1  6425 138 THE TRANSCRIPTION FACTOR REST UP-REGULATES TYROSINE HYDROXYLASE AND ANTIAPOPTOTIC GENES AND PROTECTS DOPAMINERGIC NEURONS AGAINST MANGANESE TOXICITY. DOPAMINERGIC FUNCTIONS ARE IMPORTANT FOR VARIOUS BIOLOGICAL ACTIVITIES, AND THEIR IMPAIRMENT LEADS TO NEURODEGENERATION, A HALLMARK OF PARKINSON'S DISEASE (PD). CHRONIC MANGANESE (MN) EXPOSURE CAUSES THE NEUROLOGICAL DISORDER MANGANISM, PRESENTING SYMPTOMS SIMILAR TO THOSE OF PD. EMERGING EVIDENCE HAS LINKED THE TRANSCRIPTION FACTOR RE1-SILENCING TRANSCRIPTION FACTOR (REST) TO PD AND ALSO ALZHEIMER'S DISEASE. BUT REST'S ROLE IN DOPAMINERGIC NEURONS IS UNCLEAR. HERE, WE INVESTIGATED WHETHER REST PROTECTS DOPAMINERGIC NEURONS AGAINST MN-INDUCED TOXICITY AND ENHANCES EXPRESSION OF THE DOPAMINE-SYNTHESIZING ENZYME TYROSINE HYDROXYLASE (TH). WE REPORT THAT REST BINDS TO RE1 CONSENSUS SITES IN THE TH GENE PROMOTER, STIMULATES TH TRANSCRIPTION, AND INCREASES TH MRNA AND PROTEIN LEVELS IN DOPAMINERGIC CELLS. REST BINDING TO THE TH PROMOTER RECRUITED THE EPIGENETIC MODIFIER CAMP-RESPONSE ELEMENT-BINDING PROTEIN-BINDING PROTEIN/P300 AND THEREBY UP-REGULATED TH EXPRESSION. REST RELIEVED MN-INDUCED REPRESSION OF TH PROMOTER ACTIVITY, MRNA, AND PROTEIN LEVELS AND ALSO REDUCED MN-INDUCED OXIDATIVE STRESS, INFLAMMATION, AND APOPTOSIS IN DOPAMINERGIC NEURONS. REST REDUCED MN-INDUCED PROINFLAMMATORY CYTOKINES, INCLUDING TUMOR NECROSIS FACTOR ALPHA, INTERLEUKIN 1BETA (IL-1BETA), IL-6, AND INTERFERON GAMMA. MOREOVER, REST INHIBITED THE MN-INDUCED PROAPOPTOTIC PROTEINS BCL-2-ASSOCIATED X PROTEIN (BAX) AND DEATH-ASSOCIATED PROTEIN 6 (DAXX) AND ATTENUATED AN MN-INDUCED DECREASE IN THE ANTIAPOPTOTIC PROTEINS BCL-2 AND BCL-XL. REST ALSO ENHANCED THE EXPRESSION OF ANTIOXIDANT PROTEINS, INCLUDING CATALASE, NF-E2-RELATED FACTOR 2 (NRF2), AND HEME OXYGENASE 1 (HO-1). OUR FINDINGS INDICATE THAT REST ACTIVATES TH EXPRESSION AND THEREBY PROTECTS NEURONS AGAINST MN-INDUCED TOXICITY AND NEUROLOGICAL DISORDERS ASSOCIATED WITH DOPAMINERGIC NEURODEGENERATION.	2020	
                                                                                                                                                              
2  5917  32 TARGETING BCL-2 IN B-CELL MALIGNANCIES AND OVERCOMING THERAPEUTIC RESISTANCE. DEFECTS IN APOPTOSIS CAN PROMOTE TUMORIGENESIS AND IMPAIR RESPONSES OF MALIGNANT B CELLS TO CHEMOTHERAPEUTICS. MEMBERS OF THE B-CELL LEUKEMIA/LYMPHOMA-2 (BCL-2) FAMILY OF PROTEINS ARE KEY REGULATORS OF THE INTRINSIC, MITOCHONDRIAL APOPTOTIC PATHWAY. OVEREXPRESSION OF ANTIAPOPTOTIC BCL-2 FAMILY PROTEINS IS ASSOCIATED WITH TREATMENT RESISTANCE AND POOR PROGNOSIS. THUS, INHIBITION OF BCL-2 FAMILY PROTEINS IS A RATIONAL THERAPEUTIC OPTION FOR MALIGNANCIES THAT ARE DEPENDENT ON ANTIAPOPTOTIC BCL-2 FAMILY PROTEINS. VENETOCLAX (ABT-199, GDC-0199) IS A HIGHLY SELECTIVE BCL-2 INHIBITOR THAT REPRESENTS THE FIRST APPROVED AGENT OF THIS CLASS AND IS CURRENTLY WIDELY USED IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AS WELL AS ACUTE MYELOID LEUKEMIA (AML). DESPITE IMPRESSIVE CLINICAL ACTIVITY, VENETOCLAX MONOTHERAPY FOR A PROLONGED DURATION CAN LEAD TO DRUG RESISTANCE OR LOSS OF DEPENDENCE ON THE TARGETED PROTEIN. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE MECHANISM OF ACTION OF BCL-2 INHIBITION AND THE ROLE OF THIS APPROACH IN THE CURRENT TREATMENT PARADIGM OF B-CELL MALIGNANCIES. WE SUMMARIZE THE DRIVERS OF DE NOVO AND ACQUIRED RESISTANCE TO VENETOCLAX THAT ARE CLOSELY ASSOCIATED WITH COMPLEX CLONAL SHIFTS, INTERPLAY OF EXPRESSION AND INTERACTIONS OF BCL-2 FAMILY MEMBERS, TRANSCRIPTIONAL REGULATORS, AND METABOLIC MODULATORS. WE ALSO EXAMINE HOW TUMORS INITIALLY RESISTANT TO VENETOCLAX BECOME RESPONSIVE TO IT FOLLOWING PRIOR THERAPIES. HERE, WE SUMMARIZE PRECLINICAL DATA PROVIDING A RATIONALE FOR EFFICACIOUS COMBINATION STRATEGIES OF VENETOCLAX TO OVERCOME THERAPEUTIC RESISTANCE BY A TARGETED APPROACH DIRECTED AGAINST ALTERNATIVE ANTIAPOPTOTIC BCL-2 FAMILY PROTEINS (MCL-1, BCL-XL), COMPENSATORY PROSURVIVAL PATHWAYS, EPIGENETIC MODIFIERS, AND DYSREGULATED CELLULAR METABOLISM/ENERGETICS FOR DURABLE CLINICAL REMISSIONS.	2020	
                                                                                                                                                                                                                                            
3  3470  26 HYPOXIA-INDUCIBLE KDM3A ADDICTION IN MULTIPLE MYELOMA. IN MULTIPLE MYELOMA (MM), THE BONE MARROW (BM) MICROENVIRONMENT MAY CONTAIN A MYELOMA CELL FRACTION THAT HAS ACQUIRED TREATMENT RESISTANCE BY UNDERGOING AN EPIGENETIC GENE EXPRESSION CHANGE. HYPOXIC STRESS IS AN IMPORTANT FACTOR IN THE BM MICROENVIRONMENT. RECENTLY, WE DEMONSTRATED THAT MIR-210 WAS UPREGULATED IN HYPOXIA AND DOWNREGULATED IRF4, WHICH IS KNOWN AS AN ESSENTIAL FACTOR IN MYELOMA ONCOGENESIS IN NORMOXIA. IN THE STUDY, WE DEMONSTRATED THAT MYELOMA CELLS STILL SHOWED A STRONG ANTIAPOPTOTIC PHENOTYPE DESPITE IRF4 DOWNREGULATION, SUGGESTING THAT ANOTHER ANTIAPOPTOTIC FACTOR MIGHT BE INVOLVED UNDER HYPOXIC STRESS. TO DETERMINE THE FACTOR OR FACTORS, WE CONDUCTED GENE EXPRESSION ANALYSIS ON MYELOMA CELLS (PRIMARY SAMPLES AND CELL LINES) THAT WERE EXPOSED TO CHRONIC HYPOXIA AND OBSERVED UPREGULATION OF GLYCOLYTIC GENES AND GENES ENCODING H3K9 DEMETHYLASES IN MYELOMA CELLS WITH HYPOXIA. AMONG THESE, KDM3A WAS MOST SIGNIFICANTLY UPREGULATED IN ALL EXAMINED CELLS, AND ITS KNOCKDOWN INDUCED APOPTOSIS OF MYELOMA CELLS IN CHRONIC HYPOXIA. EXPRESSION OF KDM3A WAS DEPENDENT ON HIF-1ALPHA, WHICH IS A TRANSCRIPTION FACTOR SPECIFICALLY UPREGULATED IN HYPOXIA. WE FURTHER DEMONSTRATED THAT AN ESSENTIAL TARGET OF KDM3A WAS A NONCODING GENE, MALAT1, WHOSE UPREGULATION CONTRIBUTED TO ACQUISITION OF AN ANTIAPOPTOTIC PHENOTYPE BY ACCUMULATION OF HIF-1ALPHA, LEADING TO UPREGULATION OF GLYCOLYTIC GENES UNDER HYPOXIA. THIS PROCESS WAS INDEPENDENT FROM IRF4. THESE RESULTS LED US TO CONCLUDE THAT THE HYPOXIA-INDUCIBLE HIF-1ALPHA-KDM3A-MALAT1 AXIS ALSO CONTRIBUTES TO ACQUISITION OF THE ANTIAPOPTOTIC PHENOTYPE VIA UPREGULATION OF GLYCOLYSIS-PROMOTING GENES. THUS, THIS AXIS IS A PROMISING THERAPEUTIC TARGET AGAINST MYELOMA CELLS IN THE BM MICROENVIRONMENT.	2018	
                                                                                                                                                                                                                                                                                                                                                      
4  1333  27 DEREGULATION AND EPIGENETIC MODIFICATION OF BCL2-FAMILY GENES CAUSE RESISTANCE TO VENETOCLAX IN HEMATOLOGIC MALIGNANCIES. THE BCL2 INHIBITOR VENETOCLAX HAS BEEN APPROVED TO TREAT DIFFERENT HEMATOLOGICAL MALIGNANCIES. BECAUSE THERE IS NO COMMON GENETIC ALTERATION CAUSING RESISTANCE TO VENETOCLAX IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND B-CELL LYMPHOMA, WE ASKED IF EPIGENETIC EVENTS MIGHT BE INVOLVED IN VENETOCLAX RESISTANCE. THEREFORE, WE EMPLOYED WHOLE-EXOME SEQUENCING, METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING, AND GENOME-WIDE CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS (CRISPR)/CRISPR-ASSOCIATED PROTEIN 9 SCREENING TO INVESTIGATE VENETOCLAX RESISTANCE IN AGGRESSIVE LYMPHOMA AND HIGH-RISK CLL PATIENTS. WE IDENTIFIED A REGULATORY CPG ISLAND WITHIN THE PUMA PROMOTER THAT IS METHYLATED UPON VENETOCLAX TREATMENT, MEDIATING PUMA DOWNREGULATION ON TRANSCRIPT AND PROTEIN LEVEL. PUMA EXPRESSION AND SENSITIVITY TOWARD VENETOCLAX CAN BE RESTORED BY INHIBITION OF METHYLTRANSFERASES. WE CAN DEMONSTRATE THAT LOSS OF PUMA RESULTS IN METABOLIC REPROGRAMMING WITH HIGHER OXIDATIVE PHOSPHORYLATION AND ADENOSINE TRIPHOSPHATE PRODUCTION, RESEMBLING THE METABOLIC PHENOTYPE THAT IS SEEN UPON VENETOCLAX RESISTANCE. ALTHOUGH PUMA LOSS IS SPECIFIC FOR ACQUIRED VENETOCLAX RESISTANCE BUT NOT FOR ACQUIRED MCL1 RESISTANCE AND IS NOT SEEN IN CLL PATIENTS AFTER CHEMOTHERAPY-RESISTANCE, BAX IS ESSENTIAL FOR SENSITIVITY TOWARD BOTH VENETOCLAX AND MCL1 INHIBITION. AS WE FOUND LOSS OF BAX IN RICHTER'S SYNDROME PATIENTS AFTER VENETOCLAX FAILURE, WE DEFINED BAX-MEDIATED APOPTOSIS TO BE CRITICAL FOR DRUG RESISTANCE BUT NOT FOR DISEASE PROGRESSION OF CLL INTO AGGRESSIVE DIFFUSE LARGE B-CELL LYMPHOMA IN VIVO. A COMPOUND SCREEN REVEALED TRAIL-MEDIATED APOPTOSIS AS A TARGET TO OVERCOME BAX DEFICIENCY. FURTHERMORE, ANTIBODY OR CAR T CELLS ELIMINATED VENETOCLAX RESISTANT LYMPHOMA CELLS, PAVING A CLINICALLY APPLICABLE WAY TO OVERCOME VENETOCLAX RESISTANCE.	2022	
                                                                                                                                                                                                      
5  4908  37 P53 ACTIVATION BY NI(II) IS A HIF-1ALPHA INDEPENDENT RESPONSE CAUSING CASPASES 9/3-MEDIATED APOPTOSIS IN HUMAN LUNG CELLS. HYPOXIA MIMIC NICKEL(II) IS A HUMAN RESPIRATORY CARCINOGEN WITH A SUSPECTED EPIGENETIC MODE OF ACTION. WE EXAMINED WHETHER NI(II) ELICITS A TOXICOLOGICALLY SIGNIFICANT ACTIVATION OF THE TUMOR SUPPRESSOR P53, WHICH IS TYPICALLY ASSOCIATED WITH GENOTOXIC RESPONSES. WE FOUND THAT TREATMENTS OF H460 HUMAN LUNG EPITHELIAL CELLS WITH NICL2 CAUSED ACTIVATING PHOSPHORYLATION AT P53-SER15, ACCUMULATION OF P53 PROTEIN AND DEPLETION OF ITS INHIBITOR MDM4 (HDMX). CONFIRMING THE ACTIVATION OF P53, ITS KNOCKDOWN SUPPRESSED THE ABILITY OF NI(II) TO UPREGULATE MDM2 AND P21 (CDKN1A). UNLIKE DNA DAMAGE, INDUCTION OF GADD45A BY NI(II) WAS P53-INDEPENDENT. NI(II) ALSO INCREASED P53-SER15 PHOSPHORYLATION AND P21 EXPRESSION IN NORMAL HUMAN LUNG FIBROBLASTS. ALTHOUGH NI(II)-INDUCED STABILIZATION OF HIF-1ALPHA OCCURRED EARLIER, IT HAD NO EFFECT ON P53 ACCUMULATION AND SER15 PHOSPHORYLATION. NI(II)-TREATED H460 CELLS SHOWED NO EVIDENCE OF NECROSIS AND THEIR APOPTOSIS AND CLONOGENIC DEATH WERE SUPPRESSED BY P53 KNOCKDOWN. THE APOPTOTIC ROLE OF P53 INVOLVED A TRANSCRIPTION-DEPENDENT PROGRAM TRIGGERING THE INITIATOR CASPASE 9 AND ITS DOWNSTREAM EXECUTIONER CASPASE 3. TWO MOST PROMINENTLY UPREGULATED PROAPOPTOTIC GENES BY NI(II) WERE PUMA AND NOXA BUT ONLY PUMA INDUCTION REQUIRED P53. KNOCKDOWN OF P53 ALSO LED TO DEREPRESSION OF ANTIAPOPTOTIC MCL1 IN NI(II)-TREATED CELLS. OVERALL, OUR RESULTS INDICATE THAT P53 PLAYS A MAJOR ROLE IN APOPTOTIC DEATH OF HUMAN LUNG CELLS BY NI(II). CHRONIC EXPOSURE TO NI(II) MAY PROMOTE SELECTION OF RESISTANT CELLS WITH INACTIVATED P53, PROVIDING AN EXPLANATION FOR THE ORIGIN OF P53 MUTATIONS BY THIS EPIGENETIC CARCINOGEN.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                     
6  3725  33 INHIBITION OF GLYCOGEN SYNTHASE KINASE-3 ACTIVITY LEADS TO EPIGENETIC SILENCING OF NUCLEAR FACTOR KAPPAB TARGET GENES AND INDUCTION OF APOPTOSIS IN CHRONIC LYMPHOCYTIC LEUKEMIA B CELLS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS COMMONLY DEFINED AS A DISEASE OF FAILED APOPTOSIS OF B CELLS AND REMAINS AN INCURABLE DISEASE. THE MECHANISM OF RESISTANCE TO APOPTOSIS IN CLL IS COMPLEX AND INFLUENCED BY NUMEROUS FACTORS, INCLUDING NUCLEAR FACTOR KAPPAB (NFKAPPAB)-MEDIATED EXPRESSION OF ANTIAPOPTOTIC MOLECULES. RECENT EVIDENCE INDICATES THAT GLYCOGEN SYNTHASE KINASE-3BETA (GSK-3BETA) POSITIVELY REGULATES NFKAPPAB-MEDIATED GENE TRANSCRIPTION AND CELL SURVIVAL. USING MALIGNANT B CELLS COLLECTED FROM PATIENTS WITH CLL, WE FIND THAT BOTH GSK-3BETA AND NFKAPPAB ACCUMULATE IN THE NUCLEUS OF CLL B CELLS, AND PHARMACOLOGIC INHIBITION OF GSK-3 RESULTS IN DECREASED EXPRESSION OF TWO NFKAPPAB TARGET GENES BCL-2 AND XIAP AND A SUBSEQUENT INCREASE IN CLL B-CELL APOPTOSIS EX VIVO. FURTHERMORE, WE OBSERVED THAT INHIBITION OF GSK-3 LEADS TO A DECREASE IN NFKAPPAB-MEDIATED GENE TRANSCRIPTION BUT DOES NOT AFFECT THE NUCLEAR ACCUMULATION OF NFKAPPAB IN CLL B CELLS. LAST, USING CHROMATIN IMMUNOPRECIPITATION, WE SHOW THAT GSK-3 INHIBITION ABROGATES NFKAPPAB BINDING TO ITS TARGET GENE PROMOTERS (XIAP, BCL-2), IN PART THROUGH EPIGENETIC MODIFICATION OF HISTONES. OUR RESULTS ESTABLISH THAT INHIBITION OF GSK-3 ABROGATES NFKAPPAB BINDING TO ITS TARGET GENE PROMOTERS THROUGH AN EPIGENETIC MECHANISM, ENHANCES APOPTOSIS IN CLL B CELLS EX VIVO AND IDENTIFIES GSK-3 AS A POTENTIAL THERAPEUTIC TARGET IN THE TREATMENT OF CLL.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  4175  33 MELATONIN PROTECTS CHOLANGIOCYTES FROM OXIDATIVE STRESS-INDUCED PROAPOPTOTIC AND PROINFLAMMATORY STIMULI VIA MIR-132 AND MIR-34. BIOSYNTHESIS OF MELATONIN BY CHOLANGIOCYTES IS ESSENTIAL FOR MAINTAINING THE FUNCTION OF BILIARY EPITHELIUM. HOWEVER, THIS CYTOPROTECTIVE MECHANISM APPEARS TO BE IMPAIRED IN PRIMARY BILIARY CHOLANGITIS (PBC). MIR-132 HAS EMERGED AS A MEDIATOR OF INFLAMMATION IN CHRONIC LIVER DISEASES. THE EFFECT OF MELATONIN ON OXIDATIVE STRESS AND BILE ACID-INDUCED APOPTOSIS WAS ALSO EXAMINED IN CHOLANGIOCYES OVEREXPRESSING MIR506, AS A PBC-LIKE CELLULAR MODEL. IN PBC PATIENTS THE SERUM LEVELS OF MELATONIN WERE FOUND INCREASED IN COMPARISON TO HEALTHY CONTROLS. WHEREAS, IN CHOLANGIOCYTES WITHIN CIRRHOTIC PBC LIVERS THE MELATONIN BIOSYNTHETIC PATHWAY WAS SUBSTANTIALLY SUPPRESSED EVEN THOUGH THE EXPRESSIONS OF MELATONIN RATE-LIMITING ENZYME ARALKYLAMINE N-ACETYLTRANSFERASE (AANAT), AND CK-19 (MARKER OF CHOLANGIOCYTES) WERE ENHANCED. IN CHOLANGIOCYTES EXPOSED TO MITOCHONDRIAL OXIDATIVE STRESS MELATONIN DECREASED THE EXPRESSION OF PROAPOPTOTIC STIMULI (PTEN, BAX, MIR-34), WHICH WAS ACCOMPANIED BY THE INHIBITION OF A PIVOTAL MEDIATOR OF INFLAMMATORY RESPONSE NF-KAPPAB-P65 AND THE ACTIVATION OF ANTIAPOPTOTIC SIGNALING (MIR-132, BCL2). SIMILARLY, MELATONIN REDUCED BILE ACID-INDUCED PROAPOPTOTIC CASPASE 3 AND BIM LEVELS. IN SUMMARY, THE INSUFFICIENT HEPATIC EXPRESSION OF MELATONIN IN PBC PATIENTS MAY PREDISPOSE CHOLANGIOCYTES TO OXIDATIVE STRESS-RELATED DAMAGE. MELATONIN, VIA EPIGENETIC MODULATION, WAS ABLE TO SUPPRESS NF-KAPPAB SIGNALING ACTIVATION AND PROTECT AGAINST BILIARY CELLS APOPTOTIC SIGNALING.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8  3175  30 H2AX PHOSPHORYLATION REGULATED BY P38 IS INVOLVED IN BIM EXPRESSION AND APOPTOSIS IN CHRONIC MYELOGENOUS LEUKEMIA CELLS INDUCED BY IMATINIB. INCREASING EVIDENCE SUGGESTS THAT HISTONE H2AX PLAYS A CRITICAL ROLE IN REGULATION OF TUMOR CELL APOPTOSIS AND ACTS AS A NOVEL HUMAN TUMOR SUPPRESSOR PROTEIN. HOWEVER, THE ACTION OF H2AX IN CHRONIC MYELOGENOUS LEUKEMIA (CML) CELLS IS UNKNOWN. THE DETAILED MECHANISM AND EPIGENETIC REGULATION BY H2AX REMAIN ELUSIVE IN CANCER CELLS. HERE, WE REPORT THAT H2AX WAS INVOLVED IN APOPTOSIS OF CML CELLS. OVEREXPRESSION OF H2AX INCREASED APOPTOTIC SENSITIVITY OF CML CELLS (K562) INDUCED BY IMATINIB. HOWEVER, OVEREXPRESSION OF SER139-MUTATED H2AX (BLOCKING PHOSPHORYLATION) DECREASED SENSITIVITY OF K562 CELLS TO APOPTOSIS. SIMILARLY, KNOCKDOWN OF H2AX MADE K562 CELLS RESISTANT TO APOPTOTIC INDUCTION. THESE RESULTS REVEALED THAT THE FUNCTION OF H2AX INVOLVED IN APOPTOSIS IS STRICTLY RELATED TO ITS PHOSPHORYLATION (SER139). OUR DATA FURTHER INDICATED THAT IMATINIB MAY STIMULATE MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) FAMILY MEMBER P38, AND H2AX PHOSPHORYLATION FOLLOWED A SIMILAR TIME COURSE, SUGGESTING A PARALLEL RESPONSE. H2AX PHOSPHORYLATION CAN BE BLOCKED BY P38 SIRNA OR ITS INHIBITOR. THESE DATA DEMONSTRATED THAT H2AX PHOSPHORYLATION WAS REGULATED BY P38 MAPK PATHWAY IN K562 CELLS. HOWEVER, THE P38 MAPK DOWNSTREAM, MITOGEN- AND STRESS-ACTIVATED PROTEIN KINASE-1 AND -2, WHICH PHOSPHORYLATED HISTONE H3, WERE NOT REQUIRED FOR H2AX PHOSPHORYLATION DURING APOPTOSIS. FINALLY, WE PROVIDED EPIGENETIC EVIDENCE THAT H2AX PHOSPHORYLATION REGULATED APOPTOSIS-RELATED GENE BIM EXPRESSION. BLOCKING OF H2AX PHOSPHORYLATION INHIBITED BIM GENE EXPRESSION. TAKEN TOGETHER, THESE DATA DEMONSTRATED THAT H2AX PHOSPHORYLATION REGULATED BY P38 IS INVOLVED IN BIM EXPRESSION AND APOPTOSIS IN CML CELLS INDUCED BY IMATINIB.	2014	
                                                                                                                                                                                                                                                                                                                     
9   574  27 BCR/ABL INCREASES EZH2 LEVELS WHICH REGULATES XIAP EXPRESSION VIA MIRNA-219 IN CHRONIC MYELOID LEUKEMIA CELLS. IN THIS STUDY, WE SHOWED THAT THE LEVELS OF EZH2 IN BONE MARROW MONONUCLEAR CELLS (BMMNCS) ISOLATED FROM INDIVIDUALS WITH CHRONIC MYELOID LEUKEMIA (CML) (N=12) WERE SIGNIFICANTLY GREATER THAN THOSE IN BMMNCS ISOLATED FROM HEALTHY VOLUNTEERS (N=6) AS WELL AS INDIVIDUALS WITH PHILADELPHIA CHROMOSOME-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS. LENTIVIRAL TRANSDUCTION OF THE BCR/ABL GENE IN BA/F3 CELLS INCREASED EZH2 LEVELS IN PARALLEL WITH PHOSPHORYLATION OF STAT5. NOTABLY, CHROMATIN IMMUNOPRECIPITATION ASSAYS SHOWED THAT STAT5A BOUND TO A PROMOTER REGION OF THE EZH2 GENE, RESULTING IN AN INCREASE IN THE TRANSCRIPTIONAL ACTIVITY OF EZH2 IN LEUKEMIA CELLS. IMPORTANTLY, DOWNREGULATION OF EZH2 BY SHORT HAIRPIN RNAS (SHRNAS) INHIBITED THE EXPRESSION OF XIAP AND INCREASED THE MIR-219 LEVELS ASSOCIATED WITH A DECREASE IN HYPERMETHYLATION OF MIR-219-1 CPG ISLANDS. MOREOVER, OVEREXPRESSION OF MIR-219 DECREASED THE LEVELS OF XIAP IN CML CELLS. SINCE THE 3'-UNTRANSLATED REGION (3'-UTR) OF XIAP CONTAINS MIR219-5P-COMPLEMENTARY BINDING SITE, MIR-219 MIGHT MODULATE THE EXPRESSION OF XIAP THROUGH BINDING OF MIR-219 ON THE 3'-UTR OF XIAP. TAKEN TOGETHER, BCR/ABL POSITIVELY REGULATES THE EXPRESSION OF EZH2 VIA STAT5 SIGNALING. EZH2 MODULATES EPIGENETIC CHANGES AT DNA METHYLATED REGIONS ENCODING MIR-219 AND DOWNREGULATES THE LEVEL OF MIR-219, RESULTING IN UPREGULATION OF XIAP.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10  3877  31 KDM6A PROMOTES IMATINIB RESISTANCE THROUGH YY1-MEDIATED TRANSCRIPTIONAL UPREGULATION OF TRKA INDEPENDENTLY OF ITS DEMETHYLASE ACTIVITY IN CHRONIC MYELOGENOUS LEUKEMIA. RATIONALE: DESPITE LANDMARK THERAPY OF CHRONIC MYELOGENOUS LEUKEMIA (CML) WITH TYROSINE KINASE INHIBITORS (TKIS), DRUG RESISTANCE REMAINS PROBLEMATIC. CANCER PATHOGENESIS INVOLVES EPIGENETIC DYSREGULATION AND IN PARTICULAR, HISTONE LYSINE DEMETHYLASES (KDMS) HAVE BEEN IMPLICATED IN TKI RESISTANCE. WE SOUGHT TO IDENTIFY KDMS WITH ALTERED EXPRESSION IN CML AND DEFINE THEIR CONTRIBUTION TO IMATINIB RESISTANCE. METHODS: BIOINFORMATICS SCREENING COMPARED KDM EXPRESSION IN CML VERSUS NORMAL BONE MARROW WITH SHRNA KNOCKDOWN AND FLOW CYTOMETRY USED TO MEASURE EFFECTS ON IMATINIB-INDUCED APOPTOSIS IN K562 CELLS. TRANSCRIPTOMIC ANALYSES WERE PERFORMED AGAINST KDM6A CRISPR KNOCKOUT/SHRNA KNOCKDOWN K562 CELLS ALONG WITH GENE RESCUE EXPERIMENTS USING WILDTYPE AND MUTANT DEMETHYLASE-DEAD KDM6A CONSTRUCTS. CO-IMMUNOPRECIPITATION, LUCIFERASE REPORTER AND CHIP WERE EMPLOYED TO ELUCIDATE MECHANISMS OF KDM6A-DEPENDENT RESISTANCE. RESULTS: AMONGST FIVE KDMS UPREGULATED IN CML, ONLY KDM6A DEPLETION SENSITIZED CML CELLS TO IMATINIB-INDUCED APOPTOSIS. RE-INTRODUCTION OF DEMETHYLASE-DEAD KDM6A AS WELL AS WILD-TYPE KDM6A RESTORED IMATINIB RESISTANCE. RNA-SEQ IDENTIFIED NTRK1 GENE DOWNREGULATION AFTER DEPLETION OF KDM6A. MOREOVER, NTRK1 EXPRESSION POSITIVELY CORRELATED WITH KDM6A IN A SUBSET OF CLINICAL CML SAMPLES AND KDM6A KNOCKDOWN IN FRESH CML ISOLATES DECREASED NTRK1 ENCODED PROTEIN (TRKA) EXPRESSION. MECHANISTICALLY, KDM6A WAS RECRUITED TO THE NTRK1 PROMOTER BY THE TRANSCRIPTION FACTOR YY1 WITH SUBSEQUENT TRKA UPREGULATION ACTIVATING DOWN-STREAM SURVIVAL PATHWAYS TO INVOKE IMATINIB RESISTANCE. CONCLUSION: CONTRARY TO ITS REPORTED ROLE AS A TUMOR SUPPRESSOR AND INDEPENDENT OF ITS DEMETHYLASE FUNCTION, KDM6A PROMOTES IMATINIB-RESISTANCE IN CML CELLS. THE IDENTIFICATION OF THE KDM6A/YY1/TRKA AXIS AS A NOVEL IMATINIB-RESISTANCE MECHANISM REPRESENTS AN UNEXPLORED AVENUE TO OVERCOME TKI RESISTANCE IN CML.	2021	
                                                                                  
11  1945  38 EPIGALLOCATECHIN-3-GALLATE, A HISTONE ACETYLTRANSFERASE INHIBITOR, INHIBITS EBV-INDUCED B LYMPHOCYTE TRANSFORMATION VIA SUPPRESSION OF RELA ACETYLATION. BECAUSE THE P300/CBP-MEDIATED HYPERACETYLATION OF RELA (P65) IS CRITICAL FOR NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) ACTIVATION, THE ATTENUATION OF P65 ACETYLATION IS A POTENTIAL MOLECULAR TARGET FOR THE PREVENTION OF CHRONIC INFLAMMATION. DURING OUR ONGOING SCREENING STUDY TO IDENTIFY NATURAL COMPOUNDS WITH HISTONE ACETYLTRANSFERASE INHIBITOR (HATI) ACTIVITY, WE IDENTIFIED EPIGALLOCATECHIN-3-GALLATE (EGCG) AS A NOVEL HATI WITH GLOBAL SPECIFICITY FOR THE MAJORITY OF HAT ENZYMES BUT WITH NO ACTIVITY TOWARD EPIGENETIC ENZYMES INCLUDING HDAC, SIRT1, AND HMTASE. AT A DOSE OF 100 MICROMOL/L, EGCG ABROGATES P300-INDUCED P65 ACETYLATION IN VITRO AND IN VIVO, INCREASES THE LEVEL OF CYTOSOLIC IKAPPABALPHA, AND SUPPRESSES TUMOR NECROSIS FACTOR ALPHA (TNFALPHA)-INDUCED NF-KAPPAB ACTIVATION. WE ALSO SHOWED THAT EGCG PREVENTS TNFALPHA-INDUCED P65 TRANSLOCATION TO THE NUCLEUS, CONFIRMING THAT HYPERACETYLATION IS CRITICAL FOR NF-KAPPAB TRANSLOCATION AS WELL AS ACTIVITY. FURTHERMORE, EGCG TREATMENT INHIBITED THE ACETYLATION OF P65 AND THE EXPRESSION OF NF-KAPPAB TARGET GENES IN RESPONSE TO DIVERSE STIMULI. FINALLY, EGCG REDUCED THE BINDING OF P300 TO THE PROMOTER REGION OF INTERLEUKIN-6 GENE WITH AN INCREASED RECRUITMENT OF HDAC3, WHICH HIGHLIGHTS THE IMPORTANCE OF THE BALANCE BETWEEN HATS AND HISTONE DEACETYLASES IN THE NF-KAPPAB-MEDIATED INFLAMMATORY SIGNALING PATHWAY. IMPORTANTLY, EGCG AT 50 MICROMOL/L DOSE COMPLETELY BLOCKS EBV INFECTION-INDUCED CYTOKINE EXPRESSION AND SUBSEQUENTLY THE EBV-INDUCED B LYMPHOCYTE TRANSFORMATION. THESE RESULTS SHOW THE CRUCIAL ROLE OF ACETYLATION IN THE DEVELOPMENT OF INFLAMMATORY-RELATED DISEASES.	2009	
                                                                                                                                                                                                                                                                                                                                                                                    
12  5940  23 TARGETING METHYLTRANSFERASE PRMT5 ELIMINATES LEUKEMIA STEM CELLS IN CHRONIC MYELOGENOUS LEUKEMIA. IMATINIB-INSENSITIVE LEUKEMIA STEM CELLS (LSCS) ARE BELIEVED TO BE RESPONSIBLE FOR RESISTANCE TO BCR-ABL TYROSINE KINASE INHIBITORS AND RELAPSE OF CHRONIC MYELOGENOUS LEUKEMIA (CML). IDENTIFYING THERAPEUTIC TARGETS TO ERADICATE CML LSCS MAY BE A STRATEGY TO CURE CML. IN THE PRESENT STUDY, WE DISCOVERED A POSITIVE FEEDBACK LOOP BETWEEN BCR-ABL AND PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5) IN CML CELLS. OVEREXPRESSION OF PRMT5 WAS OBSERVED IN HUMAN CML LSCS. SILENCING PRMT5 WITH SHRNA OR BLOCKING PRMT5 METHYLTRANSFERASE ACTIVITY WITH THE SMALL-MOLECULE INHIBITOR PJ-68 REDUCED SURVIVAL, SERIAL REPLATING CAPACITY, AND LONG-TERM CULTURE-INITIATING CELLS (LTC-ICS) IN LSCS FROM CML PATIENTS. FURTHER, PRMT5 KNOCKDOWN OR PJ-68 TREATMENT DRAMATICALLY PROLONGED SURVIVAL IN A MURINE MODEL OF RETROVIRAL BCR-ABL-DRIVEN CML AND IMPAIRED THE IN VIVO SELF-RENEWAL CAPACITY OF TRANSPLANTED CML LSCS. PJ-68 ALSO INHIBITED LONG-TERM ENGRAFTMENT OF HUMAN CML CD34+ CELLS IN IMMUNODEFICIENT MICE. MOREOVER, INHIBITION OF PRMT5 ABROGATED THE WNT/BETA-CATENIN PATHWAY IN CML CD34+ CELLS BY DEPLETING DISHEVELLED HOMOLOG 3 (DVL3). THIS STUDY SUGGESTS THAT EPIGENETIC METHYLATION MODIFICATION ON HISTONE PROTEIN ARGININE RESIDUES IS A REGULATORY MECHANISM TO CONTROL SELF-RENEWAL OF LSCS AND INDICATES THAT PRMT5 MAY REPRESENT A POTENTIAL THERAPEUTIC TARGET AGAINST LSCS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
13  1287  25 DECITABINE-INDUCED APOPTOSIS IS DERIVED BY PUMA AND NOXA INDUCTION IN CHRONIC MYELOID LEUKEMIA CELL LINE AS WELL AS IN PBL AND IS POTENTIATED BY SAHA. RESTORATION OF CELLULAR APOPTOTIC PATHWAYS PLAYS A CRUCIAL ROLE IN CANCER THERAPY STRATEGIES. IN A BROAD SPECTRUM OF ANTICANCER DRUGS, EPIGENETIC EFFECTORS ARE IN THE CENTER OF INTEREST MOSTLY BECAUSE OF POTENTIAL REVERSIBILITY OF THEIR ACTION. METHYLATION STATUS OF THE CELLS IS INFLUENCED BY METHYLTRANSFERASE INHIBITOR 2-DEOXY-5'-AZACYTIDINE (DECITABINE, DAC), BUT HIGHER CONCENTRATIONS OF THIS AGENT CAUSE A DNA-DAMAGE. IN OUR STUDY, TUMOR SUPRESSOR P53-APOPTOTIC PATHWAY WAS ACTIVATED IN DECITABINE-INDUCED CELL DEATH. EXPRESSION OF P53-INDUCIBLE BH3-ONLY APOPTOTIC PROTEINS PUMA AND NOXA WAS ELEVATED AND LARGE ACTIVATION OF EXECUTIVE CASPASES WAS OBSERVED. THE EXTENT OF ACETYLATION IN THE CELL IS AFFECTED BY HISTONEDEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID (SAHA). COMBINATION OF SAHA WITH DECITABINE BROUGHT SYNERGISTIC EFFECT ON APOPTOSIS TRIGGERING IN CML-T1 CELL LINE, BUT APOPTOSIS AS WELL AS NECROSIS OCCURRED ALSO IN NORMAL PERIPHERAL BLOOD LYMPHOCYTES. THEREFORE, PROMISING POTENTIAL OF SUCH COMBINED THERAPY CALLS FOR MORE DETAILED INVESTIGATION OF UNWANTED EFFECTS IN NORMAL CELLS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14  5319  28 PTEN IS FUNDAMENTAL FOR ELIMINATION OF LEUKEMIA STEM CELLS MEDIATED BY GSK126 TARGETING EZH2 IN CHRONIC MYELOGENOUS LEUKEMIA. PURPOSE: LEUKEMIA STEM CELLS (LSCS) ARE AN IMPORTANT SOURCE OF TYROSINE KINASE INHIBITOR RESISTANCE AND DISEASE RELAPSE IN PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA (CML). TARGETING LSCS MAY BE AN ATTRACTIVE STRATEGY TO OVERRIDE THIS THORNY PROBLEM. GIVEN THAT EZH2 WAS OVEREXPRESSED IN PRIMARY CML CD34(+) CELLS, OUR PURPOSE IN THIS STUDY WAS TO EVALUATE THE EFFECTS OF TARGETING EZH2 ON CML LSCS AND CLARIFY ITS UNDERLYING MECHANISM.EXPERIMENTAL DESIGN: HUMAN PRIMARY CML CD34(+) CELLS AND RETROVIRALLY BCR-ABL-DRIVEN CML MOUSE MODELS WERE EMPLOYED TO EVALUATE THE EFFECTS OF SUPPRESSION OF EZH2 BY GSK126- OR EZH2-SPECIFIC SHRNA IN VITRO AND IN VIVO RECRUITMENT OF EZH2 AND H3K27ME3 ON THE PROMOTER OF TUMOR-SUPPRESSOR GENE PTEN IN CML CELLS WAS MEASURED BY CHROMATIN IMMUNOPRECIPITATION ASSAY.RESULTS: OUR RESULTS SHOWED THAT PHARMACOLOGIC INHIBITION OF EZH2 BY GSK126 NOT ONLY ELICITED APOPTOSIS AND RESTRICTED CELL GROWTH IN CML BULK LEUKEMIA CELLS, BUT ALSO DECREASED LSCS IN CML CD34(+) CELLS WHILE SPARING THOSE FROM NORMAL BONE MARROW CD34(+) CELLS. SUPPRESSION OF EZH2 BY GSK126 OR SPECIFIC SHRNA PROLONGED SURVIVAL OF CML MICE AND REDUCED THE NUMBER OF LSCS IN MICE. EZH2 KNOCKDOWN RESULTED IN ELEVATION OF PTEN AND LED TO IMPAIRED RECRUITMENT OF EZH2 AND H3K27ME3 ON THE PROMOTER OF PTEN GENE. THE EFFECT OF EZH2 KNOCKDOWN IN THE CML MICE WAS AT LEAST PARTIALLY REVERSED BY PTEN KNOCKDOWN.CONCLUSIONS: THESE FINDINGS IMPROVE THE UNDERSTANDING OF THE EPIGENETIC REGULATION OF STEMNESS IN CML LSCS AND WARRANT CLINICAL TRIAL OF GSK126 IN REFRACTORY PATIENTS WITH CML. CLIN CANCER RES; 24(1); 145-57. (C)2017 AACR.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                           
15  6688  25 VALPROATE SYNERGIZES WITH PURINE NUCLEOSIDE ANALOGUES TO INDUCE APOPTOSIS OF B-CHRONIC LYMPHOCYTIC LEUKAEMIA CELLS. RESISTANCE TO CHEMOTHERAPY AND DRUG TOXICITY ARE TWO MAJOR CONCERNS OF CHRONIC LYMPHOCYTIC LEUKAEMIA (B-CLL) TREATMENT BY PURINE NUCLEOSIDE ANALOGUES (PNA, I.E. FLUDARABINE AND CLADRIBINE). WE HYPOTHESIZED THAT TARGETING EPIGENETIC CHANGES MIGHT ADDRESS THESE ISSUES AND EVALUATED THE EFFECT OF THE HISTONE DEACETYLASE INHIBITOR VALPROATE (VPA) AT A CLINICALLY RELEVANT CONCENTRATION. VPA ACTED IN A HIGHLY SYNERGISTIC/ADDITIVE MANNER WITH FLUDARABINE AND CLADRIBINE TO INDUCE APOPTOSIS OF B-CLL CELLS. IMPORTANTLY, VPA ALSO RESTORED SENSITIVITY TO FLUDARABINE IN B CELLS FROM POOR PROGNOSIS CLL PATIENTS WHO BECAME RESISTANT TO CHEMOTHERAPY. MECHANISM OF APOPTOSIS INDUCED BY VPA ALONE OR COMBINED WITH FLUDARABINE OR TO CLADRIBINE WAS CASPASE-DEPENDENT AND INVOLVED THE EXTRINSIC PATHWAY. VPA, BUT NEITHER FLUDARABINE NOR CLADRIBINE, ENHANCED THE PRODUCTION OF REACTIVE OXYGEN SPECIES (ROS) AND INHIBITION OF ROS WITH N-ACETYLCYSTEINE DECREASES APOPTOSIS OF CLL CELLS. VPA STIMULATES HYPERPHOSPHORYLATION OF P42/P44 ERK, CYTOCHROME C RELEASE AND OVEREXPRESSION OF BAX AND FAS. TOGETHER, OUR DATA INDICATE THAT VPA MAY AMELIORATE THE OUTCOME OF PNA-BASED THERAPEUTIC PROTOCOLS AND PROVIDE A POTENTIAL ALTERNATIVE TREATMENT IN BOTH THE RELAPSED AND FRONT-LINE RESISTANT PATIENTS AND IN PATIENTS WITH HIGH RISK FEATURES.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  6402  20 THE ROLES OF EPIGENETIC MODIFICATIONS OF PROAPOPTOTIC BID AND BIM GENES IN IMATINIB-RESISTANT CHRONIC MYELOID LEUKEMIA CELLS. IN CHRONIC MYELOID LEUKEMIA (CML), EPIGENETIC MODIFICATIONS SUCH AS PROMOTER HYPERMETHYLATION AND INACTIVE HISTONE MODIFICATION ARE KNOWN MECHANISMS OF DRUG RESISTANCE. IN OUR STUDY, WE INVESTIGATED THE ROLES OF PROMOTER HYPERMETHYLATION OF BIM AND BID GENES AND H3K27ME3 HISTONE MODIFICATION ON IMATINIB RESISTANCE. WE DETECTED HIGHER EXPRESSION LEVELS OF BIM AND BID GENES AND LOWER EXPRESSION LEVELS OF EZH2, EED2, SIRT1, AND SUZ12 GENES IN IMATINIB-RESISTANT K562/IMA-3 CELLS COMPARED TO IMATINIB-NON-RESISTANT K562 CELLS. WHILE WE DETERMINED THE EZH2 AND DNMT ENZYMES AS BOUNDED TO THE PROMOTER OF THE BIM GENE, WE DID NOT DETECT HYPERMETHYLATION OF THIS PROMOTER. WE ALSO FOUND THE H3K27ME3 HISTONE MODIFICATION PROMOTER OF BIM AND BID GENES IN BOTH CELL LINES. IN CONCLUSION, OUR RESULTS SUPPORT THE NOTION THAT DNA PROMOTER METHYLATION MAY BE FORMED INDEPENDENTLY FROM EZH2-H3K27ME3 AND PRO-APOPTOTIC BIM AND BID GENES ARE NOT METHYLLATED IN THE IMATINIB RESISTANCE OF CML CELLS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17  2081  30 EPIGENETIC DOWN-REGULATION OF BIM EXPRESSION IS ASSOCIATED WITH REDUCED OPTIMAL RESPONSES TO IMATINIB TREATMENT IN CHRONIC MYELOID LEUKAEMIA. BACKGROUND: EXPRESSION OF THE PRO-APOPTOTIC BCL-2-INTERACTING MEDIATOR (BIM) HAS RECENTLY BEEN IMPLICATED IN IMATINIB-INDUCED APOPTOSIS OF BCR-ABL1(+) CELLS. HOWEVER, THE MECHANISMS INVOLVED IN THE REGULATION OF BIM IN CML AND ITS ROLE IN THE CLINICAL SETTING HAVE NOT BEEN ESTABLISHED. DESIGN AND METHODS: WE ANALYSED THE MRNA EXPRESSION OF BIM IN 100 NEWLY DIAGNOSED PATIENTS WITH CML IN CHRONIC PHASE BY Q-RT-PCR AND THE PROTEIN LEVELS BY WESTERN BLOT ANALYSIS. METHYLATION STATUS WAS ANALYSED BY BISULPHITE GENOMIC SEQUENCING AND MSP. CML CELL LINES WERE TREATED WITH IMATINIB AND 5-AZA-2'-DEOXYCYTIDINE, AND WERE TRANSFECTED WITH TWO DIFFERENT SIRNAS AGAINST BIM AND CELL PROLIFERATION AND APOPTOSIS WERE ANALYSED. RESULTS: WE DEMONSTRATED THAT DOWN-REGULATION OF BIM EXPRESSION WAS PRESENT IN 36% OF THE PATIENTS AND WAS SIGNIFICANTLY ASSOCIATED WITH A LACK OF OPTIMAL RESPONSE TO IMATINIB AS INDICATED BY THE DECREASE IN CYTOGENETIC AND MOLECULAR RESPONSES AT 6, 12 AND 18 MONTHS IN COMPARISON WITH PATIENTS WITH NORMAL BIM EXPRESSION (P<0.05). EXPRESSION OF BIM WAS MEDIATED BY PROMOTER HYPERMETHYLATION AS DEMONSTRATED BY RESTORATION OF BIM EXPRESSION AFTER TREATMENT OF CML CELLS WITH 5-AZA-2'-DEOXYCYTIDINE. USING CML CELL LINES WITH LOW AND NORMAL EXPRESSION OF BIM WE FURTHER DEMONSTRATED THAT THE EXPRESSION OF BIM IS REQUIRED FOR IMATINIB-INDUCED CML APOPTOSIS. CONCLUSION: OUR DATA INDICATE THAT DOWN-REGULATION OF BIM IS EPIGENETICALLY CONTROLLED BY METHYLATION IN A PERCENTAGE OF CML PATIENTS AND HAS AN UNFAVOURABLE PROGNOSTIC IMPACT, AND THAT THE COMBINATION OF IMATINIB WITH A DE-METHYLATING AGENT MAY RESULT IN IMPROVED RESPONSES IN PATIENTS WITH DECREASED EXPRESSION OF BIM.	2009	
                                                                                                                                                                                                                                                                                                                                   
18  6277  28 THE PATHOGENIC ROLE OF PERSISTENT MILK SIGNALING IN MTORC1- AND MILK-MICRORNA-DRIVEN TYPE 2 DIABETES MELLITUS. MILK, THE SECRETORY PRODUCT OF THE LACTATION GENOME, PROMOTES GROWTH OF THE NEWBORN MAMMAL. MILK DELIVERS INSULINOTROPIC AMINO ACIDS, THUS MAINTAINS A MOLECULAR CROSSTALK WITH THE PANCREATIC BETA-CELL OF THE MILK RECIPIENT. HOMEOSTASIS OF BETA-CELLS AND INSULIN PRODUCTION DEPEND ON THE APPROPRIATE MAGNITUDE OF MTORC1 SIGNALING. MTORC1 IS ACTIVATED BY BRANCHED-CHAIN AMINO ACIDS (BCAAS), GLUTAMINE, AND PALMITIC ACID, ABUNDANT NUTRIENT SIGNALS OF COW S MILK. FURTHERMORE, MILK DELIVERS BIOACTIVE EXOSOMAL MICRORNAS. AFTER MILK CONSUMPTION, BOVINE MICRORNA-29B, A MEMBER OF THE DIABETOGENIC MICRORNA-29- FAMILY, REACHES THE SYSTEMIC CIRCULATION AND THE CELLS OF THE MILK CONSUMER. MICRORNA-29B DOWNREGULATES BRANCHEDCHAIN ALPHA-KETOACID DEHYDROGENASE, A POTENTIAL EXPLANATION FOR INCREASED BCAA SERUM LEVELS, THE METABOLIC SIGNATURE OF INSULIN RESISTANCE AND TYPE 2 DIABETES MELLITUS (T2DM). IN NON-OBESE DIABETIC MICE, MICRORNA-29B DOWNREGULATES THE ANTIAPOPTOTIC PROTEIN MCL-1, WHICH LEADS TO EARLY BETA-CELL DEATH. IN ALL MAMMALS EXCEPT NEOLITHIC HUMANS, MILK-DRIVEN MTORC1 SIGNALING IS PHYSIOLOGICALLY RESTRICTED TO THE POSTNATAL PERIOD. IN CONTRAST, CHRONIC HYPERACTIVATED MTORC1 SIGNALING HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF AGE-RELATED DISEASES OF CIVILIZATION INCLUDING T2DM. NOTABLY, CHRONIC HYPERACTIVATION OF MTORC1 ENHANCES ENDOPLASMIC RETICULUM STRESS THAT PROMOTES APOPTOSIS. IN FACT, HYPERACTIVATED BETA-CELL MTORC1 SIGNALING INDUCED EARLY BETA-CELL APOPTOSIS IN A MOUSE MODEL. THE EPIC-INTERACT STUDY DEMONSTRATED AN ASSOCIATION BETWEEN MILK CONSUMPTION AND T2DM IN FRANCE, ITALY, UNITED KINGDOM, GERMANY, AND SWEDEN. IN CONTRAST, FERMENTED MILK PRODUCTS AND CHEESE EXHIBIT AN INVERSE CORRELATION. SINCE THE EARLY 1950 S, REFRIGERATION TECHNOLOGY ALLOWED WIDESPREAD CONSUMPTION OF FRESH PASTEURIZED MILK, WHICH FACILITATES DAILY INTAKE OF BIOACTIVE BOVINE MICRORNAS. PERSISTENT UPTAKE OF COW S MILK-DERIVED MICRORNAS APPARENTLY TRANSFERS AN OVERLOOKED EPIGENETIC DIABETOGENIC PROGRAM THAT SHOULD NOT REACH THE HUMAN FOOD CHAIN.	2015	

19   690  20 BRD4 DEGRADATION BLOCKS EXPRESSION OF MYC AND MULTIPLE FORMS OF STEM CELL RESISTANCE IN PH(+) CHRONIC MYELOID LEUKEMIA. IN MOST PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) CLONAL CELLS CAN BE KEPT UNDER CONTROL BY BCR::ABL1 TYROSINE KINASE INHIBITORS (TKI). HOWEVER, OVERT RESISTANCE OR INTOLERANCE AGAINST THESE TKI MAY OCCUR. WE IDENTIFIED THE EPIGENETIC READER BRD4 AND ITS DOWNSTREAM-EFFECTOR MYC AS GROWTH REGULATORS AND THERAPEUTIC TARGETS IN CML CELLS. BRD4 AND MYC WERE FOUND TO BE EXPRESSED IN PRIMARY CML CELLS, CD34(+) /CD38(-) LEUKEMIC STEM CELLS (LSC), AND IN THE CML CELL LINES KU812, K562, KCL22, AND KCL22(T315I) . THE BRD4-TARGETING DRUG JQ1 WAS FOUND TO SUPPRESS PROLIFERATION IN KU812 CELLS AND PRIMARY LEUKEMIC CELLS IN THE MAJORITY OF PATIENTS WITH CHRONIC PHASE CML. IN THE BLAST PHASE OF CML, JQ1 WAS LESS EFFECTIVE. HOWEVER, THE BRD4 DEGRADER DBET6 WAS FOUND TO BLOCK PROLIFERATION AND/OR SURVIVAL OF PRIMARY CML CELLS IN ALL PATIENTS TESTED, INCLUDING BLAST PHASE CML AND CML CELLS EXHIBITING THE T315I VARIANT OF BCR::ABL1. MOREOVER, DBET6 WAS FOUND TO BLOCK MYC EXPRESSION AND TO SYNERGIZE WITH BCR::ABL1 TKI IN INHIBITING THE PROLIFERATION IN THE JQ1-RESISTANT CELL LINE K562. FURTHERMORE, BRD4 DEGRADATION WAS FOUND TO OVERCOME OSTEOBLAST-INDUCED TKI RESISTANCE OF CML LSC IN A CO-CULTURE SYSTEM AND TO BLOCK INTERFERON-GAMMA-INDUCED UPREGULATION OF THE CHECKPOINT ANTIGEN PD-L1 IN LSC. FINALLY, DBET6 WAS FOUND TO SUPPRESS THE IN VITRO SURVIVAL OF CML LSC AND THEIR ENGRAFTMENT IN NSG MICE. TOGETHER, TARGETING OF BRD4 AND MYC THROUGH BET DEGRADATION SENSITIZES CML CELLS AGAINST BCR::ABL1 TKI AND IS A POTENT APPROACH TO OVERCOME MULTIPLE FORMS OF DRUG RESISTANCE IN CML LSC.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  5301  26 PROTEIN PHOSPHATASE 2A CATALYTIC SUBUNIT ALPHA PLAYS A MYD88-DEPENDENT, CENTRAL ROLE IN THE GENE-SPECIFIC REGULATION OF ENDOTOXIN TOLERANCE. MYD88, THE INTRACELLULAR ADAPTOR OF MOST TLRS, MEDIATES EITHER PROINFLAMMATORY OR IMMUNOSUPPRESSIVE SIGNALING THAT CONTRIBUTES TO CHRONIC INFLAMMATION-ASSOCIATED DISEASES. ALTHOUGH GENE-SPECIFIC CHROMATIN MODIFICATIONS REGULATE INFLAMMATION, THE ROLE OF MYD88 SIGNALING IN ESTABLISHING SUCH EPIGENETIC LANDSCAPES UNDER DIFFERENT INFLAMMATORY STATES REMAINS ELUSIVE. USING QUANTITATIVE PROTEOMICS TO ENUMERATE THE INFLAMMATION-PHENOTYPIC CONSTITUENTS OF THE MYD88 INTERACTOME, WE FOUND THAT IN ENDOTOXIN-TOLERANT MACROPHAGES, PROTEIN PHOSPHATASE 2A CATALYTIC SUBUNIT ALPHA (PP2AC) ENHANCES ITS ASSOCIATION WITH MYD88 AND IS CONSTITUTIVELY ACTIVATED. KNOCKDOWN OF PP2AC PREVENTS SUPPRESSION OF PROINFLAMMATORY GENES AND RESISTANCE TO APOPTOSIS. THROUGH SITE-SPECIFIC DEPHOSPHORYLATION, CONSTITUTIVELY ACTIVE PP2AC DISRUPTS THE SIGNAL-PROMOTING TLR4-MYD88 COMPLEX AND BROADLY SUPPRESSES THE ACTIVITIES OF MULTIPLE PROINFLAMMATORY/PROAPOPTOTIC PATHWAYS AS WELL, SHIFTING PROINFLAMMATORY MYD88 SIGNALING TO A PROSURVIVAL MODE. CONSTITUTIVELY ACTIVE PP2AC TRANSLOCATED WITH MYD88 INTO THE NUCLEI OF TOLERANT MACROPHAGES ESTABLISHES THE IMMUNOSUPPRESSIVE PATTERN OF CHROMATIN MODIFICATIONS AND REPRESSES CHROMATIN REMODELING TO SELECTIVELY SILENCE PROINFLAMMATORY GENES, COORDINATING THE MYD88-DEPENDENT INFLAMMATION CONTROL AT BOTH SIGNALING AND EPIGENETIC LEVELS UNDER ENDOTOXIN-TOLERANT CONDITIONS.	2013