1  867 171 CHRONIC ACTIVE EPSTEIN-BARR VIRUS INFECTION OF T/NK-CELL TYPE MIMICKING CLASSIC HODGKIN LYMPHOMA: CLINICOPATHOLOGIC AND GENETIC FEATURES OF 8 CASES SUPPORTING A VARIANT WITH "HODGKIN/REED-STERNBERG-LIKE" CELLS OF NK PHENOTYPE. CHRONIC ACTIVE EPSTEIN-BARR VIRUS (EBV) INFECTION OF T-CELL AND NK-CELL TYPE, SYSTEMIC FORM (CAEBV-T/NK-S) IS CHARACTERIZED BY EBV T-CELL AND/OR NK-CELL PROLIFERATION WITH NO CHANGES SUGGESTING MALIGNANCY. THEREFORE, WHEN HODGKIN/REED-STERNBERG (HRS)-LIKE CELLS ARE SCATTERED IN CAEBV-T/NK-S, IT IS MORE LIKELY TO BE MISDIAGNOSED AS CLASSIC HODGKIN LYMPHOMA. WE ENCOUNTERED A CASE WHEREIN THE PATIENT SHOWED HRS-LIKE CELLS WITH TYPICAL NK PHENOTYPE. THEREFORE, WE FURTHER INVESTIGATED 8 SIMILAR CASES TO PROVIDE CLINICOPATHOLOGIC AND GENETIC FEATURES AND DISCUSS THEIR DISTINCTION FROM OTHER RELATED DISEASES. CLINICALLY, ALL CASES MET THE DIAGNOSTIC CRITERIA OF CAEBV. MOREOVER, 4/8 PATIENTS HAD HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS. THE MEDIAN SURVIVAL WAS 16 MONTHS (RANGE, 5 TO 35 MO). PATHOLOGICALLY, ALL LYMPH NODE SAMPLES HAD A REMARKABLY SIMILAR MORPHOLOGY WITH SCATTERED HRS-LIKE CELLS SURROUNDED BY A MIXTURE OF SMALL-SIZED LYMPHOCYTES, PLASMA CELLS, AND MACROPHAGES THAT MASQUERADED CLASSIC HODGKIN LYMPHOMA. BESIDES, ERYTHROPHAGOCYTOSIS WAS DETECTED IN 4/11 SAMPLES. THE HRS-LIKE CELLS WERE POSITIVE FOR CD2, CD3P, CD30, CD56, GRB, AND EBER-ISH, BUT NEGATIVE FOR CD20, CD5, PAX-5, AND LMP-1. THE SURROUNDING LYMPHOCYTES WERE MAINLY CD8 CYTOTOXIC T CELLS, WITHOUT OBVIOUS ABERRANT EXPRESSION. IN ADDITION, ALL PATIENTS WERE POLYCLONAL IN THE T-CELL RECEPTOR GAMMA REARRANGEMENT TEST. THE HARBORED MUTATIONS WERE MAINLY IN EPIGENETIC MODIFIERS, JAK-STAT SIGNALING PATHWAY, AND APOPTOSIS/CELL CYCLE PATHWAY, INCLUDING SOCS1, DDX3X, AND KMT2D, SIMILAR TO OTHER EBV-ASSOCIATED T/NK-CELL LYMPHOPROLIFERATIVE DISORDERS. THEREFORE, THE EVIDENCE INDICATES THAT "HRS-LIKE CELLS OF NK PHENOTYPE" IS A VARIANT OF CAEBV-T/NK-S. THIS STUDY MAY RAISE AWARENESS OF SUCH CONFOUNDING CAEBV-T/N-S CASES IN CLINICAL PRACTICE TO AVOID MISDIAGNOSIS AND TREATMENT DELAY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2   62  37 A HIGH DEFINITION PICTURE OF SOMATIC MUTATIONS IN CHRONIC LYMPHOPROLIFERATIVE DISORDER OF NATURAL KILLER CELLS. THE MOLECULAR PATHOGENESIS OF CHRONIC LYMPHOPROLIFERATIVE DISORDER OF NATURAL KILLER (NK) CELLS (CLPD-NK) IS POORLY UNDERSTOOD. FOLLOWING THE SCREENING OF 57 CLPD-NK PATIENTS, ONLY FIVE PRESENTED STAT3 MUTATIONS. WES PROFILING OF 13 CASES NEGATIVE FOR STAT3/STAT5B MUTATIONS UNCOVERED AN AVERAGE OF 18 CLONAL, POPULATION RARE AND DELETERIOUS SOMATIC VARIANTS PER PATIENT. THE MUTATIONAL LANDSCAPE OF CLPD-NK SHOWED THAT MOST PATIENTS CARRY A HEAVY MUTATIONAL BURDEN, WITH MAJOR AND SUBCLONAL DELETERIOUS MUTATIONS CO-EXISTING IN THE LEUKEMIC CLONE. SOMATIC MUTATIONS HIT GENES WIRED TO CANCER PROLIFERATION, SURVIVAL, AND MIGRATION PATHWAYS, IN THE FIRST PLACE RAS/MAPK, PI3K-AKT, IN ADDITION TO JAK/STAT (PIK3R1 AND PTK2). WE CONFIRMED VARIANTS WITH PUTATIVE DRIVER ROLE OF MAP10, MPZL1, RPS6KA1, SETD1B, TAOK2, TMEM127, AND TNFRSF1A GENES, AND OF GENES LINKED TO VIRAL INFECTIONS (DDX3X AND RSF1) AND DNA REPAIR (PAXIP1). A TRUNCATING MUTATION OF THE EPIGENETIC REGULATOR TET2 AND A VARIANT LIKELY ABROGATING PIK3R1-NEGATIVE REGULATORY ACTIVITY WERE VALIDATED. THIS STUDY SIGNIFICANTLY FURTHERED THE VIEW OF THE GENES AND PATHWAYS INVOLVED IN CLPD-NK, INDICATED SIMILARITIES WITH AGGRESSIVE DISEASES OF NK CELLS AND DETECTED MUTATED GENES TARGETABLE BY APPROVED DRUGS, BEING A STEP FORWARD TO PERSONALIZED PRECISION MEDICINE FOR CLPD-NK PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3 2761  29 EXPRESSION OF TESTIS-SPECIFIC GENES, TEX101 AND ODF4, IN CHRONIC MYELOID LEUKEMIA AND EVALUATION OF TEX101 IMMUNOGENICITY. BACKGROUND AND OBJECTIVES: CANCER-TESTIS (CT) ANTIGENS ARE A GROUP OF ANTIGENS WITH A RESTRICTED EXPRESSION IN NORMAL TISSUES, EXCEPT TESTIS, AND THEY HAVE ABERRANT EXPRESSION IN DIFFERENT TUMORS. THIS PATTERN OF EXPRESSION HAS MADE THEM PROMISING TARGETS FOR IMMUNOTHERAPY AND CANCER DETECTION. OUR AIM WAS TO FIND NEW MEMBERS OF THIS GROUP THAT MIGHT BE USEFUL AS MARKERS IN THE DETECTION OF CANCER AND IMMUNOTHERAPY. DESIGN AND SETTING: A DESCRIPTIVE STUDY CONDUCTED IN REFERRAL CENTERS OF TEHRAN UNIVERSITY OF MEDICAL SCIENCE FROM JANUARY 2008 TO JANUARY 2009. PATIENTS AND METHODS: WE ANALYZED THE EXPRESSION OF TWO TESTIS-SPECIFIC GENES NAMED ODF4 (OUTER DENSE FIBER OF SPERM TAILS 4) AND TEX101 (TESTIS EXPRESSED 101) IN 20 CHRONIC MYELOID LEUKEMIA (CML) AND 20 NORMAL SAMPLES BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND SEQUENCING. IMMUNOGENICITY OF TEX101 WAS EVALUATED BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY. RESULTS: THESE TWO GENES WERE EXPRESSED IN 30% OF CML PATIENTS BUT NOT IN ANY OF THE HEALTHY DONORS. HUMORAL RESPONSE AGAINST TEX101 WAS NOT DETECTED IN ANY SAMPLES. CONCLUSIONS: TEX101 AND ODF4 ARE CT GENES USEFUL FOR DETECTION OF CML. UNLIKE MANY CT GENES, OVEREXPRESSION OF TEX101 WAS NOT SHOWN TO INDUCE IMMUNOLOGIC RESPONSES IN THESE SAMPLES. ACCORDING TO THE PREVIOUS STUDIES, OVEREXPRESSION OF TEX101 LEADS TO SUPPRESSION OF CANCER INVASION AND METASTASIS; THUS, THE INDUCTION OF THE EXPRESSION OF TEX101 IN CANCER BY EPIGENETIC MECHANISMS MAY BE A TREATMENT STRATEGY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
4 1044  50 CLINICAL CHARACTERISTICS OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH NON-HODGKIN B-CELL LYMPHOMA: A MULTICENTER RETROSPECTIVE STUDY. BACKGROUND: HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ASSOCIATED WITH B-CELL LYMPHOMA IS A HIGHLY AGGRESSIVE DISEASE WITH UNCLEAR CLINICAL FEATURES AND HAS NO STANDARD TREATMENT. PATIENTS AND METHODS: WE ANALYZED THE CLINICAL CHARACTERISTICS OF 31 PATIENTS FROM TWO INDIVIDUAL CENTERS. RESULTS: THE MEDIAN OVERALL SURVIVAL WAS ONLY 1.5 MONTHS. BOTH UNIVARIATE AND MULTIVARIATE ANALYSES, BASED ON LYMPHOMA OR HLH-RELATED CHARACTERISTICS, REVEALED THAT PATIENTS WITH HIGH EPSTEIN-BARR VIRUS (EBV) DNA LOAD AND >/= 2 EXTRANODAL LESIONS, OR HYPOFIBRINOGENEMIA, RESPECTIVELY, SHOWED SIGNIFICANTLY POORER OVERALL SURVIVAL. INTERESTINGLY, SOME PATIENTS WITH HIGH EBV DNA LOAD HAD EBV-POSITIVE NATURAL KILLER (NK) AND/OR T CELLS, WHICH MAY BE RELATED TO THE COEXISTENCE OF IMMUNODEFICIENCY AND/OR CHRONIC ACTIVE EBV INFECTION. MOLECULAR GENETICS EXAMINATION CONFIRMED THAT 47.4% (9/19) OF PATIENTS HAD COMPLEX KARYOTYPES, 37.5% (3/8) OF PATIENTS HAD TP53 DELETIONS, AND 21.34% (3/14) OF PATIENTS HAD TP53 MUTATION OR ALTERATION OF MALIGNANCY-RELATED PATHWAYS, INCLUDING BCR/NF-KAPPAB, JAK-STAT, AND EPIGENETIC REGULATORY PATHWAYS, WHICH MAY PROVIDE CLUES TO CHOOSE TARGETS FOR THERAPY. TREATMENT REGIMENS CONTAINING ETOPOSIDE, ANTI-CD20 MONOCLONAL ANTIBODIES, OR ANTHRACYCLINES IMPROVED PATIENT PROGNOSIS (P = .0183, .025, AND .0436, RESPECTIVELY). PATIENTS WITH INFECTIONS HAD SIGNIFICANTLY SHORTER SURVIVAL THAN THOSE WITHOUT INFECTIONS (P = .00019). CONCLUSION: THE PATIENTS' PERFORMANCE STATUS, NUMBER OF EXTRANODAL LESIONS, HIGH EBV DNA LOAD, AND HYPOFIBRINOGENEMIA ARE POOR PROGNOSTIC FACTORS FOR HLH ASSOCIATED WITH B-CELL LYMPHOMA. MOLECULAR GENETIC HIGH-RISK FACTORS ARE OF PARTICULAR IMPORTANCE BECAUSE THESE FACTORS CAN PROVIDE INFORMATION FOR PROGNOSIS PREDICTION, TREATMENT DECISIONS, AND DISEASE SURVEILLANCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5  493  30 ASSESSMENT OF P53 AND ATM FUNCTIONALITY IN CHRONIC LYMPHOCYTIC LEUKEMIA BY MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION. THE ATM-P53 DNA-DAMAGE RESPONSE (DDR) PATHWAY HAS A CRUCIAL ROLE IN CHEMORESISTANCE IN CLL, AS INDICATED BY THE ADVERSE PROGNOSTIC IMPACT OF GENETIC ABERRATIONS OF TP53 AND ATM. IDENTIFYING AND DISTINGUISHING TP53 AND ATM FUNCTIONAL DEFECTS HAS BECOME RELEVANT AS EPIGENETIC AND POSTTRANSCRIPTIONAL DYSREGULATION OF THE ATM/P53 AXIS IS INCREASINGLY BEING RECOGNIZED AS THE UNDERLYING CAUSE OF CHEMORESISTANCE. ALSO, SPECIFIC TREATMENTS SENSITIZING TP53- OR ATM-DEFICIENT CLL CELLS ARE EMERGING. WE THEREFORE DEVELOPED A NEW ATM-P53 FUNCTIONAL ASSAY WITH THE AIM TO (I) IDENTIFY AND (II) DISTINGUISH ABNORMALITIES OF TP53 VERSUS ATM AND (III) ENABLE THE IDENTIFICATION OF ADDITIONAL DEFECTS IN THE ATM-P53 PATHWAY. REVERSED TRANSCRIPTASE MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION (RT-MLPA) WAS USED TO MEASURE ATM AND/OR P53-DEPENDENT GENES AT THE RNA LEVEL FOLLOWING DNA DAMAGE USING IRRADIATION. HERE, WE SHOWED THAT THIS ASSAY IS ABLE TO IDENTIFY AND DISTINGUISH THREE SUBGROUPS OF CLL TUMORS (I.E., TP53-DEFECTIVE, ATM-DEFECTIVE AND WT) AND IS ALSO ABLE TO DETECT ADDITIONAL SAMPLES WITH A DEFECTIVE DDR, WITHOUT MOLECULAR ABERRATIONS IN TP53 AND/OR ATM. THESE FINDINGS MAKE THE ATM-P53 RT-MLPA FUNCTIONAL ASSAY A PROMISING PROGNOSTIC TOOL FOR PREDICTING TREATMENT RESPONSES IN CLL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6 2763  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7 6634  21 UNINTEGRATED TWO-LONG TERMINAL REPEAT CIRCULAR HUMAN T LYMPHOTROPIC VIRUS DNA ACCUMULATION DURING CHRONIC HTLV INFECTION. ACCUMULATION OF UNINTEGRATED HUMAN T LYMPHOTROPIC VIRUS (HTLV) DNA WAS ANALYZED IN LONG-TERM T CELL LINES INFECTED WITH HTLV TYPE I (HTLV-I) OR TYPE II (HTLV-II). BY USING A POLYMERASE CHAIN REACTION-BASED ASSAY, AMPLIFIED PRODUCTS OF EXPECTED SIZE WERE OBTAINED IN ALL OF THE HTLV-I-INFECTED (N = 7) AND HTLV-II-INFECTED (N = 8) CELL LINES. THE SIGNAL INTENSITIES OF THE HYBRIDIZING BAND VARIED GREATLY AMONG THE CELL LINES AND DID NOT CORRELATE WITH HTLV P24GAG ANTIGEN PRODUCTION. FURTHER ANALYSIS OF HTLV-I-INFECTED CLONES DEMONSTRATED CONSIDERABLE VARIABILITY IN THE UNINTEGRATED DNA ACCUMULATION, SUGGESTING THAT EITHER THE EPIGENETIC STATUS OF THE HOST CELL OR SOME ENVIRONMENTAL FACTOR DETERMINES THE OCCURRENCE OF UNINTEGRATED DNA. THE PRESENCE OF LOWER LEVELS OF UNINTEGRATED DNA IN MOST OF THE HTLV-INFECTED, LONG-TERM CELL LINES PRESUMABLY RESULTS IN PERSISTENT NONCYTOPATHIC INFECTION.	1993	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8 3484  38 IDENTIFICATION OF CHROMATIN REMODELING GENES ARID4A AND ARID4B AS LEUKEMIA SUPPRESSOR GENES. BACKGROUND: LEUKEMIA EVOLVES THROUGH A MULTISTEP PROCESS FROM PREMALIGNANCY TO MALIGNANCY. EPIGENETIC ALTERATIONS, INCLUDING HISTONE MODIFICATIONS, HAVE BEEN PROPOSED TO PLAY AN IMPORTANT ROLE IN TUMORIGENESIS. THE INVOLVEMENT OF TWO CHROMATIN REMODELING GENES, RETINOBLASTOMA-BINDING PROTEIN 1 (RBBP1/ARID4A) AND RBBP1-LIKE 1 (RBBP1L1/ARID4B), IN LEUKEMOGENESIS WAS NOT CHARACTERIZED. METHODS: THE LEUKEMIC PHENOTYPE OF MICE DEFICIENT FOR ARID4A WITH OR WITHOUT HAPLOINSUFFICIENCY FOR ARID4B WAS INVESTIGATED BY SERIALLY MONITORING COMPLETE BLOOD COUNTS TOGETHER WITH MICROSCOPIC HISTOLOGIC ANALYSIS AND FLOW CYTOMETRIC ANALYSIS OF BONE MARROW AND SPLEEN FROM THE ARID4A(-/-) MICE OR ARID4A(-/-)ARID4B(+/-) MICE. REGULATION IN BONE MARROW CELLS OF DOWNSTREAM GENES IMPORTANT FOR NORMAL HEMATOPOIESIS WAS ANALYZED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION. GENOTYPIC EFFECTS ON HISTONE MODIFICATIONS WERE EXAMINED BY WESTERN BLOTTING AND IMMUNOFLUORESCENCE ANALYSIS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: YOUNG (2-5 MONTHS OLD) ARID4A-DEFICIENT MICE HAD INEFFECTIVE BLOOD CELL PRODUCTION IN ALL HEMATOPOIETIC LINEAGES. BEYOND 5 MONTHS OF AGE, THE ARID4A(-/-) MICE MANIFESTED MONOCYTOSIS, ACCOMPANIED BY SEVERE ANEMIA AND THROMBOCYTOPENIA. THESE SICK ARID4A(-/-) MICE SHOWED BONE MARROW FAILURE WITH MYELOFIBROSIS ASSOCIATED WITH SPLENOMEGALY AND HEPATOMEGALY. FIVE OF 42 ARID4A(-/-) MICE AND 10 OF 12 ARID4A(-/-)ARID4B(+/-) MICE PROGRESSED TO ACUTE MYELOID LEUKEMIA (AML) AND HAD RAPID FURTHER INCREASES OF LEUKOCYTE COUNTS. EXPRESSION OF HOX GENES (HOXB3, HOXB5, HOXB6, AND HOXB8) WAS DECREASED IN ARID4A-DEFICIENT BONE MARROW CELLS WITH OR WITHOUT ARID4B HAPLOINSUFFICIENCY, AND FOXP3 EXPRESSION WAS REDUCED IN ARID4A(-/-)ARID4B(+/-) BONE MARROW. INCREASES OF HISTONE TRIMETHYLATION OF H3K4, H3K9, AND H4K20 (FOLD INCREASES IN TRIMETHYLATION = 32, 95% CONFIDENCE INTERVAL [CI] = 27 TO 32; 45, 95% CI = 41 TO 49; AND 2.2, 95% CI = 1.7 TO 2.7, RESPECTIVELY) WERE OBSERVED IN THE BONE MARROW OF ARID4A-DEFICIENT MICE. CONCLUSIONS: ARID4A-DEFICIENT MICE INITIALLY DISPLAY INEFFECTIVE HEMATOPOIESIS, FOLLOWED BY TRANSITION TO CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)-LIKE MYELODYSPLASTIC/MYELOPROLIFERATIVE DISORDER, AND THEN TRANSFORMATION TO AML. THE DISEASE PROCESSES IN THE ARID4A-DEFICIENT MICE ARE VERY SIMILAR TO THE COURSE OF EVENTS IN HUMANS WITH CMML AND AML. THIS MOUSE MODEL HAS THE POTENTIAL TO FURNISH ADDITIONAL INSIGHTS INTO THE ROLE OF EPIGENETIC ALTERATIONS IN LEUKEMOGENESIS, AND IT MAY BE USEFUL IN DEVELOPING NOVEL PHARMACOLOGICAL APPROACHES TO TREATMENT OF PRELEUKEMIC AND LEUKEMIC STATES.	2008	

9 5934  31 TARGETING FEATURES OF CURAXIN CBL0137 ON HEMATOLOGICAL MALIGNANCIES IN VITRO AND IN VIVO. THE ANTICANCER ACTIVITY OF CURAXIN CBL0137, A DNA-BINDING SMALL MOLECULE WITH CHROMATIN REMODULATING EFFECT, HAS BEEN DEMONSTRATED IN DIFFERENT CANCERS. HEREIN, A COMPARATIVE EVALUATION OF CBL0137 ACTIVITY WAS PERFORMED IN RESPECT TO ACUTE MYELOID LEUKEMIA (AML), ACUTE LYMPHOBLASTIC LEUKEMIA (ALL), CHRONIC MYELOID LEUKEMIA AND MULTIPLE MYELOMA (MM) CULTURED IN VITRO. MTT ASSAY SHOWED AML AND MM HIGHER SENSITIVITY TO CBL0137'S CYTOSTATIC EFFECT COMPARATIVELY TO OTHER HEMATOLOGICAL MALIGNANCY CELLS. FLOW CYTOMETRY CELL CYCLE ANALYSIS REVEALED AN INCREASE IN SUBG1 AND G2/M POPULATIONS AFTER CBL0137 CELL TREATMENT, BUT THE PREVALENT TYPE OF ARREST VARIED. APOPTOSIS ACTIVATION BY CBL0137 MEASURED BY ANNEXIN-V/PI DUAL STAINING WAS MORE ACTIVE IN AML AND MM CELLS. RT2 PCR ARRAY SHOWED THAT CHANGES CAUSED BY CBL0137 IN SIGNALING PATHWAYS INVOLVED IN CANCER PATHOGENESIS WERE MORE INTENSIVE IN AML AND MM CELLS. ON THE MURINE MODEL OF AML WEHI-3, CBL0137 SHOWED SIGNIFICANT ANTICANCER EFFECTS IN VIVO, WHICH WERE EVALUATED BY CORRESPONDING CHANGES IN SPLEEN AND LIVER. THUS, MORE PRONOUNCED ANTICANCER EFFECTS OF CBL0137 IN VITRO WERE OBSERVED IN RESPECT TO AML AND MM. EXPERIMENTS IN VIVO ALSO INDICATED THE PERSPECTIVE OF CBL0137 USE FOR AML TREATMENT. THIS IN ACCORDANCE WITH THE FRONTLINE TREATMENT APPROACH IN AML USING EPIGENETIC DRUGS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
10 2974  32 GENETIC AND METHYLATION STATUS OF CDKN2A (P14(ARF)/P16(INK4A)) AND TP53 GENES IN RECURRENT RESPIRATORY PAPILLOMATOSIS. RECURRENT RESPIRATORY PAPILLOMATOSIS (RRP) IS A RARE AND CHRONIC DISEASE AFFECTING THE UPPER AIRWAY WITH PAPILLOMATOUS LESIONS CAUSED BY THE HUMAN PAPILLOMAVIRUS (HPV) INFECTION, ESPECIALLY HPV-6 AND/OR HPV-11 TYPES. LITTLE IS KNOWN ABOUT THE GENETIC AND EPIGENETIC DRIVERS IN RRP PATHOPHYSIOLOGY. FOR THIS PURPOSE, WE ANALYZED 27 PAPILLOMATOUS LESIONS FROM PATIENTS WITH RRP TO EVALUATE SOMATIC MUTATIONS AND METHYLATION STATUS IN CDKN2A (P14(ARF)/P16(INK4A)) AND TP53, WHICH ARE KEY TUMOR SUPPRESSOR GENES FOR THE CELL CYCLE CONTROL. SANGER SEQUENCING ANALYSIS REVEALED ONE SOMATIC MUTATION IN TP53 (C.733_734INSA) AND FOUR MUTATIONS IN CDKN2A (C.-30G > T, C.29_30INSA, C.69DELT, AND C.300C > A). THESE MUTATIONS WERE OBSERVED IN 10 PATIENTS, 6 OF WHICH CARRIED DOUBLE MUTATION. FURTHERMORE, 50% (5/10) OF THESE PATIENTS CARRYING SOMATIC MUTATIONS HAD RRP SEVERITY, REPRESENTING 62.5% (5/8) OF THE SEVERITY CASES IN THIS STUDY, ALBEIT NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN SOMATIC MUTATIONS AND DISEASE SEVERITY. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION ASSAYS REVEALED P14(ARF) PROMOTER HYPERMETHYLATION IN 100% OF CASES, FOLLOWED BY TP53 (96.3%) AND P16(INK4A) (55.6%), SUGGESTING THE INFLUENCE OF HPV IN THE DNA METHYLATION MACHINERY. IN CONCLUSION, SOMATIC MUTATIONS WERE NOT COMMON EVENTS IDENTIFIED IN PATIENTS WITH RRP. HOWEVER, EPIGENETIC MODULATION BY HIGH METHYLATION RATES, PARTICULARLY FOR THE P14(ARF)/TP53 PATHWAY, SEEMS TO BE IN THE COURSE OF RRP DEVELOPMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11 1334  27 DEREGULATION OF AIOLOS EXPRESSION IN CHRONIC LYMPHOCYTIC LEUKEMIA IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY A CLONAL ACCUMULATION OF MATURE NEOPLASTIC B CELLS THAT ARE RESISTANT TO APOPTOSIS. AIOLOS, A MEMBER OF THE IKAROS FAMILY OF ZINC-FINGER TRANSCRIPTION FACTORS, PLAYS AN IMPORTANT ROLE IN THE CONTROL OF MATURE B LYMPHOCYTE DIFFERENTIATION AND MATURATION. IN THIS STUDY, WE SHOWED THAT AIOLOS EXPRESSION IS UP-REGULATED IN B-CLL CELLS. THIS OVEREXPRESSION DOES NOT IMPLICATE ISOFORM IMBALANCE OR DISTURB AIOLOS SUBCELLULAR LOCALIZATION. THE CHROMATIN STATUS AT THE AIOLOS PROMOTER IN CLL IS DEFINED BY THE DEMETHYLATION OF DNA AND AN ENRICHMENT OF EUCHROMATIN ASSOCIATED HISTONE MARKERS, SUCH AS THE DIMETHYLATION OF THE LYSINE 4 ON HISTONE H3. THESE EPIGENETIC MODIFICATIONS SHOULD ALLOW ITS UPSTREAM EFFECTORS, SUCH AS NUCLEAR FACTOR-KAPPAB, CONSTITUTIVELY ACTIVATED IN CLL, TO GAIN ACCESS TO PROMOTER, RESULTING UP-REGULATION OF AIOLOS. TO DETERMINE THE CONSEQUENCES OF AIOLOS DEREGULATION IN CLL, WE ANALYZED THE EFFECTS OF AIOLOS OVEREXPRESSION OR DOWN-REGULATION ON APOPTOSIS. AIOLOS IS INVOLVED IN CELL SURVIVAL BY REGULATING THE EXPRESSION OF SOME BCL-2 FAMILY MEMBERS. OUR RESULTS STRONGLY SUGGEST THAT AIOLOS DEREGULATION BY EPIGENETIC MODIFICATIONS MAY BE A HALLMARK OF CLL.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12 3198  33 HDAC-LINKED "PROLIFERATIVE" MIRNA EXPRESSION PATTERN IN PANCREATIC NEUROENDOCRINE TUMORS. EPIGENETIC FACTORS ARE ESSENTIALLY INVOLVED IN CARCINOGENESIS, TUMOR PROMOTION, AND CHEMORESISTANCE. TWO EPIGENETIC KEY PLAYERS ARE MIRNAS AND HISTONE DEACETYLASES (HDACS). AS PREVIOUSLY SHOWN BY OWN THEORETICAL DATABANK ANALYSIS, THE CROSSTALK BETWEEN MIRNAS AND HDACS IS RELEVANT IN DIFFERENT HUMAN CHRONIC DISEASES AND CANCEROGENIC PATHWAYS. WE AIMED TO INVESTIGATE A POTENTIAL CONNECTION BETWEEN THE EXPRESSION OF A WELL-DEFINED SUBSET OF "PROLIFERATION-ASSOCIATED" MIRNAS AND THE EXPRESSION OF HDACS AS WELL AS CLINICAL PARAMETERS IN PANCREATIC NEUROENDOCRINE TUMORS (PNETS). MATERIALS AND METHODS: EXPRESSION LEVELS OF MIRNA132-3P, MIRNA145-5P, MIRNA183-5P, MIRNA34A-5P, AND MIRNA449A IN 57 PNETS RESECTED BETWEEN 1997 AND 2015 WERE MEASURED AND LINKED TO THE IMMUNOHISTOCHEMICAL EXPRESSION PATTERN OF MEMBERS OF THE FOUR HDAC CLASSES ON HUMAN TISSUE MICROARRAYS. ALL PNET CASES WERE CLINICALLY AND PATHOLOGICALLY CHARACTERIZED ACCORDING TO PUBLISHED GUIDELINES. CORRELATION ANALYSIS REVEALED A SIGNIFICANT ASSOCIATION BETWEEN EXPRESSION OF SPECIFIC MIRNAS AND TWO MEMBERS OF THE HDAC FAMILY (HDAC3 AND HDAC4). ADDITIONALLY, A LINKAGE BETWEEN MIRNA EXPRESSION AND CLINICO-PATHOLOGICAL PARAMETERS LIKE GRADING, TNM-STAGING, AND HORMONE ACTIVITY WAS FOUND. MOREOVER, OVERALL AND DISEASE-FREE SURVIVAL IS STATISTICALLY CORRELATED WITH THE EXPRESSION OF THE INVESTIGATED MIRNAS. OVERALL, WE DEMONSTRATED THAT SPECIFIC MIRNAS COULD BE LINKED TO HDAC EXPRESSION IN PNETS. ESPECIALLY MIRNA449A (ASSOCIATED WITH HDAC3/4) SEEMS TO PLAY AN IMPORTANT ROLE IN PNET PROLIFERATION AND COULD BE A POTENTIAL PROGNOSTIC FACTOR FOR POOR SURVIVAL. THESE FIRST DATA COULD HELP, TO IMPROVE OUR KNOWLEDGE OF THE COMPLEX INTERACTIONS OF THE EPIGENETIC DRIVERS IN PNETS FOR FURTHER THERAPEUTIC APPROACHES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
13 3500  35 IDENTIFICATION OF NOVEL, CLONALLY STABLE, SOMATIC MUTATIONS TARGETING TRANSCRIPTION FACTORS PAX5 AND NKX2-3, THE EPIGENETIC REGULATOR LRIF1, AND BRAF IN A CASE OF ATYPICAL B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA HARBORING A T(14;18)(Q32;Q21). DIAGNOSIS OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) IS USUALLY STRAIGHTFORWARD, INVOLVING CLINICAL, IMMUNOPHENOTYPIC (MATUTES SCORE), AND (IMMUNO)GENETIC ANALYSES (TO REFINE PATIENT PROGNOSIS FOR TREATMENT). CLL CASES WITH ATYPICAL PRESENTATION (E.G., MATUTES </= 3) ARE ALSO ENCOUNTERED, AND FOR THESE DISEASES, BIOLOGY AND PROGNOSTIC IMPACT ARE LESS CLEAR. HERE WE REPORT THE GENOMIC CHARACTERIZATION OF A CASE OF ATYPICAL B-CLL IN A 70-YR-OLD MALE PATIENT; B-CLL CELLS SHOWED A MATUTES SCORE OF 3, CHROMOSOMAL TRANSLOCATION T(14;18)(Q32;Q21) (BCL2/IGH), MUTATED IGHV, DELETION 17P, AND MUTATIONS IN BCL2, NOTCH1 (SUBCLONAL), AND TP53 (SUBCLONAL). QUITE STRIKINGLY, A NOVEL PAX5 MUTATION THAT WAS PREDICTED TO BE LOSS OF FUNCTION WAS ALSO SEEN. EXOME SEQUENCING IDENTIFIED, IN ADDITION, A POTENTIALLY ACTIONABLE BRAF MUTATION, TOGETHER WITH NOVEL SOMATIC MUTATIONS AFFECTING THE HOMEOBOX TRANSCRIPTION FACTOR NKX2-3, KNOWN TO CONTROL B-LYMPHOCYTE DEVELOPMENT AND HOMING, AND THE EPIGENETIC REGULATOR LRIF1, WHICH IS IMPLICATED IN CHROMATIN COMPACTION AND GENE SILENCING. NEITHER NKX2-3 NOR LRIF1 MUTATIONS, PREDICTED TO BE LOSS OF FUNCTION, HAVE PREVIOUSLY BEEN REPORTED IN B-CLL. SEQUENCING CONFIRMED THE PRESENCE OF THESE MUTATIONS TOGETHER WITH BCL2, NOTCH1, AND BRAF MUTATIONS, WITH THE T(14;18)(Q32;Q21) TRANSLOCATION, IN THE INITIAL DIAGNOSTIC SAMPLE OBTAINED 12 YR PRIOR. THIS IS SUGGESTIVE OF A ROLE FOR THESE NOVEL MUTATIONS IN B-CLL INITIATION AND STABLE CLONAL EVOLUTION, INCLUDING UPON TREATMENT WITHDRAWAL. THIS CASE EXTENDS THE SPECTRUM OF ATYPICAL B-CLL WITH T(14;18)(Q32;Q21) AND HIGHLIGHTS THE VALUE OF MORE GLOBAL PRECISION GENOMICS FOR PATIENT FOLLOW-UP AND TREATMENT IN THESE PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14 4545  26 MUTANT P53 GAIN OF FUNCTION AND CHEMORESISTANCE: THE ROLE OF MUTANT P53 IN RESPONSE TO CLINICAL CHEMOTHERAPY. PURPOSE: TO REVIEW MECHANISMS UNDERLYING MUTANT P53 (MUTP53) GAIN OF FUNCTION (GOF) AND MUTP53-INDUCED CHEMORESISTANCE, AND TO INVESTIGATE THE ROLE OF MUTP53 IN RESPONSE TO CLINICAL CHEMOTHERAPY. METHODS: WE SEARCHED THE PUBMED DATABASE FOR CLINICAL STUDIES FROM THE PAST DECADE, INCLUDING DATA EVALUATING THE IMPACT OF MUTP53 IN CLINICAL CHEMOTHERAPY RESPONSE. RESULTS: INTERACTIONS BETWEEN MUTP53 AND TRANSCRIPTIONAL FACTORS, PROTEINS OR DNA STRUCTURES, AS WELL AS EPIGENETIC REGULATION, CONTRIBUTE TO MUTP53 GOF. MAJOR MECHANISMS OF MUTP53-INDUCED CHEMORESISTANCE INCLUDE ENHANCED DRUG EFFLUX AND METABOLISM, PROMOTING SURVIVAL, INHIBITING APOPTOSIS, UPREGULATING DNA REPAIR, SUPPRESSING AUTOPHAGY, ELEVATING MICROENVIRONMENTAL RESISTANCE AND INDUCING A STEM-LIKE PHENOTYPE. CLINICALLY, MUTP53 PREDICTED RESISTANCE TO CHEMOTHERAPY IN DIFFUSE LARGE B-CELL LYMPHOMA, AND ESOPHAGEAL AND OROPHARYNGEAL CANCERS, BUT ITS IMPACT ON CHRONIC LYMPHOCYTIC LEUKEMIA WAS UNCLEAR. IN BLADDER CANCER, MUTP53 DID NOT PREDICT RESISTANCE, WHEREAS IN SOME BREAST AND OVARIAN CANCERS, IT WAS ASSOCIATED WITH SENSITIVITY TO CERTAIN CHEMOTHERAPEUTIC AGENTS. CONCLUSION: MUTP53 HAS AN INTRICATE ROLE IN THE RESPONSE TO CLINICAL CHEMOTHERAPY AND SHOULD NOT BE INTERPRETED IN ISOLATION. FURTHERMORE, WHEN PREDICTING TUMOR RESPONSE TO CHEMOTHERAPY BASED ON THE P53 STATUS, THE DRUGS USED SHOULD ALSO BE TAKEN INTO CONSIDERATION. THESE CONCEPTS REQUIRE FURTHER INVESTIGATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
15 5004  27 PERIPHERAL B CELLS FROM PATIENTS WITH HEPATITIS C VIRUS-ASSOCIATED LYMPHOMA EXHIBIT CLONAL EXPANSION AND AN ANERGIC-LIKE TRANSCRIPTIONAL PROFILE. CHRONIC HCV INFECTION REMAINS A GLOBAL HEALTH CONCERN DUE TO ITS INVOLVEMENT IN HEPATIC AND EXTRAHEPATIC DISEASES, INCLUDING B CELL NON-HODGKIN LYMPHOMA (BNHL). CLINICAL AND EPIDEMIOLOGICAL EVIDENCE SUPPORT A CAUSAL ROLE FOR HCV IN BNHL DEVELOPMENT, ALTHOUGH MECHANISTIC INSIGHT IS LACKING. WE PERFORMED RNA-SEQUENCING ON PERIPHERAL B CELLS FROM PATIENTS WITH HCV ALONE, BNHL ALONE, AND HCV-ASSOCIATED BNHL TO IDENTIFY UNIQUE AND SHARED TRANSCRIPTIONAL PROFILES ASSOCIATED WITH TRANSFORMATION. IN PATIENTS WITH HCV-ASSOCIATED BNHL, WE OBSERVED THE ENRICHMENT OF AN ANERGIC-LIKE GENE SIGNATURE AND EVIDENCE OF CLONAL EXPANSION THAT WAS CORRELATED WITH THE EXPRESSION OF EPIGENETIC REGULATORY GENES. OUR DATA SUPPORT A ROLE FOR VIRAL-MEDIATED CLONAL EXPANSION OF ANERGIC-LIKE B CELLS IN HCV-ASSOCIATED BNHL DEVELOPMENT AND SUGGEST EPIGENETIC DYSREGULATION AS A POTENTIAL MECHANISM DRIVING EXPANSION. WE PROPOSE EPIGENETIC MECHANISMS MAY BE INVOLVED IN BOTH HCV-ASSOCIATED LYMPHOMA AND REGULATION OF B CELL ANERGY, REPRESENTING AN ATTRACTIVE TARGET FOR CLINICAL INTERVENTIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
16 2696  25 EWING SARCOMA. EWING SARCOMA IS THE SECOND MOST FREQUENT BONE TUMOUR OF CHILDHOOD AND ADOLESCENCE THAT CAN ALSO ARISE IN SOFT TISSUE. EWING SARCOMA IS A HIGHLY AGGRESSIVE CANCER, WITH A SURVIVAL OF 70-80% FOR PATIENTS WITH STANDARD-RISK AND LOCALIZED DISEASE AND ~30% FOR THOSE WITH METASTATIC DISEASE. TREATMENT COMPRISES LOCAL SURGERY, RADIOTHERAPY AND POLYCHEMOTHERAPY, WHICH ARE ASSOCIATED WITH ACUTE AND CHRONIC ADVERSE EFFECTS THAT MAY COMPROMISE QUALITY OF LIFE IN SURVIVORS. HISTOLOGICALLY, EWING SARCOMAS ARE COMPOSED OF SMALL ROUND CELLS EXPRESSING HIGH LEVELS OF CD99. GENETICALLY, THEY ARE CHARACTERIZED BY BALANCED CHROMOSOMAL TRANSLOCATIONS IN WHICH A MEMBER OF THE FET GENE FAMILY IS FUSED WITH AN ETS TRANSCRIPTION FACTOR, WITH THE MOST COMMON FUSION BEING EWSR1-FLI1 (85% OF CASES). EWING SARCOMA BREAKPOINT REGION 1 PROTEIN (EWSR1)-FRIEND LEUKAEMIA INTEGRATION 1 TRANSCRIPTION FACTOR (FLI1) IS A TUMOUR-SPECIFIC CHIMERIC TRANSCRIPTION FACTOR (EWSR1-FLI1) WITH NEOMORPHIC EFFECTS THAT MASSIVELY REWIRES THE TRANSCRIPTOME. ADDITIONALLY, EWSR1-FLI1 REPROGRAMMES THE EPIGENOME BY INDUCING DE NOVO ENHANCERS AT GGAA MICROSATELLITES AND BY ALTERING THE STATE OF GENE REGULATORY ELEMENTS, CREATING A UNIQUE EPIGENETIC SIGNATURE. ADDITIONAL MUTATIONS AT DIAGNOSIS ARE RARE AND MAINLY INVOLVE STAG2, TP53 AND CDKN2A DELETIONS. EMERGING STUDIES ON THE MOLECULAR MECHANISMS OF EWING SARCOMA HOLD PROMISE FOR IMPROVEMENTS IN EARLY DETECTION, DISEASE MONITORING, LOWER TREATMENT-RELATED TOXICITY, OVERALL SURVIVAL AND QUALITY OF LIFE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17   11  30 15Q12 VARIANTS, SPUTUM GENE PROMOTER HYPERMETHYLATION, AND LUNG CANCER RISK: A GWAS IN SMOKERS. BACKGROUND: LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED MORTALITY WORLDWIDE. DETECTION OF PROMOTER HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES IN EXFOLIATED CELLS FROM THE LUNG PROVIDES AN ASSESSMENT OF FIELD CANCERIZATION THAT IN TURN PREDICTS LUNG CANCER. THE IDENTIFICATION OF GENETIC DETERMINANTS FOR THIS VALIDATED CANCER BIOMARKER SHOULD PROVIDE NOVEL INSIGHTS INTO MECHANISMS UNDERLYING EPIGENETIC REPROGRAMMING DURING LUNG CARCINOGENESIS. METHODS: A GENOME-WIDE ASSOCIATION STUDY USING GENERALIZED ESTIMATING EQUATIONS AND LOGISTIC REGRESSION MODELS WAS CONDUCTED IN TWO GEOGRAPHICALLY INDEPENDENT SMOKER COHORTS TO IDENTIFY LOCI AFFECTING THE PROPENSITY FOR CANCER-RELATED GENE METHYLATION THAT WAS ASSESSED BY A 12-GENE PANEL INTERROGATED IN SPUTUM. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: TWO SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AT 15Q12 (RS73371737 AND RS7179575) THAT DROVE GENE METHYLATION WERE DISCOVERED AND REPLICATED WITH RS73371737 REACHING GENOME-WIDE SIGNIFICANCE (P = 3.3X10(-8)). A HAPLOTYPE CARRYING RISK ALLELES FROM THE TWO 15Q12 SNPS CONFERRED 57% INCREASED RISK FOR GENE METHYLATION (P = 2.5X10(-9)). RS73371737 REDUCED GABRB3 EXPRESSION IN LUNG CELLS AND INCREASED RISK FOR SMOKING-INDUCED CHRONIC MUCOUS HYPERSECRETION. FURTHERMORE, SUBJECTS WITH VARIANT HOMOZYGOTE OF RS73371737 HAD A TWO-FOLD INCREASE IN RISK FOR LUNG CANCER (P = .0043). PATHWAY ANALYSIS IDENTIFIED DNA DOUBLE-STRAND BREAK REPAIR BY HOMOLOGOUS RECOMBINATION (DSBR-HR) AS A MAJOR PATHWAY AFFECTING SUSCEPTIBILITY FOR GENE METHYLATION THAT WAS VALIDATED BY MEASURING CHROMATID BREAKS IN LYMPHOCYTES CHALLENGED BY BLEOMYCIN. CONCLUSIONS: A FUNCTIONAL 15Q12 VARIANT WAS IDENTIFIED AS A RISK FACTOR FOR GENE METHYLATION AND LUNG CANCER. THE ASSOCIATIONS COULD BE MEDIATED BY GABAERGIC SIGNALING THAT DRIVES THE SMOKING-INDUCED MUCOUS CELL METAPLASIA. OUR FINDINGS ALSO SUBSTANTIATE DSBR-HR AS A CRITICAL PATHWAY DRIVING EPIGENETIC GENE SILENCING.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18 5775  35 SPERMIDINE/SPERMINE N(1)-ACETYLTRANSFERASE ACTIVITY ASSOCIATES WITH WHITE BLOOD CELL COUNT IN MYELOID LEUKEMIAS. THE METABOLISM OF POLYAMINES, THE CATIONIC SMALL MOLECULES ESSENTIAL FOR CELL PROLIFERATION AND DIFFERENTIATION, IS ALTERED IN CANCER CELLS AND CAN BE EXPLOITED IN CANCER DIAGNOSIS AND THERAPY. SPERMIDINE/SPERMINE N(1)-ACETYLTRANSFERASE (SSAT), WHICH REGULATES INTRACELLULAR LEVELS OF POLYAMINES BY CATABOLIZING SPERMIDINE AND SPERMINE, HAS A CONTROVERSIAL ROLE IN THE DEVELOPMENT OF CANCERS. IN THIS STUDY, THE POLYAMINE METABOLISM AND FUNCTION OF SSAT WERE CHARACTERIZED IN ACUTE MYELOID LEUKEMIA (AML), CHRONIC MYELOID LEUKEMIA (CML), AND ACUTE LYMPHOID LEUKEMIA PATIENT SAMPLES. ALSO, MICE OVEREXPRESSING SSAT AND HAVING A MYELOPROLIFERATIVE PHENOTYPE WERE ANALYZED FOR THEIR RESPONSE TO DECITABINE AND HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A. THE PRESENCE OF EPIGENETIC FACTORS IN THE BONE MARROW CELLS OF SSAT MICE WAS ANALYZED. ELEVATED LEVELS OF SPERMIDINE AND SPERMINE, AS WELL AS INCREASED ACTIVITY OF SSAT, WERE DETECTED IN AML, CML, AND ACUTE LYMPHOID LEUKEMIA PATIENTS COMPARED WITH THE CONTROLS. HOWEVER, WE FOUND SSAT ACTIVITY TO BE ASSOCIATED WITH WHITE BLOOD CELL COUNT ONLY IN AML AND CML PATIENTS. DECITABINE TREATMENT BROUGHT THE PERIPHERAL BLOOD AND BONE MARROW CELL COUNTS OF SSAT MICE TO THE LEVEL OF WILD-TYPE MICE. SPERMIDINE/SPERMINE N(1)-ACETYLTRANSFERASE MICE HAD INCREASED HISTONE METHYLATION AND AN INCREASED LEVEL OF HISTONE DEACETYLASE 1 IN THEIR BONE MARROW CELLS. THE STUDY SUGGESTS THAT SSAT INFLUENCES THE DEVELOPMENT OF MYELOID MALIGNANCIES, AND EPIGENETIC FACTORS PARTLY CONTRIBUTE TO THE SSAT OVEREXPRESSION-INDUCED MYELOPROLIFERATIVE DISEASE IN MICE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19 5433  28 REL/NF-KAPPA B/I KAPPA B SIGNAL TRANSDUCTION IN THE GENERATION AND TREATMENT OF HUMAN CANCER. THE REL/NF-KAPPA B FAMILY IS A GROUP OF STRUCTURALLY-RELATED, TIGHTLY-REGULATED TRANSCRIPTION FACTORS THAT CONTROL THE EXPRESSION OF A MULTITUDE OF GENES INVOLVED IN KEY CELLULAR AND ORGANISMAL PROCESSES. THE REL/NF-KAPPA B SIGNAL TRANSDUCTION PATHWAY IS MISREGULATED IN A VARIETY OF HUMAN CANCERS, ESPECIALLY ONES OF LYMPHOID CELL ORIGIN, DUE EITHER TO GENETIC CHANGES (SUCH AS CHROMOSOMAL REARRANGEMENTS, AMPLIFICATIONS, AND MUTATIONS) OR TO CHRONIC ACTIVATION OF THE PATHWAY BY EPIGENETIC MECHANISMS. CONSTITUTIVE ACTIVATION OF THE REL/NF-KAPPA B PATHWAY CAN CONTRIBUTE TO THE ONCOGENIC STATE IN SEVERAL WAYS, FOR EXAMPLE, BY DRIVING PROLIFERATION, BY ENHANCING CELL SURVIVAL, OR BY PROMOTING ANGIOGENESIS OR METASTASIS. IN MANY CASES, INHIBITION OF REL/NF-KAPPA B ACTIVITY REVERSES ALL OR PART OF THE MALIGNANT STATE. THUS, THE REL/NF-KAPPA B PATHWAY HAS RECEIVED MUCH ATTENTION AS A FOCAL POINT FOR CLINICAL INTERVENTION.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20 1000  33 CHRONIC T CELL RECEPTOR STIMULATION UNMASKS NK RECEPTOR SIGNALING IN PERIPHERAL T CELL LYMPHOMAS VIA EPIGENETIC REPROGRAMMING. PERIPHERAL T CELL LYMPHOMAS (PTCLS) REPRESENT A SIGNIFICANT UNMET MEDICAL NEED WITH DISMAL CLINICAL OUTCOMES. THE T CELL RECEPTOR (TCR) IS EMERGING AS A KEY DRIVER OF T LYMPHOCYTE TRANSFORMATION. HOWEVER, THE ROLE OF CHRONIC TCR ACTIVATION IN LYMPHOMAGENESIS AND IN LYMPHOMA CELL SURVIVAL IS STILL POORLY UNDERSTOOD. USING A MOUSE MODEL, WE REPORT THAT CHRONIC TCR STIMULATION DROVE T CELL LYMPHOMAGENESIS, WHEREAS TCR SIGNALING DID NOT CONTRIBUTE TO PTCL SURVIVAL. THE COMBINATION OF KINOME, TRANSCRIPTOME, AND EPIGENOME ANALYSES OF MOUSE PTCLS REVEALED A NK CELL-LIKE REPROGRAMMING OF PTCL CELLS WITH EXPRESSION OF NK RECEPTORS (NKRS) AND DOWNSTREAM SIGNALING MOLECULES SUCH AS TYROBP AND SYK. ACTIVATING NKRS WERE FUNCTIONAL IN PTCLS AND DEPENDENT ON SYK ACTIVITY. IN VIVO BLOCKADE OF NKR SIGNALING PROLONGED MOUSE SURVIVAL, DEMONSTRATING THE ADDICTION OF PTCLS TO NKRS AND DOWNSTREAM SYK/MTOR ACTIVITY FOR THEIR SURVIVAL. WE STUDIED A LARGE COLLECTION OF HUMAN PRIMARY SAMPLES AND IDENTIFIED SEVERAL PTCLS RECAPITULATING THE PHENOTYPE DESCRIBED IN THIS MODEL BY THEIR EXPRESSION OF SYK AND THE NKR, SUGGESTING A SIMILAR MECHANISM OF LYMPHOMAGENESIS AND ESTABLISHING A RATIONALE FOR CLINICAL STUDIES TARGETING SUCH MOLECULES.	2021