1 6579 136 TREFOIL FACTORS AND HUMAN GASTRIC CANCER (REVIEW). TFF1/PS2, TFF2/SP AND TFF3/ITF ARE SOLUBLE PEPTIDES WITH TREFOIL DOMAIN(S) AND C-TERMINAL DIMERIZATION DOMAIN, WHICH ARE CONSERVED AMONG HUMAN, COW, MOUSE AND RAT. TFF1 MRNA IS EXPRESSED IN STOMACH (MUCOUS CELLS IN FUNDUS AND ANTRUM), TFF2 MRNA IN STOMACH (MUCOUS NECK CELLS IN FUNDUS AND BASAL CELLS IN ANTRAL AND PYLORIC GLANDS) AND DUODENUM (BRUNNER'S GLAND), TFF3 MRNA IN SMALL INTESTINE AND LARGE INTESTINE (GOBLET CELLS). EXPRESSION OF TFF1, TFF2 AND TFF3 MRNAS ARE DIFFERENTIALLY REGULATED BY FGF2/BFGF, FGF7/KGF, ESTROGEN, ASPIRIN, ARACHIDONIC ACID, X-RAY IRRADIATION, AND HYDROGEN PEROXIDE. GASTRIC CANCER IS CLASSIFIED INTO THE INTESTINAL TYPE AND THE DIFFUSE TYPE. TFF MRNAS ARE PREFERENTIALLY EXPRESSED IN DIFFUSE-TYPE GASTRIC CANCER CELLS. CUSTOM-MADE MICROARRAY (TFF MRNAS) AND ELISA (TFF PROTEINS) MIGHT BE APPLICABLE FOR SCREENING METHODS OF PERITONEAL AND BONE MARROW DISSEMINATION FROM DIFFUSE-TYPE GASTRIC CANCER. TFF1 AND TFF2 MRNAS ARE FREQUENTLY DOWN-REGULATED IN INTESTINAL-TYPE GASTRIC CANCER. TFF1 GENE, INACTIVATED BY DELETION, MISSENSE MUTATION AND PROMOTER HYPERMETHYLATION, IS A TUMOR SUPPRESSOR GENE IMPLICATED IN GASTRIC CANCER. TFF2 IS A CANDIDATE TUMOR SUPPRESSOR GENE; HOWEVER, GENETIC AND EPIGENETIC ALTERATIONS OF TFF2 GENE IN HUMAN GASTRIC CANCER REMAIN UNCLEAR. TFF1, TFF2 AND TFF3 PLAY KEY ROLES IN MUCOSAL PROTECTION THROUGH MUCOUS-BARRIER FORMATION, AND ALSO IN MUCOSAL REPAIR THROUGH PROMOTION OF RESTITUTION AFTER INJURY. PATIENTS WITH CHRONIC ATROPHIC GASTRITIS AND THOSE WITH ULCERATIVE COLITIS ARE AT RISK OF GASTRIC CANCER AND COLORECTAL CANCER, RESPECTIVELY. TFF1, TFF2 AND TFF3 PROTEINS MIGHT BE APPLICABLE FOR CHEMOPREVENTION OF GASTROINTESTINAL CANCER ASSOCIATED WITH CHRONIC PERSISTENT INFLAMMATION. 2003 2 1860 21 EMBRYONIC PROGRAM ACTIVATED DURING BLAST CRISIS OF CHRONIC MYELOGENOUS LEUKEMIA (CML) IMPLICATES A TCF7L2 AND MYC COOPERATIVE CHROMATIN BINDING. CHRONIC MYELOID LEUKEMIA (CML) IS CHARACTERIZED BY AN INHERENT GENETIC INSTABILITY, WHICH CONTRIBUTES TO THE PROGRESSION OF THE DISEASE TOWARDS AN ACCELERATED PHASE (AP) AND BLAST CRISIS (BC). SEVERAL CYTOGENETIC AND GENOMIC ALTERATIONS HAVE BEEN REPORTED IN THE PROGRESSION TOWARDS BC, BUT THE PRECISE MOLECULAR MECHANISMS OF THIS EVENT ARE UNDETERMINED. TRANSCRIPTION FACTOR 7 LIKE 2 (TFC7L2) IS A MEMBER OF THE TCF FAMILY OF PROTEINS THAT ARE KNOWN TO ACTIVATE WNT TARGET GENES SUCH AS CYCLIN D1. TCF7L2 HAS BEEN SHOWN TO BE OVEREXPRESSED IN ACUTE MYELOID LEUKEMIA (AML) AND REPRESENTS A DRUGGABLE TARGET. WE REPORT HERE THAT TCF7L2 TRANSCRIPTION FACTOR EXPRESSION WAS FOUND TO BE CORRELATED TO BLAST CELL NUMBERS DURING THE PROGRESSION OF THE DISEASE. IN THESE CELLS, TCF7L2 CHIP-SEQUENCING HIGHLIGHTED DISTAL CIS ACTIVE ENHANCER, SUCH AS ELEMENTS IN SMAD3, ATF5, AND PRMT1 GENOMIC REGIONS AND A PROXIMAL ACTIVE TRANSCRIPTIONAL PROGRAM OF 144 GENES. THE ANALYSIS OF CHIP-SEQUENCING OF MYC REVEALED A SIGNIFICANT OVERLAPPING OF TCF7L2 EPIGENETIC PROGRAM WITH MYC. THE BETA-CATENIN ACTIVATOR LITHIUM CHLORIDE AND THE MYC-MAX DIMERIZATION INHIBITOR 10058-F4 SIGNIFICANTLY MODIFIED THE EXPRESSION OF THREE EPIGENETIC TARGETS IN THE BC CELL LINE K562. THESE RESULTS SUGGEST FOR THE FIRST TIME THE COOPERATIVE ROLE OF TCF7L2 AND MYC DURING CML-BC AND THEY STRENGTHEN PREVIOUS DATA SHOWING A POSSIBLE INVOLVEMENT OF EMBRYONIC GENES IN THIS PROCESS. 2020 3 1798 38 EFFECT OF HELICOBACTER PYLORI INFECTION ON GATA-5 AND TFF1 REGULATION, COMPARISON BETWEEN PEDIATRIC AND ADULT PATIENTS. BACKGROUND: GATA FACTORS, WHICH CONSTITUTE A FAMILY OF TRANSCRIPTION REGULATORY PROTEINS, PARTICIPATE IN GASTROINTESTINAL DEVELOPMENT. TREFOIL FACTOR 1 (TFF1) PLAYS A CRUCIAL ROLE IN MUCOSAL DEFENSE AND HEALING, AND EVIDENCE SUGGESTS THAT GATA-5 MEDIATED ITS REGULATION. GASTRIC CANCER IS A MULTIPLE-STEP PROCESS TRIGGERED BY HELICOBACTER PYLORI AND IS CHARACTERIZED BY ACCUMULATION OF MOLECULAR AND EPIGENETIC ALTERATION. THE AIM OF THIS STUDY WAS TO EVALUATE THE EFFECT OF H. PYLORI INFECTION ON THE REGULATION OF GATA-5 AND TFF1 IN VITRO AND IN VIVO. RESULTS: INFECTED CELLS EXHIBITED UPREGULATION OF GATA-5 AND TFF1 AFTER 48 H. AN INCREASE IN GATA-5 AND TFF1 MRNA LEVELS WAS ALSO FOUND IN MICE SAMPLES AFTER 6 AND 12 MONTHS OF INFECTION, RESPECTIVELY. IN HUMAN SAMPLES, WE FOUND AN ASSOCIATION BETWEEN H. PYLORI INFECTION AND GATA-5 UPREGULATION. IN FACT, AMONG H. PYLORI-INFECTED PATIENTS, HYPERMETHYLATION WAS OBSERVED IN 45.5% OF PEDIATRIC SAMPLES, IN 62.6% OF CHRONIC GASTRITIS SAMPLES, AND IN 63% OF GASTRIC CANCER SAMPLES. REGARDING TFF1, THE EXPRESSION LEVELS WERE SIMILAR IN PEDIATRICS AND ADULTS PATIENTS, AND WERE INDEPENDENT OF H. PYLORI INFECTION, AND THE EXPRESSION OF THESE FACTORS WAS DOWNREGULATED IN GASTRIC CANCER SAMPLES. GATA-5 PROMOTER METHYLATION WAS ASSOCIATED WITH A DECREASE IN TFF1 MRNA LEVELS. CONCLUSIONS: OUR RESULTS SUGGEST THAT THE UPREGULATION OF GATA-5 AND TFF1 OBSERVED IN VITRO AND IN VIVO MAY BE CORRELATED WITH A PROTECTIVE EFFECT OF THE MUCOSA IN RESPONSE TO INFECTION. THE EPIGENETIC INACTIVATION OF GATA-5 OBSERVED IN HUMAN BIOPSIES FROM INFECTED PATIENTS MAY SUGGEST THAT THIS ALTERATION IS AN EARLY EVENT OCCURRING IN ASSOCIATION WITH H. PYLORI INFECTION. 2018 4 4361 28 MIR-96 ACTS AS A TUMOR SUPPRESSOR VIA TARGETING THE BCR-ABL1 ONCOGENE IN CHRONIC MYELOID LEUKEMIA BLASTIC TRANSFORMATION. MICRORNA-MEDIATED POSTTRANSCRIPTIONAL REGULATION IS AN IMPORTANT EPIGENETIC REGULATORY MECHANISM OF GENE EXPRESSION, AND ITS DYSREGULATION IS INVOLVED IN THE DEVELOPMENT AND PROGRESSION OF A VARIETY OF MALIGNANCIES, INCLUDING CHRONIC MYELOID LEUKEMIA (CML). THE BCR-ABL1 FUSION GENE IS NOT ONLY THE INITIATING FACTOR OF CML, BUT IT IS ALSO AN IMPORTANT DRIVING FACTOR FOR BLASTIC TRANSFORMATION. TYROSINE KINASE INHIBITORS (TKIS) TARGETING BCR-ABL1 TYROSINE KINASE ACTIVITY, REPRESENTED BY IMATINIB, ARE CURRENTLY THE FIRST-LINE TREATMENT FOR CML. HOWEVER, DUE TO PRIMARY RESISTANCE OR SECONDARY RESISTANCE CAUSED BY MUTATIONS IN THE BCR-ABL1 KINASE DOMAIN, TKIS CANNOT COMPLETELY PREVENT THE PROGRESSION OF CML; THUS, THE STUDY OF BCR-ABL1 GENE EXPRESSION REGULATION IS OF GREAT SIGNIFICANCE. IN THIS STUDY, BIOINFORMATICS ANALYSIS AND OUR RESULTS SHOWED THAT MIR-96 COULD DIRECTLY BIND TO THE 3'UTR REGION OF BCR-ABL1 TO REGULATE FUSION PROTEIN EXPRESSION, THEREBY REGULATING ITS DOWNSTREAM SIGNALING PATHWAY ACTIVITY. WE ALSO FOUND THAT MIR-96 WAS DOWNREGULATED DURING THE PROGRESSION FROM THE CHRONIC PHASE (CML-CP) TO THE BLAST CRISIS (CML-BC). DOWNREGULATION OF MIR-96 COULD PROMOTE THE PROLIFERATION AND PARTICIPATE IN THE CELL DIFFERENTIATION OF CML-BC CELLS. ADDITIONALLY, WE FOUND THAT THE NOVEL HISTONE DEACETYLASE DRUG CHIDAMIDE AND THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE COULD RESTORE THE LOW EXPRESSION OF MIR-96 IN CML CELLS, AND THERE WERE TWO ABNORMAL HYPERMETHYLATED SITES IN THE PROMOTER REGION OF MIR-96 IN CML, SUGGESTING THAT ITS LOW EXPRESSION MIGHT BE AT LEAST PARTIALLY REGULATED BY EPIGENETIC MECHANISMS. IN ADDITION, RE-EXPRESSION OF MIR-96 COULD INCREASE THE SENSITIVITY OF CML-BC CELLS TO IMATINIB. THUS, MIR-96 FUNCTIONS AS A TUMOR SUPPRESSOR, AND RE-EXPRESSION OF THIS MICRORNA MIGHT HAVE THERAPEUTIC BENEFITS IN CML BLASTIC TRANSFORMATION. 2019 5 6871 23 [PATHOGENETIC IMPORTANCE OF HELICOBACTER PYLORI INFECTION]. H. PYLORI ARE ETIOLOGICAL FACTOR OF HUMAN ACUTE AND CHRONIC GASTRITIS. DEPENDING ON PATHOGENIC FACTORS OF MICROORGANISM AND POLYMORPHISM OF HUMAN GENES, CHRONIC GASTRITIS CAN BE A CAUSE FOR ULCERATIVE ENTERITIS OF THE DUODENUM OR STOMACH, GASTRIC ADENOCARCINOMA AND MALT-LYMPHOMA DEVELOPMENT. WE REVEALED GENETIC FEATURES OF BACTERIA, DETERMINED THE INTENSITY OF INFLAMMATION, SUCH AS PATHOGENIC FACTORS--CAG, PLASTIC REGION OF THE GENOME AND ADHESIN CODING GENES. EPIGENETIC CHANGES, FOR EXAMPLE THE METHYLATION OF E-CADHERIN GENE ASSOCIATED WITH H PYLORI, ARE CRUCIAL FOR CARCINOGENESIS. THEREBY, PREDISPOSITION OF CHRONIC GASTRITIS ASSOCIATED WITH H. PYLORI TO ULCERATIVE ENTERITIS OF THE DUODENUM, ULCERATIVE STOMACH DISEASE OR GASTRIC ADENOCARCINOMA DEPENDS ON TOPOGRAPHY, THE INTENSITY OF INFLAMMATION AND CHANGES OF ACID PRODUCTION IN THE STOMACH. 2012 6 6793 23 [DOWN-REGULATION OF TRANSCRIPTION FACTOR PU.1 VIA ABNORMAL EPIGENETIC MODIFICATION IN CHRONIC MYELOID LEUKEMIA]. OBJECTIVE: TO INVESTIGATE THE UNDERLYING MECHANISM AND CLINICAL SIGNIFICANCE OF PU.1 DOWN-EXPRESSION IN CHRONIC MYELOID LEUKEMIA (CML) PATIENTS. METHODS: DIFFERENT METHYLATION STATUS OF PU.1 PROMOTER REGION CONTAINING 20 CPG ISLANDS IN NORMAL INDIVIDUALS, CML CHRONIC PHASE AND BLAST CRISIS PATIENTS, COMPLETE CYTOGENETIC REMISSION PATIENTS AFTER IMATINIB TREATMENT, AND BLAST CRISIS BONE MARROW K562 CML CELLS WAS DETECTED BY BISULFITE SEQUENCING. SEMI-QUANTITATIVE PCR WAS USED TO DETECT THE PU.1 MRNA EXPRESSION IN NORMAL CONTROLS, CML CHRONIC PHASE AND BLAST CRISIS PATIENTS, AND BLAST CRISIS BONE MARROW K562 CML CELLS. INDIRECT IMMUNE FLUORESCENCE AND WESTERN BLOT WERE USED TO ANALYZE THE EXPRTESSION OF PU.1 PROTEIN IN NORMAL INDIVIDUALS, CML CHRONIC PHASE AND BLAST CRISIS PATIENTS, AND BLAST CRISIS BONE MARROW K562 CML CELLS. RESULTS: ABERRANT METHYLATION IN THE PROMOTER REGION OF TRANSCRIPTION FACTOR PU.1 WAS FOUND IN BOTH CML CHRONIC PHASE AND BLAST CRISIS PHASE BONE MARROW CELLS, AS WELL AS IN CML BLAST K562 CELLS. DOWN-EXPRESSION OF PU.1 MRNA AND PROTEIN LEVELS WAS FOUND IN ABOVE CELLS. NO METHYLATION IN THE PROMOTER REGION OF PU.1 WAS OBSERVED IN NORMAL INDIVIDUALS, AND THE PU.1 MRNA AND PROTEIN EXPRESSIONS WERE NOT REDUCED AT ALL. FURTHERMORE, HIGH METHYLATION STATUS OF BONE MARROW CELLS WAS EVEN OBSERVED IN THE CML PATIENTS WHO ACQUIRED COMPLETE CYTOGENETIC REMISSION. CONCLUSIONS: THE RESULTS OF OUR STUDY INDICATE THAT THE EPIGENETIC MODIFICATION OF PU.1 IN CML PATIENTS AND K562 CELL LINE MIGHT BE RESPONSIBLE FOR THE DOWN-EXPRESSION OF PU.1. THE DATA SUGGEST THAT ABERRANT METHYLATION OF PU.1 PLAYS A ROLE IN CML PATHOGENESIS, THEREFORE, IT MIGHT SERVE AS A USEFUL BIOMARKER AND POTENTIAL TARGET IN THERAPY FOR CHRONIC MYELOID LEUKEMIA. 2012 7 2391 30 EPIGENETIC REPRESSION OF DNA MISMATCH REPAIR BY INFLAMMATION AND HYPOXIA IN INFLAMMATORY BOWEL DISEASE-ASSOCIATED COLORECTAL CANCER. SPORADIC HUMAN MISMATCH REPAIR (MMR)-DEFICIENT COLORECTAL CANCERS ACCOUNT FOR APPROXIMATELY 12.5% OF ALL CASES OF COLORECTAL CANCER. MMR-DEFICIENT COLORECTAL CANCERS ARE CLASSICALLY CHARACTERIZED BY RIGHT-SIDED LOCATION, MULTIFOCALITY, MUCINOUS HISTOLOGY, AND LYMPHOCYTIC INFILTRATION. HOWEVER, TUMORS IN GERM-LINE MMR-DEFICIENT MOUSE MODELS LACK THESE HISTOPATHOLOGIC FEATURES. MICE LACKING THE HETEROTRIMERIC G PROTEIN ALPHA SUBUNIT GIALPHA2 DEVELOP CHRONIC COLITIS AND MULTIFOCAL, RIGHT-SIDED CANCERS WITH MUCINOUS HISTOPATHOLOGY, SIMILAR TO HUMAN MMR-DEFICIENT COLORECTAL CANCER. YOUNG GIALPHA2-/- COLONIC EPITHELIUM HAS NORMAL MMR EXPRESSION BUT SELECTIVELY LOSES MLH1 AND CONSEQUENTLY PMS2 EXPRESSION FOLLOWING INFLAMMATION. GIALPHA2-/- CANCERS HAVE MICROSATELLITE INSTABILITY. MLH1 IS EPIGENETICALLY SILENCED NOT BY PROMOTER HYPERMETHYLATION BUT BY DECREASED HISTONE ACETYLATION. CHRONICALLY INFLAMED GIALPHA2-/- COLONIC MUCOSA CONTAINS PATCHY HYPOXIA, WITH INCREASED CRYPT EXPRESSION OF THE HYPOXIA MARKERS DEC-1 AND BNIP3. CHROMATIN IMMUNOPRECIPITATION IDENTIFIED INCREASED BINDING OF THE TRANSCRIPTIONAL REPRESSOR DEC-1 TO THE PROXIMAL MLH1 PROMOTER IN HYPOXIC YAMC CELLS AND COLITIC GIALPHA2-/- CRYPTS. TREATING GIALPHA2-/- MICE WITH THE HISTONE DEACETYLASE INHIBITOR SUBEROYLANILIDE HYDROXAMIC ACID SIGNIFICANTLY DECREASED COLITIS ACTIVITY AND RESCUED MLH1 EXPRESSION IN CRYPT EPITHELIAL CELLS, WHICH WAS ASSOCIATED WITH INCREASED ACETYL HISTONE H3 LEVELS AND DECREASED DEC-1 BINDING AT THE PROXIMAL MLH1 PROMOTER, CONSISTENT WITH A HISTONE DEACETYLASE-DEPENDENT MECHANISM. THESE DATA LINK CHRONIC HYPOXIC INFLAMMATION, EPIGENETIC MMR PROTEIN DOWN-REGULATION, DEVELOPMENT OF MMR-DEFICIENT COLORECTAL CANCER, AND THE FIRSTMOUSE MODEL OF SOMATICALLY ACQUIRED MMR-DEFICIENT COLORECTAL CANCER. 2009 8 6780 24 [BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM ACCOMPANIED BY CHRONIC MYELOMONOCYTIC LEUKEMIA SUCCESSFULLY TREATED WITH AZACITIDINE]. BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN) IS A RARE DISEASE THAT DEVELOPS WITH A SKIN LESION AND IS OFTEN ACCOMPANIED BY LEUKEMIC TRANSFORMATION. THE NORMAL COUNTERPARTS OF BPDCN TUMOR CELLS ARE PROGENITORS OF PLASMACYTOID DENDRITIC CELLS, WHEREAS THE ORIGINS ARE THOUGHT TO BE HEMATOPOIETIC STEM CELLS. APPROXIMATELY 10%-20% OF BPDCN PATIENTS DEVELOP OTHER HEMATOLOGIC MALIGNANCIES, INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). MUTATIONS IN EPIGENETIC REGULATORS ARE FREQUENTLY OBSERVED IN BOTH BPDCN AND CMML TUMORS. AZACITIDINE, A DRUG THAT TARGETS EPIGENETIC DYSREGULATION, IS KNOWN TO BE AN EFFECTIVE TREATMENT FOR CMML. HOWEVER, IT HAS BEEN USED IN FEW BPDCN PATIENTS. HERE, WE REPORT A BPDCN PATIENT WITH SKIN LESIONS, BONE MARROW INFILTRATION, AND LYMPHADENOPATHY. CMML ALSO DEVELOPED DURING THE COURSE OF BPDCN. AZACITIDINE HAD POSITIVE EFFECTS ON CMML; HOWEVER, BPDCN AGGRESSIVELY RELAPSED DURING TREATMENT. TWO TET2 MUTATIONS WERE FOUND IN BOTH BPDCN AND CMML TUMORS; ONE OF WHICH WAS COMMONLY IDENTIFIED IN BOTH TUMORS. 2018 9 690 18 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 10 571 15 BCR-ABL INDUCES AUTOCRINE IGF-1 SIGNALING. BCR-ABL ONCOGENE IS RESPONSIBLE FOR THE INITIAL PHASE OF CHRONIC MYELOGENOUS LEUKEMIA (CML), WHICH IS EFFECTIVELY TREATED BY THE BCR-ABL INHIBITOR IMATINIB. OVER TIME PATIENTS BECOME RESISTANT TO TREATMENT AND PROGRESS TO BLAST CRISIS, AN EVENT THAT IS DRIVEN BY ADDITIONAL GENETIC AND EPIGENETIC ABERRATIONS. RECENTLY, WE SHOWED THAT RIZ1 EXPRESSION DECREASES IN BLAST CRISIS AND THAT RE-EXPRESSION OF RIZ1 INHIBITS IGF-1 EXPRESSION. IGF-1 SIGNALING IS REQUIRED IN MANY STAGES OF HEMATOPOIESIS AND INAPPROPRIATE ACTIVATION OF AUTOCRINE IGF-1 SIGNALING MAY FACILITATE TRANSFORMATION TO BLAST CRISIS. WE OBSERVED THAT IN 8 OUT OF 11 MATCHED CML PATIENT BIOPSIES THE IGF-1 EXPRESSION IS ELEVATED IN BLAST CRISIS. WE EXAMINED MECHANISMS USED BY CML BLAST CRISIS CELL LINES TO ACTIVATE IGF-1 EXPRESSION. WE FOUND THAT BCR-ABL ACTIVATES AUTOCRINE IGF-1 SIGNALING USING HCK AND STAT5B. INHIBITION OF THESE SIGNALING COMPONENTS USING SMALL MOLECULE DRUGS OR SHRNA DECREASES PROLIFERATION AND ENHANCES APOPTOSIS. TOGETHER, OUR STUDY SUGGESTS THAT ABERRANT IGF-1 SIGNALING IS AN IMPORTANT EVENT IN BLAST CRISIS TRANSFORMATION AND IT PROVIDES A MECHANISM TO EXPLAIN THE ACTIVITY OF IGF-1R AND HCK INHIBITORS IN BLOCKING CML BLAST CRISIS PHENOTYPES. 2008 11 1660 23 DOWN-REGULATION OF HEMATOPOIESIS MASTER REGULATOR PU.1 VIA ABERRANT METHYLATION IN CHRONIC MYELOID LEUKEMIA. THE PU.1 TRANSCRIPTION FACTOR IS A CRUCIAL REGULATOR OF HEMATOPOIESIS, AND ITS EXPRESSION IS ALTERED IN VARIOUS LEUKEMIC PROCESSES. IT HAS BEEN SHOWN THAT EXPRESSION OF PU.1 IS SEVERELY IMPAIRED IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML), BUT THE MECHANISM UNDERLYING THIS EFFECT REMAINS UNKNOWN. THROUGH BISULFITE SEQUENCING, SEMI-QUANTITATIVE PCR, AND INDIRECT IMMUNOFLUORESCENCE AND WESTERN BLOT TECHNIQUES, WE FOUND ABERRANT METHYLATION IN THE PROMOTER REGION OF TRANSCRIPTION FACTOR PU.1 IN CML PATIENTS BOTH IN THE CHRONIC AND BLAST CRISIS PHASES, AS WELL AS IN THE CML BLAST K562 CELL LINE. OF THESE, SEVERAL CPG SITES WERE MORE HIGHLY METHYLATED IN BLAST CRISIS THAN CHRONIC PHASE, WHILE NO METHYLATION OF THESE SITES WAS OBSERVED IN HEALTHY INDIVIDUALS. INTERESTINGLY, CML PATIENTS ACHIEVED COMPLETE CYTOGENETIC REMISSION UNDER IMATINIB MESYLATE TREATMENT, BUT THE ABERRANT METHYLATION STATUS OF PU.1 WAS NOT REVERSED. DOWN-REGULATION OF PU.1 EXPRESSION AT THE MRNA AND PROTEIN LEVELS WAS ALSO OBSERVED IN ASSOCIATION WITH ABERRANT METHYLATION. THUS, FOR THE FIRST TIME, WE HAVE REVEALED A POTENTIAL EPIGENETIC MODIFICATION OF PU.1 IN CML, WHICH MAY BE RESPONSIBLE FOR THE DOWN-REGULATION OF PU.1. THESE DATA SUGGEST THAT ABERRANT METHYLATION OF PU.1 MAY PLAY A ROLE IN CML PATHOGENESIS, AND MAY THEREFORE SERVE AS A USEFUL BIOMARKER AND POTENTIAL TARGET FOR DEMETHYLATING DRUGS. 2012 12 6390 25 THE ROLE OF THE GENETIC ABNORMALITIES, EPIGENETIC AND MICRORNA IN THE PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS INCREASED PROLIFERATION OF B-CELLS WITH PERIPHERAL BLOOD AND BONE MARROW INVOLVEMENT, WHICH IS USUALLY OBSERVED IN OLDER PEOPLE. GENETIC MUTATIONS, EPIGENETIC CHANGES AND MIRS PLAY A ROLE IN CLL PATHOGENESIS. DEL 11Q, DEL L17Q, DEL 6Q, TRISOMY 12, P53 AND IGVH MUTATIONS ARE THE MOST IMPORTANT GENETIC CHANGES IN CLL. DELETION OF MIR-15A AND MIR-16A CAN INCREASE BCL2 GENE EXPRESSION, MIR-29 AND MIR-181 DELETIONS DECREASE THE EXPRESSION OF TCL1, AND MIR-146A DELETION PREVENTS TUMOR METASTASIS. EPIGENETIC CHANGES SUCH AS HYPO- AND HYPERMETHYLATION, UBIQUITINATION, HYPO- AND HYPERACETYLATION OF GENE PROMOTERS INVOLVED IN CLL PATHOGENESIS CAN ALSO PLAY A ROLE IN CLL. EXPRESSION OF CD38 AND ZAP70, PRESENCE OR ABSENCE OF MUTATION IN IGVH AND P53 MUTATION ARE AMONG THE FACTORS INVOLVED IN CLL PROGNOSIS. USE OF MONOCLONAL ANTIBODIES AGAINST SURFACE MARKERS OF B-CELLS LIKE ANTI-CD20 AS WELL AS TYROSINE KINASE INHIBITORS ARE THE MOST IMPORTANT THERAPEUTIC APPROACHES FOR CLL. 2018 13 2971 18 GENETIC AND EPIGENETIC SILENCING OF MICRORNA-203 ENHANCES ABL1 AND BCR-ABL1 ONCOGENE EXPRESSION. THE MAMMALIAN GENOME CONTAINS SEVERAL HUNDRED MICRORNAS THAT REGULATE GENE EXPRESSION THROUGH MODULATION OF TARGET MRNAS. HERE, WE REPORT A FRAGILE CHROMOSOMAL REGION LOST IN SPECIFIC HEMATOPOIETIC MALIGNANCIES. THIS 7 MB REGION ENCODES ABOUT 12% OF ALL GENOMIC MICRORNAS, INCLUDING MIR-203. THIS MICRORNA IS ADDITIONALLY HYPERMETHYLATED IN SEVERAL HEMATOPOIETIC TUMORS, INCLUDING CHRONIC MYELOGENOUS LEUKEMIAS AND SOME ACUTE LYMPHOBLASTIC LEUKEMIAS. A PUTATIVE MIR-203 TARGET, ABL1, IS SPECIFICALLY ACTIVATED IN THESE HEMATOPOIETIC MALIGNANCIES IN SOME CASES AS A BCR-ABL1 FUSION PROTEIN (PHILADELPHIA CHROMOSOME). RE-EXPRESSION OF MIR-203 REDUCES ABL1 AND BCR-ABL1 FUSION PROTEIN LEVELS AND INHIBITS TUMOR CELL PROLIFERATION IN AN ABL1-DEPENDENT MANNER. THUS, MIR-203 FUNCTIONS AS A TUMOR SUPPRESSOR, AND RE-EXPRESSION OF THIS MICRORNA MIGHT HAVE THERAPEUTIC BENEFITS IN SPECIFIC HEMATOPOIETIC MALIGNANCIES. 2008 14 3158 21 GLYCOGEN SYNTHASE KINASE 3BETA MISSPLICING CONTRIBUTES TO LEUKEMIA STEM CELL GENERATION. RECENT EVIDENCE SUGGESTS THAT A RARE POPULATION OF SELF-RENEWING CANCER STEM CELLS (CSC) IS RESPONSIBLE FOR CANCER PROGRESSION AND THERAPEUTIC RESISTANCE. CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS AN IMPORTANT PARADIGM FOR UNDERSTANDING THE GENETIC AND EPIGENETIC EVENTS INVOLVED IN CSC PRODUCTION. CML PROGRESSES FROM A CHRONIC PHASE (CP) IN HEMATOPOIETIC STEM CELLS (HSC) THAT HARBOR THE BCR-ABL TRANSLOCATION, TO BLAST CRISIS (BC), CHARACTERIZED BY ABERRANT ACTIVATION OF BETA-CATENIN WITHIN GRANULOCYTE-MACROPHAGE PROGENITORS (GMP). A MAJOR BARRIER TO PREDICTING AND INHIBITING BLAST CRISIS TRANSFORMATION HAS BEEN THE IDENTIFICATION OF MECHANISMS DRIVING BETA-CATENIN ACTIVATION. HERE WE SHOW THAT BC CML MYELOID PROGENITORS, IN PARTICULAR GMP, SERIALLY TRANSPLANT LEUKEMIA IN IMMUNOCOMPROMISED MICE AND THUS ARE ENRICHED FOR LEUKEMIA STEM CELLS (LSC). NOTABLY, CDNA SEQUENCING OF WNT/BETA-CATENIN PATHWAY REGULATORY GENES, INCLUDING ADENOMATOUS POLYPOSIS COLI, GSK3BETA, AXIN 1, BETA-CATENIN, LYMPHOID ENHANCER FACTOR-1, CYCLIN D1, AND C-MYC, REVEALED A NOVEL IN-FRAME SPLICE DELETION OF THE GSK3BETA KINASE DOMAIN IN THE GMP OF BC SAMPLES THAT WAS NOT DETECTABLE BY SEQUENCING IN BLASTS OR NORMAL PROGENITORS. MOREOVER, BC CML PROGENITORS WITH MISSPLICED GSK3BETA HAVE ENHANCED BETA-CATENIN EXPRESSION AS WELL AS SERIAL ENGRAFTMENT POTENTIAL WHILE REINTRODUCTION OF FULL-LENGTH GSK3BETA REDUCES BOTH IN VITRO REPLATING AND LEUKEMIC ENGRAFTMENT. WE PROPOSE THAT CP CML IS INITIATED BY BCR-ABL EXPRESSION IN AN HSC CLONE BUT THAT PROGRESSION TO BC MAY INCLUDE MISSPLICING OF GSK3BETA IN GMP LSC, ENABLING UNPHOSPHORYLATED BETA-CATENIN TO PARTICIPATE IN LSC SELF-RENEWAL. MISSPLICING OF GSK3BETA REPRESENTS A UNIQUE MECHANISM FOR THE EMERGENCE OF BC CML LSC AND MIGHT PROVIDE A NOVEL DIAGNOSTIC AND THERAPEUTIC TARGET. 2009 15 1227 25 CRITICAL ROLE OF MICRORNAS IN CHRONIC LYMPHOCYTIC LEUKEMIA: OVEREXPRESSION OF THE ONCOGENE PLAG1 BY DEREGULATED MIRNAS. MICRORNAS (MIRNAS) ARE SMALL, GENE ENCODED RNAS WHICH ARE ABLE TO INFLUENCE GENE EXPRESSION IN BINDING TO THE 3'UTR OF MRNAS. COMPARED TO HEALTHY TISSUES, THE GLOBAL EXPRESSION OF MIRNAS IN CANCEROUS TISSUE IS FREQUENTLY DOWN-REGULATED. LIKEWISE IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), DOWN-REGULATION OF SEVERAL MIRNAS HAS BEEN REPORTED. ANALYSIS OF MIRNA PROMOTERS FOR EPIGENETIC MODIFICATIONS REVEALED A STRONGER METHYLATION OF DOWN-REGULATED MIRNAS IN CLL. TO DATE, SEVERAL TARGET GENES AFFECTED BY DEREGULATED MIRNAS HAVE BEEN IDENTIFIED THAT HAVE IMPACT ON CLL PATHOGENESIS. THE BEST-DESCRIBED CONSEQUENCE OF MIRNA DEREGULATION IS FOR MIRNA-15/16 CLUSTER DELETION, WHICH IS FREQUENTLY DOWN-REGULATED IN A SUBGROUP OF PATIENTS WITH CLL CARRYING 13Q14 DELETION. SO FAR, MODELS FOR MIRNA DEREGULATION HAVE ADDRESSED JUST SINGLE MIRNAS. FOR ASSESSMENT OF COMPLETE MIRNA DEREGULATION, FURTHER EVALUATION OF THE RESULTS FROM MICROARRAY STUDIES IS NEEDED. PREVIOUSLY WE IDENTIFIED THE ONCOGENE PLAG1, WHOSE EXPRESSION IS AFFECTED BY VARIOUS MIRNAS DEREGULATED IN CLL. THE INVOLVEMENT OF MIRNAS IN PLAG1 EXPRESSION WAS SHOWN TO BE RELEVANT IN PLEOMORPHIC ADENOMAS OF THE SALIVARY GLAND, TOO. AS PLAG1 IS HIGHLY OVEREXPRESSED, AND ITS TARGET GENES APPEAR TO BE DEREGULATED IN CLL, E.G. BCL-2, PLAG1 IS A PUTATIVE NEW RELEVANT ONCOGENE INVOLVED IN THE PATHOGENESIS OF CLL. 2010 16 1830 25 EFFECTS OF LONG-TERM ASPIRIN USE ON MOLECULAR ALTERATIONS IN PRECANCEROUS GASTRIC MUCOSA IN PATIENTS WITH AND WITHOUT GASTRIC CANCER. THE RISK OF GASTRIC CANCER (GC) REMAINS EVEN AFTER H. PYLORI ERADICATION; THUS, OTHER COMBINATION TREATMENTS, SUCH AS CHEMOPREVENTIVE DRUGS, ARE NEEDED. WE EVALUATED THE EFFECTS OF ASPIRIN ON GENETIC/EPIGENETIC ALTERATIONS IN PRECANCEROUS CONDITIONS, I.E., ATROPHIC MUCOSA (AM) AND INTESTINAL METAPLASIA (IM), IN PATIENTS WITH CHRONIC GASTRITIS WHO HAD TAKEN ASPIRIN FOR MORE THAN 3 YEARS. A TOTAL OF 221 BIOPSY SPECIMENS FROM 74 PATIENTS, INCLUDING ATROPHIC GASTRITIS (AG) CASES WITHOUT ASPIRIN USE (CONTROL), AG CASES WITH ASPIRIN USE (AG GROUP), AND GC CASES WITH ASPIRIN USE (GC GROUP), WERE ANALYZED. ASPIRIN USE WAS ASSOCIATED WITH A SIGNIFICANT REDUCTION OF CDH1 METHYLATION IN AM (OR: 0.15, 95% CI: 0.06-0.41, P = 0.0002), BUT WAS LESS EFFECTIVE IN REVERSING THE METHYLATION THAT OCCURRED IN IM. FREQUENT HYPERMETHYLATION INCLUDING THAT OF CDH1 IN AM INCREASED IN THE GC GROUP COMPARED TO THE AG GROUP, AND CDH1 METHYLATION WAS AN INDEPENDENT PREDICTIVE MARKER OF GC (OR: 8.50, 95% CI: 2.64-25.33, P = 0.0003). IN PATIENTS WITH LONG-TERM ASPIRIN USE, THE CHANGES OF MOLECULAR EVENTS IN AM BUT NOT IM MAY BE AN IMPORTANT FACTOR IN THE REDUCTION OF CANCER INCIDENCE. IN ADDITION, METHYLATION OF THE CDH1 GENE IN AM MAY BE A SURROGATE OF GC. 2017 17 2087 23 EPIGENETIC DYSREGULATION OF ID4 PREDICTS DISEASE PROGRESSION AND TREATMENT OUTCOME IN MYELOID MALIGNANCIES. PROMOTER HYPERMETHYLATION-MEDIATED INACTIVATION OF ID4 PLAYS A CRUCIAL ROLE IN THE DEVELOPMENT OF SOLID TUMOURS. THIS STUDY AIMED TO INVESTIGATE ID4 METHYLATION AND ITS CLINICAL RELEVANCE IN MYELOID MALIGNANCIES. ID4 HYPERMETHYLATION WAS ASSOCIATED WITH HIGHER IPSS SCORES, BUT WAS NOT AN INDEPENDENT PROGNOSTIC BIOMARKER AFFECTING OVERALL SURVIVAL (OS) IN MYELODYSPLASTIC SYNDROME (MDS). HOWEVER, ID4 HYPERMETHYLATION CORRELATED WITH SHORTER OS AND LEUKAEMIA-FREE SURVIVAL (LFS) TIME AND ACTED AS AN INDEPENDENT RISK FACTOR AFFECTING OS IN ACUTE MYELOID LEUKAEMIA (AML). MOREOVER, ID4 METHYLATION WAS SIGNIFICANTLY DECREASED IN THE FOLLOW-UP PAIRED AML PATIENTS WHO ACHIEVED COMPLETE REMISSION (CR) AFTER INDUCTION THERAPY. IMPORTANTLY, ID4 METHYLATION WAS INCREASED DURING MDS PROGRESSION TO AML AND CHRONIC PHASE (CP) PROGRESSION TO BLAST CRISIS (BC) IN CHRONIC MYELOID LEUKAEMIA (CML). EPIGENETIC STUDIES SHOWED THAT ID4 METHYLATION MIGHT BE ONE OF THE MECHANISMS SILENCING ID4 EXPRESSION IN MYELOID LEUKAEMIA. FUNCTIONAL STUDIES IN VITRO SHOWED THAT RESTORATION OF ID4 EXPRESSION COULD INHIBIT CELL PROLIFERATION AND PROMOTE APOPTOSIS IN BOTH K562 AND HL60 CELLS. THESE FINDINGS INDICATE THAT ID4 ACTS AS A TUMOUR SUPPRESSOR IN MYELOID MALIGNANCIES, AND ID4 METHYLATION IS A POTENTIAL BIOMARKER IN PREDICTING DISEASE PROGRESSION AND TREATMENT OUTCOME. 2017 18 3352 24 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 19 4364 23 MIRNA DEREGULATION BY EPIGENETIC SILENCING DISRUPTS SUPPRESSION OF THE ONCOGENE PLAG1 IN CHRONIC LYMPHOCYTIC LEUKEMIA. MICRORNAS (MIRNA) PLAY A KEY ROLE IN CELLULAR REGULATION AND, IF DEREGULATED, IN THE DEVELOPMENT OF NEOPLASTIC DISORDERS INCLUDING CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). RNAS FROM PRIMARY CELLS OF 50 TREATMENT-NAIVE CLL PATIENTS AND PERIPHERAL B CELLS OF 14 HEALTHY DONORS WERE APPLIED TO MIRNA EXPRESSION PROFILING USING BEAD CHIP TECHNOLOGY. IN CLL CELLS, A SET OF 7 UP- AND 19 DOWN-REGULATED MIRNAS WAS IDENTIFIED. AMONG THE MIRNAS DOWN-REGULATED IN CLL CELLS, 6 OF 10 MIRNA PROMOTERS EXAMINED SHOWED GAIN OF METHYLATION COMPARED WITH NORMAL B-CELL CONTROLS. SUBSEQUENT TARGET PREDICTION OF DEREGULATED MIRNAS REVEALED A HIGHLY SIGNIFICANT BINDING PREDICTION AT THE 3' UNTRANSLATED REGION OF THE PLEOMORPHIC ADENOMA GENE 1 (PLAG1) ONCOGENE. LUCIFERASE REPORTER ASSAYS INCLUDING SITE-DIRECTED MUTAGENESIS OF BINDING SITES REVEALED A SIGNIFICANT REGULATION OF PLAG1 BY MIR-181A, MIR-181B, MIR-107, AND MIR-424. ALTHOUGH EXPRESSION OF PLAG1 MRNA WAS NOT AFFECTED, PLAG1 PROTEIN EXPRESSION WAS SHOWN TO BE SIGNIFICANTLY ELEVATED IN CLL CELLS COMPARED WITH THE LEVELS IN HEALTHY DONOR B CELLS. IN SUMMARY, WE COULD DEMONSTRATE DISRUPTION OF MIRNA-MEDIATED TRANSLATIONAL CONTROL, PARTLY DUE TO EPIGENETIC TRANSCRIPTIONAL SILENCING OF MIRNAS, WITH SUBSEQUENT OVEREXPRESSION OF THE ONCOGENIC TRANSCRIPTION FACTOR PLAG1 AS A PUTATIVE NOVEL MECHANISM OF CLL PATHOGENESIS. 2009 20 5225 28 PRMT1 MODULATES PROCESSING OF ASTHMA-RELATED PRIMARY MICRORNAS (PRI-MIRNAS) INTO MATURE MIRNAS IN LUNG EPITHELIAL CELLS. PROTEIN ARGININE METHYLTRANSFERASE-1 (PRMT1) IS AN IMPORTANT EPIGENETIC REGULATOR OF CELL FUNCTION AND CONTRIBUTES TO INFLAMMATION AND REMODELING IN ASTHMA IN A CELL TYPE-SPECIFIC MANNER. DISEASE-SPECIFIC EXPRESSION PATTERNS OF MICRORNAS (MIRNA) ARE ASSOCIATED WITH CHRONIC INFLAMMATORY LUNG DISEASES, INCLUDING ASTHMA. THE DE NOVO SYNTHESIS OF MIRNA DEPENDS ON THE TRANSCRIPTION OF PRIMARY MIRNA (PRI-MIRNA) TRANSCRIPT. THIS STUDY ASSESSED THE ROLE OF PRMT1 ON PRI-MIRNA TO MATURE MIRNA PROCESS IN LUNG EPITHELIAL CELLS. HUMAN AIRWAY EPITHELIAL CELLS, BEAS-2B, WERE TRANSFECTED WITH THE PRMT1 EXPRESSION PLASMID PCDNA3.1-PRMT1 FOR 48 H. EXPRESSION PROFILES OF MIRNA WERE DETERMINED BY SMALL RNA DEEP SEQUENCING. COMPARING THESE MIRNAS WITH DATASETS OF MICROARRAYS FROM FIVE ASTHMA PATIENTS (GENE EXPRESSION OMNIBUS DATASET), 12 MIRNAS WERE IDENTIFIED THAT RELATED TO PRMT1 OVEREXPRESSION AND TO ASTHMA. THE OVEREXPRESSION OR KNOCKDOWN OF PRMT1 MODULATED THE EXPRESSION OF THE ASTHMA-RELATED MIRNAS AND THEIR PRI-MIRNAS. COIMMUNOPRECIPITATION SHOWED THAT PRMT1 FORMED A COMPLEX WITH STAT1 OR RUNX1 AND THUS ACTED AS A COACTIVATOR, STIMULATING THE TRANSCRIPTION OF PRI-MIRNAS. STIMULATION WITH TGF-BETA1 PROMOTED THE INTERACTION OF PRMT1 WITH STAT1 OR RUNX1, THEREBY UPREGULATING THE TRANSCRIPTION OF TWO MIRNAS: LET-7I AND MIR-423. SUBSEQUENT CHROMATIN IMMUNOPRECIPITATION ASSAYS REVEALED THAT THE BINDING OF THE PRMT1/STAT1 OR PRMT1/RUNX1 COACTIVATORS TO PRIMARY LET-7I (PRI-LET-7I) AND PRIMARY MIR (PRI-MIR) 423 PROMOTER WAS CRITICAL FOR PRI-LET-7I AND PRI-MIR-423 TRANSCRIPTION. THIS STUDY DESCRIBES A NOVEL ROLE OF PRMT1 AS A COACTIVATOR FOR STAT1 OR RUNX1, WHICH IS ESSENTIAL FOR THE TRANSCRIPTION OF PRI-LET-7I AND PRI-MIR-423 IN EPITHELIAL CELLS AND MIGHT BE RELEVANT TO EPITHELIUM DYSFUNCTION IN ASTHMA. 2021