1 5383 172 RECURRENT XPO1 MUTATIONS ALTER PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: EXPORTIN 1 (XPO1/CRM1) IS A KEY MEDIATOR OF NUCLEAR EXPORT WITH RELEVANCE TO MULTIPLE CANCERS, INCLUDING CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). WHOLE EXOME SEQUENCING HAS IDENTIFIED HOT-SPOT SOMATIC XPO1 POINT MUTATIONS WHICH WE FOUND TO DISRUPT HIGHLY CONSERVED BIOPHYSICAL INTERACTIONS IN THE NES-BINDING GROOVE, CONFERRING NOVEL CARGO-BINDING ABILITIES AND FORCING CELLULAR MIS-LOCALIZATION OF CRITICAL REGULATORS. HOWEVER, THE PATHOGENIC ROLE PLAYED BY CHANGE-IN-FUNCTION XPO1 MUTATIONS IN CLL IS NOT FULLY UNDERSTOOD. METHODS: WE PERFORMED A LARGE, MULTI-CENTER RETROSPECTIVE ANALYSIS OF CLL CASES (N = 1286) TO CORRELATE NONSYNONYMOUS MUTATIONS IN XPO1 (PREDOMINANTLY E571K OR E571G; N = 72) WITH GENETIC AND EPIGENETIC FEATURES CONTRIBUTING TO THE OVERALL OUTCOMES IN THESE PATIENTS. WE THEN ESTABLISHED A MOUSE MODEL WITH OVER-EXPRESSION OF WILDTYPE (WT) OR MUTANT (E571K OR E571G) XPO1 RESTRICTED TO THE B CELL COMPARTMENT (EMICRO-XPO1). EMICRO-XPO1 MICE WERE THEN CROSSED WITH THE EMICRO-TCL1 CLL MOUSE MODEL. LASTLY, WE DETERMINED CRYSTAL STRUCTURES OF XPO1 (WT OR E571K) BOUND TO SEVERAL SELECTIVE INHIBITORS OF NUCLEAR EXPORT (SINE) MOLECULES (KPT-185, KPT-330/SELINEXOR, AND KPT-8602/ELTANEXOR). RESULTS: WE REPORT THAT NONSYNONYMOUS MUTATIONS IN XPO1 ASSOCIATE WITH HIGH RISK GENETIC AND EPIGENETIC FEATURES AND ACCELERATED CLL PROGRESSION. USING THE NEWLY-GENERATED EMICRO-XPO1 MOUSE MODEL, WE FOUND THAT CONSTITUTIVE B-CELL OVER-EXPRESSION OF WT OR MUTANT XPO1 COULD AFFECT DEVELOPMENT OF A CLL-LIKE DISEASE IN AGED MICE. FURTHERMORE, CONCURRENT B-CELL EXPRESSION OF XPO1 WITH E571K OR E571G MUTATIONS AND TCL1 ACCELERATED THE RATE OF LEUKEMOGENESIS RELATIVE TO THAT OF EMICRO-TCL1 MICE. LASTLY, CRYSTAL STRUCTURES OF E571 OR E571K-XPO1 BOUND TO SINES, INCLUDING SELINEXOR, ARE HIGHLY SIMILAR, SUGGESTING THAT THE ACTIVITY OF THIS CLASS OF COMPOUNDS WILL NOT BE AFFECTED BY XPO1 MUTATIONS AT E571 IN PATIENTS WITH CLL. CONCLUSIONS: THESE FINDINGS INDICATE THAT MUTATIONS IN XPO1 AT E571 CAN DRIVE LEUKEMOGENESIS BY PRIMING THE PRE-NEOPLASTIC LYMPHOCYTES FOR ACQUISITION OF ADDITIONAL GENETIC AND EPIGENETIC ABNORMALITIES THAT COLLECTIVELY RESULT IN NEOPLASTIC TRANSFORMATION. 2021 2 32 45 A CASE OF TYROSINE KINASE INHIBITOR-RESISTANT CHRONIC MYELOID LEUKEMIA, CHRONIC PHASE WITH ASXL1 MUTATION. HEMATOLOGICAL MALIGNANCIES, INCLUDING CHRONIC MYELOID LEUKEMIA (CML), EXHIBIT ASXL1 MUTATIONS; HOWEVER, THE FUNCTION AND MOLECULAR MECHANISM OF THESE MUTATIONS REMAIN UNCLEAR. ASXL1 WAS ORIGINALLY IDENTIFIED AS TUMOR SUPPRESSOR GENE, IN WHICH LOSS OF FUNCTION CAUSES MYELODYSPLASTIC SYNDROME (MDS). ASXL1 MUTATIONS ARE COMMON AND ASSOCIATED WITH DISEASE PROGRESSION IN MYELOID MALIGNANCIES INCLUDING MDS, ACUTE MYELOID LEUKEMIA, AND SIMILARLY IN CML. IN MDS, ASXL1 MUTATIONS HAVE BEEN ASSOCIATED WITH POOR PROGNOSIS; HOWEVER, THE IMPACT OF ASXL1 MUTATIONS IN CML HAS NOT BEEN WELL DESCRIBED. A 31-YEAR-OLD MALE WAS DIAGNOSED AS CML-CHRONIC PHASE (CP). LABORATORY FINDINGS SHOWED A WHITE BLOOD CELL COUNT OF 187,200/MICROL, WITH ASYMPTOMATIC SPLENOMEGALY. BLAST COUNT WAS 5.0% IN PERIPHERAL BLOOD AND 7.3% IN BONE MARROW. THERE WAS NO ADDITIONAL CHROMOSOMAL ABNORMALITY EXCEPT FOR T(9;22)(Q34;Q11.2) BY CHROMOSOMAL ANALYSIS. AT ONSET, THE SOKAL SCORE WAS 1.4, INDICATING HIGH RISK. THE PATIENT RECEIVED TYROSINE KINASE INHIBITOR (TKI) THERAPY, COMPRISING NILOTINIB APPROXIMATELY 600 MG/DAY, BOSUTINIB APPROXIMATELY 600 MG/DAY, PONATINIB APPROXIMATELY 45 MG/DAY, AND DASATINIB APPROXIMATELY 100 MG/DAY. NEVERTHELESS, AFTER 1.5 YEARS OF CONTINUOUS TKI THERAPY, THE BEST OUTCOME WAS A HEMATOLOGICAL RESPONSE. ALTHOUGH ADDITIONAL CHROMOSOMAL ABERRATIONS AND ABL1 KINASE MUTATIONS WERE ANALYZED REPEATEDLY BEFORE AND DURING TKI THERAPY, KNOWN GENETIC ABNORMALITIES WERE NOT DETECTED. THEREAFTER, THE PATIENT UNDERWENT BONE MARROW TRANSPLANTATION FROM AN HLA 7/8 MATCHED UNRELATED DONOR (HLA-CW 1 LOCUS MISMATCH, GRAFT-VERSUS-HOST DIRECTION). THE PATIENT ACHIEVED NEUTROPHIL ENGRAFTMENT, 18 DAYS AFTER TRANSPLANTATION, LEADING TO COMPLETE REMISSION WITH AN UNDETECTABLE LEVEL OF BCR-ABL1 MRNA. THE PATIENT, HOWEVER, DIED FROM GRAFT-VERSUS-HOST DISEASE AND THROMBOTIC MICROANGIOPATHY AFTER 121 DAYS. GENE SEQUENCE ANALYSIS OF HIS CML CELL BEFORE STEM CELL TRANSPLANTATION REVEALED ASXL1 MUTATIONS. PHYSIOLOGICALLY, ASXL1 CONTRIBUTES TO EPIGENETIC REGULATION. IN THE CML-CP PATIENT IN THIS CASE REPORT, ASXL1 MUTATION CONFERRED RESISTANCE TO TKI THROUGH OBSCURE RESISTANCE MECHANISMS. EVEN THOUGH A MOLECULAR MECHANISM FOR TKI RESISTANCE IN ASXL1 MUTATION IN CML HAS REMAINED OBSCURE, EPIGENETIC MODULATION IS A PLAUSIBLE MODE OF CML DISEASE PROGRESSION. THE CLINICAL IMPACT INCLUDING PROGNOSIS OF ASXL1 FOR CML IS UNDERSCORED. AND THE TREATMENT STRATEGY OF CML WITH ASXL1 MUTATION HAS NOT BEEN ESTABLISHED. A DISCUSSION OF THIS CASE WAS EXPECTED TO FACILITATE TREATMENT OPTIONS. 2020 3 226 31 ACUTE TRANSCRIPTOMIC AND EPIGENETIC ALTERATIONS AT T12 AFTER RAT T10 SPINAL CORD CONTUSIVE INJURY. SPINAL CORD INJURY IS A SEVERELY DEBILITATING CONDITION AFFECTING A SIGNIFICANT POPULATION IN THE USA. SPINAL CORD INJURY PATIENTS OFTEN HAVE INCREASED RISK OF DEVELOPING PERSISTENT NEUROPATHIC PAIN AND OTHER NEURODEGENERATIVE CONDITIONS BEYOND THE PRIMARY LESION CENTER LATER IN THEIR LIFE. THE MOLECULAR MECHANISM CONFERRING TO THE "LATENT" DAMAGES AT DISTAL TISSUES, HOWEVER, REMAINS ELUSIVE. HERE, WE STUDIED MOLECULAR CHANGES CONFERRING ABNORMAL FUNCTIONALITY AT DISTAL SPINAL CORD (T12) BEYOND THE LESION CENTER (T10) BY COMBINING NEXT-GENERATION SEQUENCING (RNA- AND BISULFITE SEQUENCING), SUPER-RESOLUTION MICROSCOPY, AND IMMUNOFLUORESCENCE STAINING AT 7 DAYS POST INJURY. WE OBSERVED SIGNIFICANT TRANSCRIPTOMIC CHANGES PRIMARILY ENRICHED IN NEUROINFLAMMATION AND SYNAPTOGENESIS ASSOCIATED PATHWAYS. TRANSCRIPTION FACTORS (TFS) THAT REGULATE NEUROGENESIS AND NEURON PLASTICITY, INCLUDING EGR1, KLF4, AND MYC, ARE SIGNIFICANTLY UPREGULATED. ALONG WITH GLOBAL CHANGES IN CHROMATIN ARRANGEMENTS AND DNA METHYLATION, INCLUDING 5-METHYLCYTOSINE (5MC) AND 5-HYDROXYMETHYLCYTOSINE (5HMC), BISULFITE SEQUENCING FURTHER REVEALS THE INVOLVEMENT OF DNA METHYLATION CHANGES IN REGULATING CYTOKINE, GROWTH FACTOR, AND ION CHANNEL EXPRESSION. COLLECTIVELY, OUR RESULTS PAVE THE WAY TOWARDS UNDERSTANDING TRANSCRIPTOMIC AND EPIGENOMIC MECHANISM IN CONFERRING LONG-TERM DISEASE RISKS AT DISTAL TISSUES AWAY FROM THE PRIMARY LESION CENTER AND SHED LIGHT ON POTENTIAL MOLECULAR TARGETS THAT GOVERN THE REGULATORY MECHANISM AT DISTAL SPINAL CORD TISSUES. 2023 4 4838 36 ONCOGENIC N-RAS AND TET2 HAPLOINSUFFICIENCY COLLABORATE TO DYSREGULATE HEMATOPOIETIC STEM AND PROGENITOR CELLS. CONCURRENT GENETIC LESIONS EXIST IN A MAJORITY OF PATIENTS WITH HEMATOLOGIC MALIGNANCIES. AMONG THESE, SOMATIC MUTATIONS THAT ACTIVATE RAS ONCOGENES AND INACTIVATE THE EPIGENETIC MODIFIER TEN-ELEVEN TRANSLOCATION 2 (TET2) FREQUENTLY CO-OCCUR IN HUMAN CHRONIC MYELOMONOCYTIC LEUKEMIAS (CMMLS) AND ACUTE MYELOID LEUKEMIAS, SUGGESTING A COOPERATIVITY IN MALIGNANT TRANSFORMATION. TO TEST THIS, WE APPLIED A CONDITIONAL MURINE MODEL THAT ENDOGENOUSLY EXPRESSED ONCOGENIC NRAS(G12D) AND MONOALLELIC LOSS OF TET2 AND EXPLORED THE COLLABORATIVE ROLE SPECIFICALLY WITHIN HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS) AT DISEASE INITIATION. WE DEMONSTRATE THAT THE 2 MUTATIONS COLLABORATED TO ACCELERATE A TRANSPLANTABLE CMML-LIKE DISEASE IN VIVO, WITH AN OVERALL SHORTENED SURVIVAL AND INCREASED DISEASE PENETRANCE COMPARED WITH SINGLE MUTANTS. AT PRELEUKEMIC STAGE, N-RAS(G12D) AND TET2 HAPLOINSUFFICIENCY TOGETHER INDUCED BALANCED HEMATOPOIETIC STEM CELL (HSC) PROLIFERATION AND ENHANCED COMPETITIVENESS. NRAS(G12D/+)/TET2(+/-) HSCS DISPLAYED INCREASED SELF-RENEWAL IN PRIMARY AND SECONDARY TRANSPLANTATIONS, WITH SIGNIFICANTLY HIGHER RECONSTITUTION THAN SINGLE MUTANTS. STRIKINGLY, THE 2 MUTATIONS TOGETHER CONFERRED LONG-TERM RECONSTITUTION AND SELF-RENEWAL POTENTIAL TO MULTIPOTENT PROGENITORS, A POOL OF CELLS THAT USUALLY HAVE LIMITED SELF-RENEWAL COMPARED WITH HSCS. MOREOVER, HSPCS FROM NRAS(G12D/+)/TET2(+/-) MICE DISPLAYED INCREASED CYTOKINE SENSITIVITY IN RESPONSE TO THROMBOPOIETIN. THEREFORE, OUR STUDIES ESTABLISH A NOVEL TRACTABLE CMML MODEL AND PROVIDE INSIGHTS INTO HOW DYSREGULATED SIGNALING PATHWAYS AND EPIGENETIC MODIFIERS COLLABORATE TO MODULATE HSPC FUNCTION AND PROMOTE LEUKEMOGENESIS. 2018 5 923 32 CHRONIC INFECTION DRIVES DNMT3A-LOSS-OF-FUNCTION CLONAL HEMATOPOIESIS VIA IFNGAMMA SIGNALING. AGE-RELATED CLONAL HEMATOPOIESIS (CH) IS A RISK FACTOR FOR MALIGNANCY, CARDIOVASCULAR DISEASE, AND ALL-CAUSE MORTALITY. SOMATIC MUTATIONS IN DNMT3A ARE DRIVERS OF CH, BUT DECADES MAY ELAPSE BETWEEN THE ACQUISITION OF A MUTATION AND CH, SUGGESTING THAT ENVIRONMENTAL FACTORS CONTRIBUTE TO CLONAL EXPANSION. WE TESTED WHETHER INFECTION PROVIDES SELECTIVE PRESSURE FAVORING THE EXPANSION OF DNMT3A MUTANT HEMATOPOIETIC STEM CELLS (HSCS) IN MOUSE CHIMERAS. WE CREATED DNMT3A-MOSAIC MICE BY TRANSPLANTING DNMT3A(-/-) AND WT HSCS INTO WT MICE AND OBSERVED THE SUBSTANTIAL EXPANSION OF DNMT3A(-/-) HSCS DURING CHRONIC MYCOBACTERIAL INFECTION. INJECTION OF RECOMBINANT IFNGAMMA ALONE WAS SUFFICIENT TO PHENOCOPY CH BY DNMT3A(-/-) HSCS UPON INFECTION. TRANSCRIPTIONAL AND EPIGENETIC PROFILING AND FUNCTIONAL STUDIES INDICATE REDUCED DIFFERENTIATION ASSOCIATED WITH WIDESPREAD METHYLATION ALTERATIONS, AND REDUCED SECONDARY STRESS-INDUCED APOPTOSIS ACCOUNTS FOR DNMT3A(-/-) CLONAL EXPANSION DURING INFECTION. DNMT3A MUTANT HUMAN HSCS SIMILARLY EXHIBIT DEFECTIVE IFNGAMMA-INDUCED DIFFERENTIATION. WE THUS DEMONSTRATE THAT IFNGAMMA SIGNALING INDUCED DURING CHRONIC INFECTION CAN DRIVE DNMT3A-LOSS-OF-FUNCTION CH. 2021 6 4921 32 PARENT-OF-ORIGIN EFFECTS IMPLICATE EPIGENETIC REGULATION OF EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS AND IDENTIFY IMPRINTED DLK1 AS A NOVEL RISK GENE. PARENT-OF-ORIGIN EFFECTS COMPRISE A RANGE OF GENETIC AND EPIGENETIC MECHANISMS OF INHERITANCE. RECENTLY, DETECTION OF SUCH EFFECTS IMPLICATED EPIGENETIC MECHANISMS IN THE ETIOLOGY OF MULTIPLE SCLEROSIS (MS), A CHRONIC INFLAMMATORY DISEASE OF THE CENTRAL NERVOUS SYSTEM. WE HERE SOUGHT TO DISSECT THE MAGNITUDE AND THE TYPE OF PARENT-OF-ORIGIN EFFECTS IN THE PATHOGENESIS OF EXPERIMENTAL NEUROINFLAMMATION UNDER CONTROLLED ENVIRONMENTAL CONDITIONS. WE INVESTIGATED INHERITANCE OF AN MS-LIKE DISEASE IN RAT, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), USING A BACKCROSS STRATEGY DESIGNED TO IDENTIFY THE PARENTAL ORIGIN OF DISEASE-PREDISPOSING ALLELES. A STRIKING 37-54% OF ALL DETECTED DISEASE-PREDISPOSING LOCI DEPENDED ON PARENTAL TRANSMISSION. ADDITIONALLY, THE Y CHROMOSOME FROM THE SUSCEPTIBLE STRAIN CONTRIBUTED TO DISEASE SUSCEPTIBILITY. ACCOUNTING FOR PARENT-OF-ORIGIN ENABLED MORE POWERFUL AND PRECISE IDENTIFICATION OF NOVEL RISK FACTORS AND INCREASED THE DISEASE VARIANCE EXPLAINED BY THE IDENTIFIED FACTORS BY 2-4-FOLD. THE MAJORITY OF LOCI DISPLAYED AN IMPRINTING-LIKE PATTERN WHEREBY A GENE EXPRESSED ONLY FROM THE MATERNAL OR PATERNAL COPY EXERTS AN EFFECT. IN PARTICULAR, A LOCUS ON CHROMOSOME 6 COMPRISES A WELL-KNOWN CLUSTER OF IMPRINTED GENES INCLUDING THE PATERNALLY EXPRESSED DLK1, AN ATYPICAL NOTCH LIGAND. DISEASE-PREDISPOSING ALLELES AT THE LOCUS CONFERRED LOWER DLK1 EXPRESSION IN RATS AND, TOGETHER WITH DATA FROM TRANSGENIC OVEREXPRESSING DLK1 MICE, DEMONSTRATE THAT REDUCED DLK1 DRIVES MORE SEVERE DISEASE AND MODULATES ADAPTIVE IMMUNE REACTIONS IN EAE. OUR FINDINGS SUGGEST A SIGNIFICANT EPIGENETIC CONTRIBUTION TO THE ETIOLOGY OF EAE. INCORPORATING THESE EFFECTS ENABLES MORE POWERFUL AND PRECISE IDENTIFICATION OF NOVEL RISK FACTORS WITH DIAGNOSTIC AND PROGNOSTIC IMPLICATIONS FOR COMPLEX DISEASE. 2014 7 2979 24 GENETIC BACKGROUND OF JUVENILE IDIOPATHIC ARTHRITIS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS THE MOST COMMON CHRONIC RHEUMATOLOGIC DISEASE IN CHILDREN. JIA IS A GROUP OF DISORDERS THAT SHARE THE CLINICAL MANIFESTATION OF CHRONIC JOINT INFLAMMATION. THE HUMAN LEUKOCYTE ANTIGEN REGION (HLA) SEEMS TO BE A MAJOR SUSCEPTIBILITY LOCUS FOR JIA THAT IS ESTIMATED TO ACCOUNT FOR 17% OF FAMILIAL SEGREGATION OF THE DISEASE. TO DATE, AROUND 20 NON-HLA LOCI CONFERRING SUSCEPTIBILITY TO JIA WERE FOUND. AT LEAST A HALF OF THOSE ARE SHARED BETWEEN JIA AND RHEUMATOID ARTHRITIS (RA), AN ADULT RHEUMATIC DISEASE, THEREBY SUGGESTING FOR SIMILARITY OF PATHOGENIC MECHANISMS OF BOTH DISEASES. NEW FINDINGS ALSO SUGGEST FOR A LIKELY ROLE OF EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF JIA THAT SHOULD BE INVESTIGATED IN THE FUTURE. 2014 8 1469 34 DISTINCT EVOLUTIONARY PATHS IN CHRONIC LYMPHOCYTIC LEUKEMIA DURING RESISTANCE TO THE GRAFT-VERSUS-LEUKEMIA EFFECT. LEUKEMIC RELAPSE REMAINS A MAJOR BARRIER TO SUCCESSFUL ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT) FOR AGGRESSIVE HEMATOLOGIC MALIGNANCIES. THE BASIS FOR RELAPSE OF ADVANCED LYMPHOID MALIGNANCIES REMAINS INCOMPLETELY UNDERSTOOD AND MAY INVOLVE ESCAPE FROM THE GRAFT-VERSUS-LEUKEMIA (GVL) EFFECT. WE HYPOTHESIZED THAT FOR PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREATED WITH ALLO-HSCT, LEUKEMIC CELL-INTRINSIC FEATURES INFLUENCE TRANSPLANT OUTCOMES BY DIRECTING THE EVOLUTIONARY TRAJECTORIES OF CLL CELLS. INTEGRATED GENETIC, TRANSCRIPTOMIC, AND EPIGENETIC ANALYSES OF CLL CELLS FROM 10 PATIENTS REVEALED THAT THE CLINICAL KINETICS OF POST-HSCT RELAPSE ARE SHAPED BY DISTINCT MOLECULAR DYNAMICS. EARLY RELAPSES AFTER ALLO-HSCT EXHIBITED NOTABLE GENETIC STABILITY; SINGLE CLL CELL TRANSCRIPTIONAL ANALYSIS DEMONSTRATED A CELLULAR HETEROGENEITY THAT WAS STATIC OVER TIME. IN CONTRAST, CLL CELLS RELAPSING LATE AFTER ALLO-HSCT DISPLAYED NOTABLE GENETIC EVOLUTION AND EVIDENCE OF NEOANTIGEN DEPLETION, CONSISTENT WITH MARKED SINGLE-CELL TRANSCRIPTIONAL SHIFTS THAT WERE UNIQUE TO EACH PATIENT. WE OBSERVED A GREATER RATE OF EPIGENETIC CHANGE FOR LATE RELAPSES NOT SEEN IN EARLY RELAPSES OR RELAPSES AFTER CHEMOTHERAPY ALONE, SUGGESTING THAT THE SELECTION PRESSURES OF THE GVL BOTTLENECK ARE UNLIKE THOSE IMPOSED BY CHEMOTHERAPY. NO SELECTIVE ADVANTAGE FOR HUMAN LEUKOCYTE ANTIGEN (HLA) LOSS WAS OBSERVED, EVEN WHEN PRESENT IN PRETRANSPLANT SUBPOPULATIONS. GAIN OF STEM CELL MODULES WAS A COMMON SIGNATURE ASSOCIATED WITH LEUKEMIA RELAPSE REGARDLESS OF POSTTRANSPLANT RELAPSE KINETICS. THESE DATA ELUCIDATE THE BIOLOGICAL PATHWAYS THAT UNDERLIE GVL RESISTANCE AND POSTTRANSPLANT RELAPSE. 2020 9 2290 44 EPIGENETIC REGULATION IN MURINE OFFSPRING AS A NOVEL MECHANISM FOR TRANSMATERNAL ASTHMA PROTECTION INDUCED BY MICROBES. BACKGROUND: BRONCHIAL ASTHMA IS A CHRONIC INFLAMMATORY DISEASE RESULTING FROM COMPLEX GENE-ENVIRONMENT INTERACTIONS. NATURAL MICROBIAL EXPOSURE HAS BEEN IDENTIFIED AS AN IMPORTANT ENVIRONMENTAL CONDITION THAT PROVIDES ASTHMA PROTECTION IN A PRENATAL WINDOW OF OPPORTUNITY. EPIGENETIC REGULATION IS AN IMPORTANT MECHANISM BY WHICH ENVIRONMENTAL FACTORS MIGHT INTERACT WITH GENES INVOLVED IN ALLERGY AND ASTHMA DEVELOPMENT. OBJECTIVE: THIS STUDY WAS DESIGNED TO TEST WHETHER EPIGENETIC MECHANISMS MIGHT CONTRIBUTE TO ASTHMA PROTECTION CONFERRED BY EARLY MICROBIAL EXPOSURE. METHODS: PREGNANT MATERNAL MICE WERE EXPOSED TO THE FARM-DERIVED GRAM-NEGATIVE BACTERIUM ACINETOBACTER LWOFFII F78. EPIGENETIC MODIFICATIONS IN THE OFFSPRING WERE ANALYZED IN T(H)1- AND T(H)2-RELEVANT GENES OF CD4(+) T CELLS. RESULTS: PRENATAL ADMINISTRATION OF A LWOFFII F78 PREVENTED THE DEVELOPMENT OF AN ASTHMATIC PHENOTYPE IN THE PROGENY, AND THIS EFFECT WAS IFN-GAMMA DEPENDENT. FURTHERMORE, THE IFNG PROMOTER OF CD4(+) T CELLS IN THE OFFSPRING REVEALED A SIGNIFICANT PROTECTION AGAINST LOSS OF HISTONE 4 (H4) ACETYLATION, WHICH WAS CLOSELY ASSOCIATED WITH IFN-GAMMA EXPRESSION. PHARMACOLOGIC INHIBITION OF H4 ACETYLATION IN THE OFFSPRING ABOLISHED THE ASTHMA-PROTECTIVE PHENOTYPE. REGARDING T(H)2-RELEVANT GENES ONLY AT THE IL4 PROMOTER, A DECREASE COULD BE DETECTED FOR H4 ACETYLATION BUT NOT AT THE IL5 PROMOTER OR THE INTERGENIC T(H)2 REGULATORY REGION CONSERVED NONCODING SEQUENCE 1 (CNS1). CONCLUSION: THESE DATA SUPPORT THE HYGIENE CONCEPT AND INDICATE THAT MICROBES OPERATE BY MEANS OF EPIGENETIC MECHANISMS. THIS PROVIDES A NEW MECHANISM IN THE UNDERSTANDING OF GENE-ENVIRONMENT INTERACTIONS IN THE CONTEXT OF ALLERGY PROTECTION. 2011 10 206 45 ACTIVATION OF NOTCH AND MYC SIGNALING VIA B-CELL-RESTRICTED DEPLETION OF DNMT3A GENERATES A CONSISTENT MURINE MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY DISORDERED DNA METHYLATION, SUGGESTING THESE EPIGENETIC CHANGES MIGHT PLAY A CRITICAL ROLE IN DISEASE ONSET AND PROGRESSION. THE METHYLTRANSFERASE DNMT3A IS A KEY REGULATOR OF DNA METHYLATION. ALTHOUGH DNMT3A SOMATIC MUTATIONS IN CLL ARE RARE, WE FOUND THAT LOW DNMT3A EXPRESSION IS ASSOCIATED WITH MORE AGGRESSIVE DISEASE. A CONDITIONAL KNOCKOUT MOUSE MODEL SHOWED THAT HOMOZYGOUS DEPLETION OF DNMT3A FROM B CELLS RESULTS IN THE DEVELOPMENT OF CLL WITH 100% PENETRANCE AT A MEDIAN AGE OF ONSET OF 5.3 MONTHS, AND HETEROZYGOUS DNMT3A DEPLETION YIELDS A DISEASE PENETRANCE OF 89% WITH A MEDIAN ONSET AT 18.5 MONTHS, CONFIRMING ITS ROLE AS A HAPLOINSUFFICIENT TUMOR SUPPRESSOR. B1A CELLS WERE CONFIRMED AS THE CELL OF ORIGIN OF DISEASE IN THIS MODEL, AND DNMT3A DEPLETION RESULTED IN FOCAL HYPOMETHYLATION AND ACTIVATION OF NOTCH AND MYC SIGNALING. AMPLIFICATION OF CHROMOSOME 15 CONTAINING THE MYC GENE WAS DETECTED IN ALL CLL MICE TESTED, AND INFILTRATION OF HIGH-MYC-EXPRESSING CLL CELLS IN THE SPLEEN WAS OBSERVED. NOTABLY, HYPERACTIVATION OF NOTCH AND MYC SIGNALING WAS EXCLUSIVELY OBSERVED IN THE DNMT3A CLL MICE, BUT NOT IN THREE OTHER CLL MOUSE MODELS TESTED (SF3B1-ATM, IKZF3, AND MDR), AND DNMT3A-DEPLETED CLL WERE SENSITIVE TO PHARMACOLOGIC INHIBITION OF NOTCH SIGNALING IN VITRO AND IN VIVO. CONSISTENT WITH THESE FINDINGS, HUMAN CLL SAMPLES WITH LOWER DNMT3A EXPRESSION WERE MORE SENSITIVE TO NOTCH INHIBITION THAN THOSE WITH HIGHER DNMT3A EXPRESSION. ALTOGETHER, THESE RESULTS SUGGEST THAT DNMT3A DEPLETION INDUCES CLL THAT IS HIGHLY DEPENDENT ON ACTIVATION OF NOTCH AND MYC SIGNALING. SIGNIFICANCE: LOSS OF DNMT3A EXPRESSION IS A DRIVING EVENT IN CLL AND IS ASSOCIATED WITH AGGRESSIVE DISEASE, ACTIVATION OF NOTCH AND MYC SIGNALING, AND ENHANCED SENSITIVITY TO NOTCH INHIBITION. 2021 11 505 31 ASSOCIATION OF DNA METHYLTRANSFERASE 3B PROMOTOR POLYMORPHISM WITH CHILDHOOD CHRONIC IMMUNE THROMBOCYTOPENIA. BACKGROUND: DNA METHYLATION IS AN EPIGENETIC PROCESS THAT REFERS TO CHROMATIN-BASED MECHANISMS IN THE REGULATION OF GENE EXPRESSION WITHOUT DNA ALTERNATION. IT IS MEDIATED BY DNA METHYLTRANSFERASES (DNMTS). THE DNA METHYLTRANSFERASE 3B (DNMT3B) GENE CONTAINS A C-TO-T SINGLE NUCLEOTIDE POLYMORPHISM (SNP; RS2424913) IN THE PROMOTOR REGION, 149 BASE PAIRS FROM THE TRANSCRIPTION START SITE, WHICH IS REPORTED TO SIGNIFICANTLY INCREASE THE PROMOTOR ACTIVITY. OBJECTIVE: TO INVESTIGATE THE PREVALANCE OF RS2424913 SINGLE NUCLEOTIDE POLYMORPHISM LOCATED IN THE DNMT3B GENE PROMOTOR. METHODS: IN THE PRESENT STUDY, WE INVESTIGATED THE PREVALENCE OF RS2424913 SINGLE NUCLEOTIDE POLYMORPHISM LOCATED IN DNMT3B GENE PROMOTOR BY RESTRICTION FRAGMENT LENGTH POLYMORPHISM (PCR-RFLP) IN EGYPTIAN PEDIATRIC CHRONIC IMMUNE THROMBOCYTOPENIA (ITP) PATIENTS AND CONTROLS. RESULTS: THE HOMOZYGOUS GENOTYPE (TT) WAS SIGNIFICANTLY HIGHER IN OUR PATIENT AND CONFERRED ALMOST 3-FOLD INCREASED RISK OF CHRONIC ITP WHEN COMPARED TO CONTROLS. CONCLUSION: THE PRESENT STUDY SHOWS THAT DNMT3B RS2424913 PROMOTOR POLYMORPHISM REPRESENTS A GENETIC RISK FACTOR THAT MAY PLAY AN IMPORTANT ROLE IN UNDERSTANDING THE PATHOGENESIS OF CHRONIC ITP. 2016 12 5965 33 TEN-ELEVEN-TRANSLOCATION 2 (TET2) NEGATIVELY REGULATES HOMEOSTASIS AND DIFFERENTIATION OF HEMATOPOIETIC STEM CELLS IN MICE. THE TEN-ELEVEN-TRANSLOCATION 2 (TET2) GENE ENCODES A MEMBER OF TET FAMILY ENZYMES THAT ALTERS THE EPIGENETIC STATUS OF DNA BY OXIDIZING 5-METHYLCYTOSINE TO 5-HYDROXYMETHYLCYTOSINE (5HMC). SOMATIC LOSS-OF-FUNCTION MUTATIONS OF TET2 ARE FREQUENTLY OBSERVED IN PATIENTS WITH DIVERSE MYELOID MALIGNANCIES, INCLUDING MYELODYSPLASTIC SYNDROMES, MYELOPROLIFERATIVE NEOPLASMS, AND CHRONIC MYELOMONOCYTIC LEUKEMIA. BY ANALYZING MICE WITH TARGETED DISRUPTION OF THE TET2 CATALYTIC DOMAIN, WE SHOW HERE THAT TET2 IS A CRITICAL REGULATOR OF SELF-RENEWAL AND DIFFERENTIATION OF HEMATOPOIETIC STEM CELLS (HSCS). TET2 DEFICIENCY LED TO DECREASED GENOMIC LEVELS OF 5HMC AND AUGMENTED THE SIZE OF THE HEMATOPOIETIC STEM/PROGENITOR CELL POOL IN A CELL-AUTONOMOUS MANNER. IN COMPETITIVE TRANSPLANTATION ASSAYS, TET2-DEFICIENT HSCS WERE CAPABLE OF MULTILINEAGE RECONSTITUTION AND POSSESSED A COMPETITIVE ADVANTAGE OVER WILD-TYPE HSCS, RESULTING IN ENHANCED HEMATOPOIESIS INTO BOTH LYMPHOID AND MYELOID LINEAGES. IN VITRO, TET2 DEFICIENCY DELAYED HSC DIFFERENTIATION AND SKEWED DEVELOPMENT TOWARD THE MONOCYTE/MACROPHAGE LINEAGE. OUR DATA INDICATE THAT TET2 HAS A CRITICAL ROLE IN REGULATING THE EXPANSION AND FUNCTION OF HSCS, PRESUMABLY BY CONTROLLING 5HMC LEVELS AT GENES IMPORTANT FOR THE SELF-RENEWAL, PROLIFERATION, AND DIFFERENTIATION OF HSCS. 2011 13 3098 36 GENOMIC DISRUPTION OF THE HISTONE METHYLTRANSFERASE SETD2 IN CHRONIC LYMPHOCYTIC LEUKAEMIA. HISTONE METHYLTRANSFERASES (HMTS) ARE IMPORTANT EPIGENETIC REGULATORS OF GENE TRANSCRIPTION AND ARE DISRUPTED AT THE GENOMIC LEVEL IN A SPECTRUM OF HUMAN TUMOURS INCLUDING HAEMATOLOGICAL MALIGNANCIES. USING HIGH-RESOLUTION SINGLE NUCLEOTIDE POLYMORPHISM (SNP) ARRAYS, WE IDENTIFIED RECURRENT DELETIONS OF THE SETD2 LOCUS IN 3% (8/261) OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) PATIENTS. FURTHER VALIDATION IN TWO INDEPENDENT COHORTS SHOWED THAT SETD2 DELETIONS WERE ASSOCIATED WITH LOSS OF TP53, GENOMIC COMPLEXITY AND CHROMOTHRIPSIS. WITH NEXT-GENERATION SEQUENCING WE DETECTED MUTATIONS OF SETD2 IN AN ADDITIONAL 3.8% OF PATIENTS (23/602). IN MOST CASES, SETD2 DELETIONS OR MUTATIONS WERE OFTEN OBSERVED AS A CLONAL EVENT AND ALWAYS AS A MONO-ALLELIC LESION, LEADING TO REDUCED MRNA EXPRESSION IN SETD2-DISRUPTED CASES. PATIENTS WITH SETD2 ABNORMALITIES AND WILD-TYPE TP53 AND ATM FROM FIVE CLINICAL TRIALS EMPLOYING CHEMOTHERAPY OR CHEMO-IMMUNOTHERAPY HAD REDUCED PROGRESSION-FREE AND OVERALL SURVIVAL COMPARED WITH CASES WILD TYPE FOR ALL THREE GENES. CONSISTENT WITH ITS POSTULATED ROLE AS A TUMOUR SUPPRESSOR, OUR DATA HIGHLIGHT SETD2 ABERRATION AS A RECURRENT, EARLY LOSS-OF-FUNCTION EVENT IN CLL PATHOBIOLOGY LINKED TO AGGRESSIVE DISEASE. 2016 14 535 32 ASXL1 MUTATION CORRECTION BY CRISPR/CAS9 RESTORES GENE FUNCTION IN LEUKEMIA CELLS AND INCREASES SURVIVAL IN MOUSE XENOGRAFTS. RECURRENT SOMATIC MUTATIONS OF THE EPIGENETIC MODIFIER AND TUMOR SUPPRESSOR ASXL1 ARE COMMON IN MYELOID MALIGNANCIES, INCLUDING CHRONIC MYELOID LEUKEMIA (CML), AND ARE ASSOCIATED WITH POOR CLINICAL OUTCOME. CRISPR/CAS9 HAS RECENTLY EMERGED AS A POWERFUL AND VERSATILE GENOME EDITING TOOL FOR GENOME ENGINEERING IN VARIOUS SPECIES. WE HAVE USED THE CRISPR/CAS9 SYSTEM TO CORRECT THE ASXL1 HOMOZYGOUS NONSENSE MUTATION PRESENT IN THE CML CELL LINE KBM5, WHICH LACKS ASXL1 PROTEIN EXPRESSION. CRISPR/CAS9-MEDIATED ASXL1 HOMOZYGOUS CORRECTION RESULTED IN PROTEIN RE-EXPRESSION WITH RESTORED NORMAL FUNCTION, INCLUDING DOWN-REGULATION OF POLYCOMB REPRESSIVE COMPLEX 2 TARGET GENES. SIGNIFICANTLY REDUCED CELL GROWTH AND INCREASED MYELOID DIFFERENTIATION WERE OBSERVED IN ASXL1 MUTATION-CORRECTED CELLS, PROVIDING NEW INSIGHTS INTO THE ROLE OF ASXL1 IN HUMAN MYELOID CELL DIFFERENTIATION. MICE XENOGRAFTED WITH MUTATION-CORRECTED KBM5 CELLS SHOWED SIGNIFICANTLY LONGER SURVIVAL THAN UNCORRECTED XENOGRAFTS. THESE RESULTS SHOW THAT THE SOLE CORRECTION OF A DRIVER MUTATION IN LEUKEMIA CELLS INCREASES SURVIVAL IN VIVO IN MICE. THIS STUDY PROVIDES PROOF-OF-CONCEPT FOR DRIVER GENE MUTATION CORRECTION VIA CRISPR/CAS9 TECHNOLOGY IN HUMAN LEUKEMIA CELLS AND PRESENTS A STRATEGY TO ILLUMINATE THE IMPACT OF ONCOGENIC MUTATIONS ON CELLULAR FUNCTION AND SURVIVAL. 2015 15 964 33 CHRONIC MYELOPROLIFERATIVE DISEASES WITH AND WITHOUT THE PH CHROMOSOME: SOME UNRESOLVED ISSUES. PH-POSITIVE CHRONIC MYELOID LEUKEMIA (CML) AND PH-NEGATIVE CHRONIC MYELOPROLIFERATIVE DISEASES (MPDS), CHARACTERIZED IN MANY CASES BY THE PRESENCE OF THE JAK2(V617F) MUTATION, HAVE MANY FEATURES IN COMMON AND YET ALSO SHOW FUNDAMENTAL DIFFERENCES. IN THIS REVIEW, WE POSE FIVE DISCRETE AND RELATED QUESTIONS RELEVANT TO BOTH CATEGORIES OF HEMATOLOGICAL MALIGNANCY, NAMELY: WHAT ARE THE MECHANISMS THAT UNDERLIE DISEASE PROGRESSION FROM A RELATIVELY BENIGN OR CHRONIC PHASE? BY WHAT THERAPEUTIC METHODS MIGHT ONE TARGET RESIDUAL LEUKEMIA STEM CELLS IN CML? IS JAK2(V617F) THE ORIGINAL MOLECULAR EVENT IN MPD? WHAT EPIGENETIC EVENTS MUST HAVE A ROLE IN DICTATING DISEASE PHENOTYPE IN MPDS? AND FINALLY, WILL THE BENEFITS CONFERRED BY CURRENT OR FUTURE JAK2(V617F) INHIBITORS EQUAL OR EVEN SURPASS THE CLINICAL SUCCESS THAT HAS RESULTED FROM THE USE OF TYROSINE KINASE INHIBITORS IN CML? THESE AND OTHERS QUESTIONS MUST BE ADDRESSED AND IN SOME CASES SHOULD BE ANSWERED IN THE FORESEEABLE FUTURE. 2009 16 6787 22 [CONTRIBUTION OF NON-HLA GENES TO JUVENILE IDIOPATHIC ARTHRITIS SUSCEPTIBILITY]. JUVENILE IDIOPATHIC ARTHRITIS (JAL4) IS THE MOST COMMON CHRONIC RHEUMATOLOGIC DISEASE IN CHILDREN. JIA IS A GROUP OF DISORDERS THAT SHARE THE CLINICAL MANIFESTATION OF CHRONIC JOINT INFLAMMATION. THE HUMAN LEUKOCYTE ANTIGEN REGION (HLA) SEEMS TO BE A MAJOR SUSCEPTIBILITY LOCUS FOR JIA THAT IS ESTIMATED TO ACCOUNT FOR 17% OF FAMILIAL SEGREGATION OF THE DISEASE. GENOME-WIDE ASSOCIATION STUDIES (GWAS), CASE-CONTROL STUDIES AND META-ANALYSES OF THE POST-GWAS ERA REVEALED OVER 20 NON-HLA LOCI CONFERRING SUSCEPTIBILITY TO JIA. AT LEAST A HALF OF THOSE ARE SHARED BETWEEN JIA AND RHEUMATOID ARTHRITIS, AN ADULT RHEUMATIC DISEASE, THEREBY SUGGESTING FOR SIMILARITY OF PATHOGENIC MECHANISMS OF BOTH DISEASES. NEW FINDINGS ALSO SUGGEST FOR A LIKELY ROLE OF EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF JIA THAT SHOULD BE INVESTIGATED IN THE FUTURE. 2014 17 2719 36 EXOME SEQUENCING REVEALS DNMT3A AND ASXL1 VARIANTS ASSOCIATE WITH PROGRESSION OF CHRONIC MYELOID LEUKEMIA AFTER TYROSINE KINASE INHIBITOR THERAPY. OBJECTIVE: THE DEVELOPMENT OF TYROSINE KINASE INHIBITORS (TKIS) HAS SIGNIFICANTLY IMPROVED THE TREATMENT OF CHRONIC MYELOID LEUKEMIA (CML). HOWEVER, APPROXIMATELY ONE THIRD OF PATIENTS ARE RESISTANT TO TKI AND/OR PROGRESS TO ADVANCED DISEASE STAGES. TKI THERAPY FAILURE HAS A WELL-KNOWN ASSOCIATION WITH ABL1 KINASE DOMAIN (KD) MUTATIONS, BUT ONLY AROUND HALF OF TKI NON-RESPONDERS HAVE DETECTABLE ABL1 KD MUTATIONS. METHOD: WE ATTEMPT TO IDENTIFY GENETIC MARKERS ASSOCIATED WITH TKI THERAPY FAILURE IN 13 PATIENTS (5 RESISTANT, 8 PROGRESSED) WITHOUT ABL1 KD MUTATIONS USING WHOLE-EXOME SEQUENCING. RESULTS: IN 6 PATIENTS, WE DETECTED MUTATIONS IN 6 GENES COMMONLY MUTATED IN OTHER MYELOID NEOPLASMS: ABL1, ASXL1, DNMT3A, IDH1, SETBP1, AND TP63. WE THEN USED TARGETED DEEP SEQUENCING TO VALIDATE OUR FINDING IN AN INDEPENDENT COHORT CONSISTING OF 100 CML PATIENTS WITH VARYING DRUG RESPONSES (74 RESPONSIVE, 18 RESISTANT, AND 8 PROGRESSED PATIENTS). MUTATIONS IN GENES ASSOCIATED WITH EPIGENETIC REGULATIONS SUCH AS DNMT3A AND ASXL1 SEEM TO PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF CML PROGRESSION AND TKI-RESISTANCE INDEPENDENT OF ABL1 KD MUTATIONS. CONCLUSION: THIS STUDY SUGGESTS THE INVOLVEMENT OF OTHER SOMATIC MUTATIONS IN THE DEVELOPMENT OF TKI RESISTANT PROGRESSION TO ADVANCED DISEASE STAGES IN CML, PARTICULARLY IN PATIENTS LACKING ABL1 KD MUTATIONS. 2017 18 4035 40 MACHINE-LEARNED ANALYSIS OF GLOBAL AND GLIAL/OPIOID INTERSECTION-RELATED DNA METHYLATION IN PATIENTS WITH PERSISTENT PAIN AFTER BREAST CANCER SURGERY. BACKGROUND: GLIAL CELLS IN THE CENTRAL NERVOUS SYSTEM PLAY A KEY ROLE IN NEUROINFLAMMATION AND SUBSEQUENT CENTRAL SENSITIZATION TO PAIN. THEY ARE THEREFORE INVOLVED IN THE DEVELOPMENT OF PERSISTENT PAIN. ONE OF THE MAIN SITES OF INTERACTION OF THE IMMUNE SYSTEM WITH PERSISTENT PAIN HAS BEEN IDENTIFIED AS NEURO-IMMUNE CROSSTALK AT THE GLIAL-OPIOID INTERFACE. THE PRESENT STUDY EXAMINED A POTENTIAL ASSOCIATION BETWEEN THE DNA METHYLATION OF TWO KEY PLAYERS OF GLIAL/OPIOID INTERSECTION AND PERSISTENT POSTOPERATIVE PAIN. METHODS: IN A COHORT OF 140 WOMEN WHO HAD UNDERGONE BREAST CANCER SURGERY, AND WERE ASSIGNED BASED ON A 3-YEAR FOLLOW-UP TO EITHER A PERSISTENT OR NON-PERSISTENT PAIN PHENOTYPE, THE ROLE OF EPIGENETIC REGULATION OF KEY PLAYERS IN THE GLIAL-OPIOID INTERFACE WAS ASSESSED. THE METHYLATION OF GENES CODING FOR THE TOLL-LIKE RECEPTOR 4 (TLR4) AS A MAJOR MEDIATOR OF GLIAL CONTRIBUTIONS TO PERSISTENT PAIN OR FOR THE MU-OPIOID RECEPTOR (OPRM1) WAS ANALYZED AND ITS ASSOCIATION WITH THE PAIN PHENOTYPE WAS COMPARED WITH THAT CONFERRED BY GLOBAL GENOME-WIDE DNA METHYLATION ASSESSED VIA QUANTIFICATION OF THE METHYLATION IN THE RETROTRANSPOSON LINE1. RESULTS: TRAINING OF MACHINE LEARNING ALGORITHMS INDICATED THAT THE GLOBAL DNA METHYLATION PROVIDED A SIMILAR DIAGNOSTIC ACCURACY FOR PERSISTENT PAIN AS PREVIOUSLY ESTABLISHED NON-GENETIC PREDICTORS. HOWEVER, THE DIAGNOSIS CAN BE BASED ON A SINGLE DNA BASED MARKER. BY CONTRAST, THE METHYLATION OF TLR4 OR OPRM1 GENES COULD NOT CONTRIBUTE FURTHER TO THE ALLOCATION OF THE PATIENTS TO THE PAIN-RELATED PHENOTYPE GROUPS. CONCLUSIONS: WHILE CLEARLY SUPPORTING A PREDICTIVE UTILITY OF EPIGENETIC TESTING, THE PRESENT ANALYSIS CANNOT PROVIDE SUPPORT FOR SPECIFIC EPIGENETIC MODULATION OF PERSISTENT POSTOPERATIVE PAIN VIA METHYLATION OF TWO KEY GENES OF THE GLIAL-OPIOID INTERFACE. 2019 19 5700 31 SINGLE NUCLEOTIDE POLYMORPHISM IN DNMT3B PROMOTER AND THE RISK FOR IDIOPATHIC THROMBOCYTOPENIC PURPURA IN CHINESE POPULATION. OBJECTIVE: EPIGENETIC CHANGES IN GENE EXPRESSION, INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS, MIGHT CONTRIBUTE TO AUTOIMMUNITY. DNA METHYLATION IS MEDIATED BY A FAMILY OF DNA METHYLTRANSFERASES. POLYMORPHISMS OF THE DNA METHYLTRANSFERASE 3B (DNMT3B) GENE MAY INFLUENCE DNMT3B ACTIVITY ON DNA METHYLATION, THEREBY MODULATING THE SUSCEPTIBILITY TO SOME DISEASES. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION BETWEEN THE SINGLE NUCLEOTIDE POLYMORPHISM (SNP) IN PROMOTER OF THE DNMT3B GENE AND THE RISK FOR DEVELOPMENT OF IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP). METHODS: IN THIS HOSPITAL-BASED CASE-CONTROL STUDY, THE DNMT3B SNP WAS GENOTYPED IN 201 PATIENTS WITH ITP AND 136 HEALTHY CONTROLS BY POLYMERASE CHAIN REACTION-RESTRICTION FRAGMENT LENGTH POLYMORPHISM. RESULTS: THE C/C GENOTYPE WAS NOT DETECTED IN BOTH THE PATIENTS WITH ITP AND THE CONTROLS. IN THE CONTROLS, THE FREQUENCIES OF T/T AND C/T GENOTYPES AND T AND C ALLELES WERE 97.8%, 2.2%, 98.9%, AND 1.1%, RESPECTIVELY. THERE WAS NO SIGNIFICANT DIFFERENCE IN GENOTYPE AND ALLELE DISTRIBUTION BETWEEN THE PATIENTS WITH ITP AND THE CONTROLS (P = 0.745 AND 0.747, RESPECTIVELY). NO SIGNIFICANT DIFFERENCE WAS OBSERVED IN GENOTYPE AND ALLELE DISTRIBUTION BETWEEN THE TWO GROUPS WHEN STRATIFIED BY THE AGE. THE SIMILAR RESULTS WERE SHOWN AMONG THE FOUR GROUPS OF PATIENTS WITH ITP: ACUTE CHILDHOOD, CHRONIC CHILDHOOD, ACUTE ADULT, AND CHRONIC ADULT. CONCLUSION: THIS POLYMORPHISM WAS DISTRIBUTED SIMILARLY BETWEEN THE PATIENTS WITH ITP AND THE CONTROLS. IT DEMONSTRATED THAT IT MAY NOT BE USED AS A STRATIFICATION MARKER TO PREDICT THE SUSCEPTIBILITY TO ITP, AT LEAST IN THE POPULATION OF NORTH CHINA. 2008 20 2997 34 GENETIC VARIANTS IN DNMT1 AND THE RISK OF CARDIAC AUTONOMIC NEUROPATHY IN WOMEN WITH TYPE 1 DIABETES. AIMS/INTRODUCTION: EPIGENETICS PARTICIPATE IN THE PATHOGENESIS OF METABOLIC MEMORY, A SITUATION IN WHICH HYPERGLYCEMIA EXERTS PROLONGED DELETERIOUS EFFECTS EVEN AFTER ITS NORMALIZATION. WE TESTED THE HYPOTHESIS THAT GENETIC VARIANTS IN AN EPIGENETIC GENE COULD PREDISPOSE TO DIABETES COMPLICATIONS. MATERIAL AND METHODS: WE ASSESSED THE FREQUENCY OF FIVE SINGLE-NUCLEOTIDE POLYMORPHISMS IN THE GENE ENCODING DEOXYRIBONUCLEIC ACID METHYTRANSFERASE 1 (DNMT1; RS8112895, RS7254567, RS11085721, RS17291414 AND RS10854076), AND THEIR ASSOCIATIONS WITH DIABETIC KIDNEY DISEASE, RETINOPATHY, DISTAL POLYNEUROPATHY AND AUTONOMIC CARDIOVASCULAR NEUROPATHY IN 359 INDIVIDUALS WITH LONG-TERM TYPE 1 DIABETES. RESULTS: NONE OF THE SINGLE-NUCLEOTIDE POLYMORPHISMS STUDIED WAS SIGNIFICANTLY ASSOCIATED WITH THE PRESENCE OF CHRONIC COMPLICATIONS IN THE OVERALL POPULATION. HOWEVER, AFTER SEX STRATIFICATION, THE MINOR ALLELE C OF RS11085721 CONFERRED RISK FOR CARDIOVASCULAR NEUROPATHY IN WOMEN AFTER ADJUSTMENT FOR CONFOUNDING VARIABLES (ODDS RATIO 2.32; 95% CONFIDENCE INTERVAL 1.26-4.33; P = 0.006). CONCLUSIONS: THE FACT THAT HETEROZYGOUS MUTATIONS IN DNMT1 ARE ASSOCIATED WITH HEREDITARY SENSORY AUTONOMIC NEUROPATHY PROVIDES PLAUSIBILITY TO THE PRESENT FINDING. IF CONFIRMED IN INDEPENDENT SAMPLES, IT SUGGESTS THAT GENETIC VARIANTS IN EPIGENETIC GENES MIGHT PREDISPOSE TO MORE OR FEWER EPIGENETIC CHANGES IN THE FACE OF SIMILAR METABOLIC DERANGEMENTS TRIGGERED BY HYPERGLYCEMIA, CONSTITUTING THE "GENETICS OF EPIGENETICS" FOR MICROVASCULAR DIABETES COMPLICATIONS. 2019