLECULAR RELAPSE AFTER TKIS DISCONTINUATION. ABERRANT DNA HYPERMETHYLATION CONTRIBUTES TO LOW TKIS SENSITIVITY AND THE PERSISTENCE OF LSCS IN CML. DNMT1 IS A KEY REGULATOR OF HEMATOPOIETIC STEM CELLS, SUGGESTING THAT ABERRANT DNA HYPERMETHYLATION TARGETING DNMT1 REPRESENTS A POTENTIAL THERAPEUTIC TARGET FOR CML. WE INVESTIGATED THE EFFICACY OF OR-2100 (OR21), THE FIRST ORALLY AVAILABLE SINGLE-COMPOUND PRODRUG OF DECITABINE. OR21 EXHIBITED ANTI-TUMOR EFFECTS AS A MONOTHERAPY, AND IN COMBINATION THERAPY IT INCREASED TKI-INDUCED APOPTOSIS AND INDUCTION OF TUMOR SUPPRESSOR GENES INCLUDING PTPN6 ENCODING SHP-1 IN CML CELLS. OR21 IN COMBINATION WITH IMATINIB SIGNIFICANTLY SUPPRESSED TUMOR GROWTH IN A XENOTRANSPLANT MODEL. OR21 AND COMBINATION THERAPY DECREASED THE ABUNDANCE OF LSCS AND INHIBITED ENGRAFTMENT IN A BCR-ABL1-TRANSDUCED MOUSE MODEL. THESE RESULTS DEMONSTRATE THAT TARGETING DNMT1 USING OR21 EXERTS ANTI-TUMOR EFFECTS AND IMPAIRS LSCS IN CML. THEREFORE, COMBINATION TREATMENT OF TKIS AND OR21 REPRESENTS A PROMISING TREATMENT STRATEGY IN CML.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14  573  29 BCR-ABL1-INDUCED DOWNREGULATION OF WASP IN CHRONIC MYELOID LEUKEMIA INVOLVES EPIGENETIC MODIFICATION AND CONTRIBUTES TO MALIGNANCY. CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE DISEASE CAUSED BY THE BCR-ABL1 TYROSINE KINASE (TK). THE DEVELOPMENT OF TK INHIBITORS (TKIS) REVOLUTIONIZED THE TREATMENT OF CML PATIENTS. HOWEVER, TKIS ARE NOT EFFECTIVE TO THOSE AT ADVANCED PHASES WHEN AMPLIFIED BCR-ABL1 LEVELS AND INCREASED GENOMIC INSTABILITY LEAD TO SECONDARY ONCOGENIC MODIFICATIONS. WISKOTT-ALDRICH SYNDROME PROTEIN (WASP) IS AN IMPORTANT REGULATOR OF SIGNALING TRANSDUCTION IN HEMATOPOIETIC CELLS AND WAS SHOWN TO BE AN ENDOGENOUS INHIBITOR OF THE C-ABL TK. HERE, WE SHOW THAT THE EXPRESSION OF WASP DECREASES WITH THE PROGRESSION OF CML, INVERSELY CORRELATES WITH THE EXPRESSION OF BCR-ABL1 AND IS PARTICULARLY LOW IN BLAST CRISIS. ENFORCED EXPRESSION OF BCR-ABL1 NEGATIVELY REGULATES THE EXPRESSION OF WASP. DECREASED EXPRESSION OF WASP IS PARTIALLY DUE TO DNA METHYLATION OF THE PROXIMAL WASP PROMOTER. IMPORTANTLY, LOWER LEVELS OF WASP IN CML ADVANCED PHASE PATIENTS CORRELATE WITH POORER OVERALL SURVIVAL (OS) AND IS ASSOCIATED WITH TKI RESPONSE. INTERESTINGLY, ENFORCED EXPRESSION OF WASP IN BCR-ABL1-POSITIVE K562 CELLS INCREASES THE SUSCEPTIBILITY TO APOPTOSIS INDUCED BY TRAIL OR CHEMOTHERAPEUTIC DRUGS AND NEGATIVELY MODULATES BCR-ABL1-INDUCED TUMORIGENESIS IN VITRO AND IN VIVO. TAKEN TOGETHER, OUR DATA REVEAL A NOVEL MOLECULAR MECHANISM THAT OPERATES IN BCR-ABL1-INDUCED TUMORIGENESIS THAT CAN BE USED TO DEVELOP NEW STRATEGIES TO HELP TKI-RESISTANT, CML PATIENTS IN BLAST CRISIS (BC).	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15 2763  26 EXPRESSION OF THE LEUKEMIC PROGNOSTIC MARKER CD7 IS LINKED TO EPIGENETIC MODIFICATIONS IN CHRONIC MYELOID LEUKEMIA. BACKGROUND: EXPRESSION LEVELS OF THE CELL SURFACE GLYCOPROTEIN, CD7, AND THE SERINE PROTEASE, ELASTASE 2 (ELA2), IN THE LEUKEMIC CELLS OF PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) HAVE BEEN ASSOCIATED WITH CLINICAL OUTCOME. HOWEVER, LITTLE IS KNOWN ABOUT THE MECHANISMS THAT UNDERLIE THE VARIABLE EXPRESSION OF THESE GENES IN THE LEUKEMIC CELLS. RESULTS: TO ADDRESS THIS QUESTION, WE COMPARED THE LEVEL OF THEIR EXPRESSION WITH THE DNA METHYLATION AND HISTONE ACETYLATION STATUS OF 5' SEQUENCES OF BOTH GENES IN LEUKEMIC CELL LINES AND PRIMITIVE (LIN-CD34+) LEUKEMIC CELLS FROM CHRONIC PHASE CML PATIENTS. DNA METHYLATION OF THE ELA2 GENE PROMOTER DID NOT CORRELATE WITH ITS EXPRESSION PATTERN IN LIN-CD34+ CELLS FROM CHRONIC PHASE CML PATIENT SAMPLES EVEN THOUGH THERE WAS CLEAR DIFFERENTIAL DNA METHYLATION OF THIS LOCUS IN ELA2-EXPRESSING AND NON-EXPRESSING CELL LINES. IN CONTRAST, WE FOUND A STRONG RELATION BETWEEN CD7 EXPRESSION AND TRANSCRIPTION-PERMISSIVE CHROMATIN MODIFICATIONS, BOTH AT THE LEVEL OF DNA METHYLATION AND HISTONE ACETYLATION WITH EVIDENCE OF HYPOMETHYLATION OF THE CD7 PROMOTER REGION IN THE LIN-CD34+ CELLS FROM CML PATIENTS WITH HIGH CD7 EXPRESSION. CONCLUSION: THESE FINDINGS INDICATE A LINK BETWEEN EPIGENETIC MODIFICATIONS AND CD7 EXPRESSION IN PRIMITIVE CML CELLS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16 5101  23 POLYCOMB FACTOR PHF19 CONTROLS CELL GROWTH AND DIFFERENTIATION TOWARD ERYTHROID PATHWAY IN CHRONIC MYELOID LEUKEMIA CELLS. POLYCOMB GROUP (PCG) OF PROTEINS ARE A GROUP OF HIGHLY CONSERVED EPIGENETIC REGULATORS INVOLVED IN MANY BIOLOGICAL FUNCTIONS, SUCH AS EMBRYONIC DEVELOPMENT, CELL PROLIFERATION, AND ADULT STEM CELL DETERMINATION. PHD FINGER PROTEIN 19 (PHF19) IS AN ASSOCIATED FACTOR OF POLYCOMB REPRESSOR COMPLEX 2 (PRC2), OFTEN UPREGULATED IN HUMAN CANCERS. IN PARTICULAR, MYELOID LEUKEMIA CELL LINES SHOW INCREASED LEVELS OF PHF19, YET LITTLE IS KNOWN ABOUT ITS FUNCTION. HERE, WE HAVE CHARACTERIZED THE ROLE OF PHF19 IN MYELOID LEUKEMIA CELLS. WE DEMONSTRATED THAT PHF19 DEPLETION DECREASES CELL PROLIFERATION AND PROMOTES CHRONIC MYELOID LEUKEMIA (CML) DIFFERENTIATION. MECHANISTICALLY, WE HAVE SHOWN HOW PHF19 REGULATES THE PROLIFERATION OF CML THROUGH A DIRECT REGULATION OF THE CELL CYCLE INHIBITOR P21. FURTHERMORE, WE OBSERVED THAT MTF2, A PHF19 HOMOLOG, PARTIALLY COMPENSATES FOR PHF19 DEPLETION IN A SUBSET OF TARGET GENES, INSTRUCTING SPECIFIC ERYTHROID DIFFERENTIATION. TAKEN TOGETHER, OUR RESULTS SHOW THAT PHF19 IS A KEY TRANSCRIPTIONAL REGULATOR FOR CELL FATE DETERMINATION AND COULD BE A POTENTIAL THERAPEUTIC TARGET FOR MYELOID LEUKEMIA TREATMENT.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
17 4694  29 NEXT-GENERATION SEQUENCING IDENTIFIES MAJOR DNA METHYLATION CHANGES DURING PROGRESSION OF PH+ CHRONIC MYELOID LEUKEMIA. LITTLE IS KNOWN ABOUT THE IMPACT OF DNA METHYLATION ON THE EVOLUTION/PROGRESSION OF PH+ CHRONIC MYELOID LEUKEMIA (CML). WE INVESTIGATED THE METHYLOME OF CML PATIENTS IN CHRONIC PHASE (CP-CML), ACCELERATED PHASE (AP-CML) AND BLAST CRISIS (BC-CML) AS WELL AS IN CONTROLS BY REDUCED REPRESENTATION BISULFITE SEQUENCING. ALTHOUGH ONLY ~600 DIFFERENTIALLY METHYLATED CPG SITES WERE IDENTIFIED IN SAMPLES OBTAINED FROM CP-CML PATIENTS COMPARED WITH CONTROLS, ~6500 DIFFERENTIALLY METHYLATED CPG SITES WERE FOUND IN SAMPLES FROM BC-CML PATIENTS. IN THE MAJORITY OF AFFECTED CPG SITES, METHYLATION WAS INCREASED. IN CP-CML PATIENTS WHO PROGRESSED TO AP-CML/BC-CML, WE IDENTIFIED UP TO 897 GENES THAT WERE METHYLATED AT THE TIME OF PROGRESSION BUT NOT AT THE TIME OF DIAGNOSIS. USING RNA-SEQUENCING, WE OBSERVED DOWNREGULATED EXPRESSION OF MANY OF THESE GENES IN BC-CML COMPARED WITH CP-CML SAMPLES. SEVERAL OF THEM ARE WELL-KNOWN TUMOR-SUPPRESSOR GENES OR REGULATORS OF CELL PROLIFERATION, AND GENE RE-EXPRESSION WAS OBSERVED BY THE USE OF EPIGENETIC ACTIVE DRUGS. TOGETHER, OUR RESULTS DEMONSTRATE THAT CPG SITE METHYLATION CLEARLY INCREASES DURING CML PROGRESSION AND THAT IT MAY PROVIDE A USEFUL BASIS FOR REVEALING NEW TARGETS OF THERAPY IN ADVANCED CML.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18 4837  24 ONCOGENIC GENE EXPRESSION AND EPIGENETIC REMODELING OF CIS-REGULATORY ELEMENTS IN ASXL1-MUTANT CHRONIC MYELOMONOCYTIC LEUKEMIA. MYELOID NEOPLASMS ARE CLONAL HEMATOPOIETIC STEM CELL DISORDERS DRIVEN BY THE SEQUENTIAL ACQUISITION OF RECURRENT GENETIC LESIONS. TRUNCATING MUTATIONS IN THE CHROMATIN REMODELER ASXL1 (ASXL1(MT)) ARE ASSOCIATED WITH A HIGH-RISK DISEASE PHENOTYPE WITH INCREASED PROLIFERATION, EPIGENETIC THERAPEUTIC RESISTANCE, AND POOR SURVIVAL OUTCOMES. WE PERFORMED A MULTI-OMICS INTERROGATION TO DEFINE GENE EXPRESSION AND CHROMATIN REMODELING ASSOCIATED WITH ASXL1(MT) IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). ASXL1(MT) ARE ASSOCIATED WITH A LOSS OF REPRESSIVE HISTONE METHYLATION AND INCREASE IN PERMISSIVE HISTONE METHYLATION AND ACETYLATION IN PROMOTER REGIONS. ASXL1(MT) ARE FURTHER ASSOCIATED WITH DE NOVO ACCESSIBILITY OF DISTAL ENHANCERS BINDING ETS TRANSCRIPTION FACTORS, TARGETING IMPORTANT LEUKEMOGENIC DRIVER GENES. CHROMATIN REMODELING OF PROMOTERS AND ENHANCERS IS STRONGLY ASSOCIATED WITH GENE EXPRESSION AND HETEROGENOUS AMONG OVEREXPRESSED GENES. THESE RESULTS PROVIDE A COMPREHENSIVE MAP OF THE TRANSCRIPTOME AND CHROMATIN LANDSCAPE OF ASXL1(MT) CMML, FORMING AN IMPORTANT FRAMEWORK FOR THE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES TARGETING ONCOGENIC CIS INTERACTIONS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  494  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20  409  27 ANALYSIS OF GENES ENCODING EPIGENETIC REGULATORS IN MYELOPROLIFERATIVE NEOPLASMS: COEXISTENCE OF A NOVEL SETBP1 MUTATION IN A PATIENT WITH A P.V617F JAK2 POSITIVE MYELOFIBROSIS. IN RECENT YEARS IT HAS BEEN SHOWN THAT THE CAUSES OF CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE MORE COMPLEX THAN A SIMPLE SIGNALING ABERRATION AND MANY OTHER MUTATED GENES AFFECTING DIFFERENT CELL PROCESSES HAVE BEEN DESCRIBED. FOR INSTANCE, MUTATIONS IN GENES ENCODING EPIGENETIC REGULATORS ARE MORE FREQUENT THAN EXPECTED. ONE OF THE LATEST GENES DESCRIBED AS MUTATED IS SET BINDING PROTEIN 1 (SETBP1). IN SILICO TOOLS HAVE REVEALED THAT THERE ARE SEVERAL HUMAN SETBP1 PARALOGOUS TO NUCLEAR RECEPTOR BINDING SET DOMAIN PROTEIN 1 (NSD1), NSD2 AND NSD3, FOR EXAMPLE, WHICH ARE ALSO INVOLVED IN THE DEVELOPMENT OF OTHER HEMATOLOGICAL MALIGNANCIES. THEREFORE, THE PRESENT STUDY ANALYZED THE MUTATIONAL STATUS OF NSD1, NSD2, NSD3 AND SETBP1 IN BCR-ABL1 NEGATIVE MPNS WITH OR WITHOUT JANUS KINASE 2 (JAK2) P.V617F MUTATION. THE PRESENT STUDY REVEALED THAT THE NSD GENES ARE NOT FREQUENTLY MUTATED IN MPNS. HOWEVER, A NOVEL SETBP1 MUTATION WAS IDENTIFIED IN A PATIENT WITH P.V617F JAK2 POSITIVE PRIMARY MYELOFIBROSIS. THESE RESULTS PROVIDE FURTHER INSIGHT INTO THE GENETIC COMPLEXITY OF MPNS.	2019