1 5425 106 REGULATION OF MYELOPOIESIS BY THE TRANSCRIPTION FACTOR IRF8. INTERFERON REGULATORY FACTOR-8 (IRF8) IS A TRANSCRIPTION FACTOR EXPRESSED IN HEMATOPOIETIC CELLS, PARTICULARLY IN MONONUCLEAR PHAGOCYTES [MONOCYTES/MACROPHAGES AND DENDRITIC CELLS (DCS)] AND THEIR PROGENITORS. VARIOUS STUDIES HAVE DEMONSTRATED THAT IRF8 IS ESSENTIAL FOR THE DEVELOPMENT OF MONOCYTES, DCS, EOSINOPHILS, AND BASOPHILS. CONVERSELY, IRF8 SUPPRESSES THE GENERATION OF NEUTROPHILS. ACCORDINGLY, IRF8 (-/-) MICE DEVELOP IMMUNODEFICIENCY AND A CHRONIC MYELOID LEUKEMIA (CML)-LIKE DISEASE. MUTATIONS AND LOSS OF EXPRESSION OF THE HUMAN IRF8 GENE ARE ALSO ASSOCIATED WITH IMMUNODEFICIENCY AND CML, RESPECTIVELY. RECENT FINDINGS HAVE BEGUN TO REVEAL THE TRANSCRIPTION FACTOR NETWORK AND EPIGENETIC CHANGES GOVERNED BY IRF8. FOR EXAMPLE, IN MONONUCLEAR PHAGOCYTE PROGENITORS, IRF8 COOPERATES WITH PU.1 TO PROMOTE THE FORMATION OF PROMOTER-DISTAL ENHANCERS TO INDUCE MONOCYTE-RELATED GENES INCLUDING THE CRITICAL DOWNSTREAM TRANSCRIPTION FACTOR GENE KLF4. ON THE OTHER HAND, IRF8 BLOCKS C/EBPALPHA ACTIVITY TO SUPPRESS THE NEUTROPHIL DIFFERENTIATION PROGRAM. INDEED, IRF8 (-/-) MONONUCLEAR PHAGOCYTE PROGENITORS FAIL TO EFFICIENTLY GENERATE MONOCYTES AND DCS AND, INSTEAD, ABERRANTLY GIVE RISE TO NEUTROPHILS. THIS ARTICLE PROVIDES AN OVERVIEW OF RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF IRF8 IN MYELOPOIESIS AND RELATED DISEASES. 2015 2 5320 34 PU.1 IS REQUIRED TO RESTRAIN MYELOPOIESIS DURING CHRONIC INFLAMMATORY STRESS. CHRONIC INFLAMMATION IS A COMMON FEATURE OF AGING AND NUMEROUS DISEASES SUCH AS DIABETES, OBESITY, AND AUTOIMMUNE SYNDROMES AND HAS BEEN LINKED TO THE DEVELOPMENT OF HEMATOLOGICAL MALIGNANCY. BLOOD-FORMING HEMATOPOIETIC STEM CELLS (HSC) CAN CONTRIBUTE TO THESE DISEASES VIA THE PRODUCTION OF TISSUE-DAMAGING MYELOID CELLS AND/OR THE ACQUISITION OF MUTATIONS IN EPIGENETIC AND TRANSCRIPTIONAL REGULATORS THAT INITIATE EVOLUTION TOWARD LEUKEMOGENESIS. WE PREVIOUSLY SHOWED THAT THE MYELOID "MASTER REGULATOR" TRANSCRIPTION FACTOR PU.1 IS ROBUSTLY INDUCED IN HSC BY PRO-INFLAMMATORY CYTOKINES SUCH AS INTERLEUKIN (IL)-1BETA AND LIMITS THEIR PROLIFERATIVE ACTIVITY. HERE, WE USED A PU.1-DEFICIENT MOUSE MODEL TO INVESTIGATE THE BROADER ROLE OF PU.1 IN REGULATING HEMATOPOIETIC ACTIVITY IN RESPONSE TO CHRONIC INFLAMMATORY CHALLENGES. WE FOUND THAT PU.1 IS CRITICAL IN RESTRAINING INFLAMMATORY MYELOPOIESIS VIA SUPPRESSION OF CELL CYCLE AND SELF-RENEWAL GENE PROGRAMS IN MYELOID-BIASED MULTIPOTENT PROGENITOR (MPP) CELLS. OUR DATA SHOW THAT WHILE PU.1 FUNCTIONS AS A KEY DRIVER OF MYELOID DIFFERENTIATION, IT PLAYS AN EQUALLY CRITICAL ROLE IN TAILORING HEMATOPOIETIC RESPONSES TO INFLAMMATORY STIMULI WHILE LIMITING EXPANSION AND SELF-RENEWAL GENE EXPRESSION IN MPPS. THESE DATA IDENTIFY PU.1 AS A KEY REGULATOR OF "EMERGENCY" MYELOPOIESIS RELEVANT TO INFLAMMATORY DISEASE AND LEUKEMOGENESIS. 2023 3 1479 25 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 4 6236 36 THE MACROPHAGE IRF8/IRF1 REGULOME IS REQUIRED FOR PROTECTION AGAINST INFECTIONS AND IS ASSOCIATED WITH CHRONIC INFLAMMATION. IRF8 AND IRF1 ARE TRANSCRIPTIONAL REGULATORS THAT PLAY CRITICAL ROLES IN THE DEVELOPMENT AND FUNCTION OF MYELOID CELLS, INCLUDING ACTIVATION OF MACROPHAGES BY PROINFLAMMATORY SIGNALS SUCH AS INTERFERON-GAMMA (IFN-GAMMA). LOSS OF IRF8 OR IRF1 FUNCTION CAUSES SEVERE SUSCEPTIBILITY TO INFECTIONS IN MICE AND IN HUMANS. WE USED CHROMATIN IMMUNOPRECIPITATION SEQUENCING AND RNA SEQUENCING IN WILD TYPE AND INIRF8ANDIRF1MUTANT PRIMARY MACROPHAGES TO SYSTEMATICALLY CATALOG ALL OF THE GENES BOUND BY (CISTROMES) AND TRANSCRIPTIONALLY ACTIVATED BY (REGULOMES) IRF8, IRF1, PU.1, AND STAT1, INCLUDING MODULATION OF EPIGENETIC HISTONE MARKS. OF THE SEVEN BINDING COMBINATIONS IDENTIFIED, TWO (CLUSTER 1 [IRF8/IRF1/STAT1/PU.1] AND CLUSTER 5 [IRF1/STAT1/PU.1]) WERE FOUND TO HAVE A MAJOR ROLE IN CONTROLLING MACROPHAGE TRANSCRIPTIONAL PROGRAMS BOTH AT THE BASAL LEVEL AND AFTER IFN-GAMMA ACTIVATION. THEY DIRECT THE EXPRESSION OF A SET OF GENES, THE IRF8/IRF1 REGULOME, THAT PLAY CRITICAL ROLES IN HOST INFLAMMATORY AND ANTIMICROBIAL DEFENSES IN MOUSE MODELS OF NEUROINFLAMMATION AND OF PULMONARY TUBERCULOSIS, RESPECTIVELY. IN ADDITION, THIS IRF8/IRF1 REGULOME IS ENRICHED FOR GENES MUTATED IN HUMAN PRIMARY IMMUNODEFICIENCIES AND WITH LOCI ASSOCIATED WITH SEVERAL INFLAMMATORY DISEASES IN HUMANS. 2016 5 851 24 CHIP-SEQ ANALYSIS OF HUMAN CHRONIC MYELOID LEUKEMIA CELLS. MANY TRANSCRIPTION FACTORS, CHROMATIN-ASSOCIATED PROTEINS AND REGULATORY DNA ELEMENTS ARE GENETICALLY AND/OR EPIGENETICALLY ALTERED IN CANCER, INCLUDING CHRONIC MYELOID LEUKEMIA (CML). THIS LEADS TO DEREGULATION OF TRANSCRIPTION THAT IS OFTEN CAUSALLY LINKED TO THE TUMORIGENIC STATE. CHROMATIN-IMMUNOPRECIPITATION COUPLED WITH MASSIVELY PARALLEL DNA SEQUENCING (CHIP-SEQ) IS THE KEY TECHNOLOGY TO STUDY TRANSCRIPTION AS IT ALLOWS IN VIVO WHOLE-GENOME MAPPING OF EPIGENETIC MODIFICATIONS AND INTERACTIONS OF PROTEINS WITH DNA OR CHROMATIN. HOWEVER, NUMEROUS DNA/CHROMATIN-BINDING PROTEINS, INCLUDING EZH2, REMAIN DIFFICULT TO "CHIP," THUS YIELDING GENOME-WIDE BINDING MAPS OF ONLY SUBOPTIMAL QUALITY. HERE, WE DESCRIBE A CHIP-SEQ PROTOCOL OPTIMIZED FOR HIGH-QUALITY PROTEIN-GENOME BINDING MAPS THAT HAVE PROVEN ESPECIALLY USEFUL FOR STUDYING DIFFICULT TO 'CHIP' TRANSCRIPTION REGULATORY FACTORS IN CHRONIC MYELOID LEUKEMIA (CML) AND RELATED MALIGNANCIES. 2016 6 2055 25 EPIGENETIC CONTROL DURING LYMPHOID DEVELOPMENT AND IMMUNE RESPONSES: ABERRANT REGULATION, VIRUSES, AND CANCER. METHYLATION OF CYTOSINES CONTROLS A NUMBER OF BIOLOGIC PROCESSES SUCH AS IMPRINTING AND X CHROMOSOMAL INACTIVATION. DNA HYPERMETHYLATION IS CLOSELY ASSOCIATED WITH TRANSCRIPTIONAL SILENCING, WHILE DNA HYPOMETHYLATION IS ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. HYPOACETYLATION OF HISTONES LEADS TO COMPACT CHROMATIN WITH REDUCED ACCESSIBILITY TO THE TRANSCRIPTIONAL MACHINERY. METHYL-CPG BINDING PROTEINS CAN RECRUIT COREPRESSORS AND HISTONE DEACETYLASES; THUS, THE INTERPLAY BETWEEN THESE EPIGENETIC MECHANISMS REGULATES GENE ACTIVATION. METHYLATION HAS BEEN IMPLICATED AS AN IMPORTANT MECHANISM DURING IMMUNE DEVELOPMENT, CONTROLLING VDJ RECOMBINATION, LINEAGE-SPECIFIC EXPRESSION OF CELL SURFACE ANTIGENS, AND TRANSCRIPTIONAL REGULATION OF CYTOKINE GENES DURING IMMUNE RESPONSES. ABERRATIONS IN EPIGENETIC MACHINERY, EITHER BY GENETIC MUTATIONS OR BY SOMATIC CHANGES SUCH AS VIRAL INFECTIONS, ARE ASSOCIATED WITH EARLY ALTERATIONS IN CHRONIC DISEASES SUCH AS IMMUNODEFICIENCY AND CANCER. 2003 7 5589 31 ROLE OF SIRT1 IN THE GROWTH AND REGULATION OF NORMAL HEMATOPOIETIC AND LEUKEMIA STEM CELLS. PURPOSE OF REVIEW: RECENT STUDIES HAVE ENHANCED OUR UNDERSTANDING OF THE ROLE OF THE SIRT1 DEACETYLASE IN REGULATION OF NORMAL HEMATOPOIETIC STEM CELLS (HSCS) AND LEUKEMIA STEM CELLS (LSCS), AND ITS IMPORTANCE IN REGULATING AUTOPHAGY AND EPIGENETIC REPROGRAMMING IN RESPONSE TO METABOLIC ALTERATIONS. RECENT FINDINGS: STUDIES EMPLOYING CONDITIONAL DELETION MOUSE MODELS INDICATE AN IMPORTANT ROLE OF SIRT1 IN MAINTENANCE OF ADULT HSCS UNDER CONDITIONS OF STRESS. SIRT1 IS SIGNIFICANTLY OVEREXPRESSED IN LSC POPULATIONS FROM ACUTE MYELOID LEUKEMIA (AML) PATIENTS WITH THE FLT3-ITD MUTATION, AND MAINTAINS THEIR SURVIVAL, GROWTH AND DRUG RESISTANCE, AS PREVIOUSLY DESCRIBED FOR CHRONIC MYELOGENOUS LEUKEMIA (CML). SIRT1 CAN ALSO ENHANCE LEUKEMIA EVOLUTION AND DRUG RESISTANCE BY PROMOTING GENETIC INSTABILITY. RECENT STUDIES INDICATE AN IMPORTANT ROLE OF SIRT1 IN REGULATING AUTOPHAGY IN RESPONSE TO OXIDATIVE STRESS AND NUTRIENT REQUIREMENTS, AND HAVE ELUCIDATED COMPLEX MECHANISMS BY WHICH SIRT1 REGULATES EPIGENETIC REPROGRAMMING OF STEM CELLS. SUMMARY: SIRT1 INHIBITION HOLDS PROMISE AS A NOVEL APPROACH FOR ABLATION OF LSCS IN CHRONIC PHASE CML OR FLT3-ITD-ASSOCIATED AML. ADDITIONAL STUDIES TO UNDERSTAND THE ROLE OF SIRT1 IN LINKING METABOLIC ALTERATIONS TO GENOMIC STABILITY, AUTOPHAGY AND EPIGENETIC REPROGRAMMING OF STEM CELLS ARE WARRANTED. 2015 8 1336 27 DESCRIBING A TRANSCRIPTION FACTOR DEPENDENT REGULATION OF THE MICRORNA TRANSCRIPTOME. WHILE THE TRANSCRIPTION REGULATION OF PROTEIN CODING GENES WAS EXTENSIVELY STUDIED, LITTLE IS KNOWN ON HOW TRANSCRIPTION FACTORS ARE INVOLVED IN TRANSCRIPTION OF NON-CODING RNAS, SPECIFICALLY OF MICRORNAS. HERE, WE PROPOSE A STRATEGY TO STUDY THE POTENTIAL ROLE OF TRANSCRIPTION FACTOR IN REGULATING TRANSCRIPTION OF MICRORNAS USING PUBLICALLY AVAILABLE DATA, COMPUTATIONAL RESOURCES AND HIGH THROUGHPUT DATA. WE USE THE H3K4ME3 EPIGENETIC SIGNATURE TO IDENTIFY MICRORNA PROMOTERS AND CHROMATIN IMMUNOPRECIPITATION (CHIP)-SEQUENCING DATA FROM THE ENCODE PROJECT TO IDENTIFY MICRORNA PROMOTERS THAT ARE ENRICHED WITH TRANSCRIPTION FACTOR BINDING SITES. BY TRANSFECTING CELLS OF INTEREST WITH SHRNA TARGETING A TRANSCRIPTION FACTOR OF INTEREST AND SUBJECTING THE CELLS TO MICRORNA ARRAY, WE STUDY THE EFFECT OF THIS TRANSCRIPTION FACTOR ON THE MICRORNA TRANSCRIPTOME. AS AN ILLUSTRATIVE EXAMPLE WE USE OUR STUDY ON THE EFFECT OF STAT3 ON THE MICRORNA TRANSCRIPTOME OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) CELLS. 2016 9 390 34 AN INTEGRATIVE MODEL OF PATHWAY CONVERGENCE IN GENETICALLY HETEROGENEOUS BLAST CRISIS CHRONIC MYELOID LEUKEMIA. TARGETED THERAPIES AGAINST THE BCR-ABL1 KINASE HAVE REVOLUTIONIZED TREATMENT OF CHRONIC PHASE (CP) CHRONIC MYELOID LEUKEMIA (CML). IN CONTRAST, MANAGEMENT OF BLAST CRISIS (BC) CML REMAINS CHALLENGING BECAUSE BC CELLS ACQUIRE COMPLEX MOLECULAR ALTERATIONS THAT CONFER STEMNESS FEATURES TO PROGENITOR POPULATIONS AND RESISTANCE TO BCR-ABL1 TYROSINE KINASE INHIBITORS. COMPREHENSIVE MODELS OF BC TRANSFORMATION HAVE PROVED ELUSIVE BECAUSE OF THE RARITY AND GENETIC HETEROGENEITY OF BC, BUT ARE IMPORTANT FOR DEVELOPING BIOMARKERS PREDICTING BC PROGRESSION AND EFFECTIVE THERAPIES. TO BETTER UNDERSTAND BC, WE PERFORMED AN INTEGRATED MULTIOMICS ANALYSIS OF 74 CP AND BC SAMPLES USING WHOLE-GENOME AND EXOME SEQUENCING, TRANSCRIPTOME AND METHYLOME PROFILING, AND CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY HIGH-THROUGHPUT SEQUENCING. EMPLOYING PATHWAY-BASED ANALYSIS, WE FOUND THE BC GENOME WAS SIGNIFICANTLY ENRICHED FOR MUTATIONS AFFECTING COMPONENTS OF THE POLYCOMB REPRESSIVE COMPLEX (PRC) PATHWAY. WHILE TRANSCRIPTOMICALLY, BC PROGENITORS WERE ENRICHED AND DEPLETED FOR PRC1- AND PRC2-RELATED GENE SETS RESPECTIVELY. BY INTEGRATING OUR DATA SETS, WE DETERMINED THAT BC PROGENITORS UNDERGO PRC-DRIVEN EPIGENETIC REPROGRAMMING TOWARD A CONVERGENT TRANSCRIPTOMIC STATE. SPECIFICALLY, PRC2 DIRECTS BC DNA HYPERMETHYLATION, WHICH IN TURN SILENCES KEY GENES INVOLVED IN MYELOID DIFFERENTIATION AND TUMOR SUPPRESSOR FUNCTION VIA SO-CALLED EPIGENETIC SWITCHING, WHEREAS PRC1 REPRESSES AN OVERLAPPING AND DISTINCT SET OF GENES, INCLUDING NOVEL BC TUMOR SUPPRESSORS. ON THE BASIS OF THESE OBSERVATIONS, WE DEVELOPED AN INTEGRATED MODEL OF BC THAT FACILITATED THE IDENTIFICATION OF COMBINATORIAL THERAPIES CAPABLE OF REVERSING BC REPROGRAMMING (DECITABINE+PRC1 INHIBITORS), NOVEL PRC-SILENCED TUMOR SUPPRESSOR GENES (NR4A2), AND GENE EXPRESSION SIGNATURES PREDICTIVE OF DISEASE PROGRESSION AND DRUG RESISTANCE IN CP. 2020 10 2928 27 GENERATION OF IPSCS FROM CULTURED HUMAN MALIGNANT CELLS. INDUCED PLURIPOTENT STEM CELLS (IPSCS) CAN BE GENERATED FROM VARIOUS DIFFERENTIATED CELL TYPES BY THE EXPRESSION OF A SET OF DEFINED TRANSCRIPTION FACTORS. SO FAR, IPSCS HAVE BEEN GENERATED FROM PRIMARY CELLS, BUT IT IS UNCLEAR WHETHER HUMAN CANCER CELL LINES CAN BE REPROGRAMMED. HERE WE DESCRIBE THE GENERATION AND CHARACTERIZATION OF IPSCS DERIVED FROM HUMAN CHRONIC MYELOID LEUKEMIA CELLS. WE SHOW THAT, DESPITE THE PRESENCE OF ONCOGENIC MUTATIONS, THESE CELLS ACQUIRED PLURIPOTENCY BY THE EXPRESSION OF 4 TRANSCRIPTION FACTORS AND UNDERWENT DIFFERENTIATION INTO CELL TYPES DERIVED OF ALL 3 GERM LAYERS DURING TERATOMA FORMATION. INTERESTINGLY, ALTHOUGH THE PARENTAL CELL LINE WAS STRICTLY DEPENDENT ON CONTINUOUS SIGNALING OF THE BCR-ABL ONCOGENE, ALSO TERMED ONCOGENE ADDICTION, REPROGRAMMED CELLS LOST THIS DEPENDENCY AND BECAME RESISTANT TO THE BCR-ABL INHIBITOR IMATINIB. THIS FINDING INDICATES THAT THE THERAPEUTIC AGENT IMATINIB TARGETS CELLS IN A SPECIFIC EPIGENETIC DIFFERENTIATED CELL STATE, AND THIS MAY CONTRIBUTE TO ITS INABILITY TO FULLY ERADICATE DISEASE IN CHRONIC MYELOID LEUKEMIA PATIENTS. 2010 11 1562 34 DNA METHYLATION OF ENHANCER ELEMENTS IN MYELOID NEOPLASMS: THINK OUTSIDE THE PROMOTERS? GENE REGULATION THROUGH DNA METHYLATION IS A WELL DESCRIBED PHENOMENON THAT HAS A PROMINENT ROLE IN PHYSIOLOGICAL AND PATHOLOGICAL CELL-STATES. THIS EPIGENETIC MODIFICATION IS USUALLY GROUPED IN REGIONS DENOMINATED CPG ISLANDS, WHICH FREQUENTLY CO-LOCALIZE WITH GENE PROMOTERS, SILENCING THE TRANSCRIPTION OF THOSE GENES. RECENT GENOME-WIDE DNA METHYLATION STUDIES HAVE CHALLENGED THIS PARADIGM, DEMONSTRATING THAT DNA METHYLATION OF REGULATORY REGIONS OUTSIDE PROMOTERS IS ABLE TO INFLUENCE CELL-TYPE SPECIFIC GENE EXPRESSION PROGRAMS UNDER PHYSIOLOGIC OR PATHOLOGIC CONDITIONS. COUPLING GENOME-WIDE DNA METHYLATION ASSAYS WITH HISTONE MARK ANNOTATION HAS ALLOWED FOR THE IDENTIFICATION OF SPECIFIC EPIGENOMIC CHANGES THAT AFFECT ENHANCER REGULATORY REGIONS, REVEALING AN ADDITIONAL LAYER OF COMPLEXITY TO THE EPIGENETIC REGULATION OF GENE EXPRESSION. IN THIS REVIEW, WE SUMMARIZE THE NOVEL EVIDENCE FOR THE MOLECULAR AND BIOLOGICAL REGULATION OF DNA METHYLATION IN ENHANCER REGIONS AND THE DYNAMISM OF THESE CHANGES CONTRIBUTING TO THE FINE-TUNING OF GENE EXPRESSION. WE ALSO ANALYZE THE CONTRIBUTION OF ENHANCER DNA METHYLATION ON THE EXPRESSION OF RELEVANT GENES IN ACUTE MYELOID LEUKEMIA AND CHRONIC MYELOPROLIFERATIVE NEOPLASMS. THE CHARACTERIZATION OF THE ABERRANT ENHANCER DNA METHYLATION PROVIDES NOT ONLY A NOVEL PATHOGENIC MECHANISM FOR DIFFERENT TUMORS BUT ALSO HIGHLIGHTS NOVEL POTENTIAL THERAPEUTIC TARGETS FOR MYELOID DERIVED NEOPLASMS. 2019 12 6773 27 [ADVANCES OF RESEARCH ON DEMETHYLATION THERAPY FOR HEMATOLOGIC MALIGNANCIES]. DNA METHYLATION IS AN IMPORTANT AND REVERSIBLE EPIGENETIC MODIFICATION WHICH REGULATES GENOMIC STABILITY. METHYLATION IS ESSENTIAL FOR MAMMALIAN DEVELOPMENT. GENERALLY, GENE EXPRESSION LEVEL AND DNA METHYLATION ARE NEGATIVE CORRELATION. TRANSCRIPTIONAL SILENCING VIA METHYLATION OF CPG ISLANDS IN THE PROMOTER IS IMPORTANT FOR CELL GROWTH AND DIFFERENTIATION AND PLAYS A KEY ROLE IN TUMORIGENESIS. DEMETHYLATION DRUG CAN MODIFY CHROMATIN AND RESTORE THE ABILITY OF ANTI-ONCOGENE. DEMETHYLATION THERAPY AS A NEW THERAPY MAY TREAT EFFICIENTLY HEMATOLOGICAL MALIGNANCIES WITH RESISTANCE AND RELAPSE. IN THIS REVIEW, DNA METHYLATION MECHANISM, RELATIONSHIP BETWEEN ABERRANT METHYLATION AND HEMATOLOGIC MALIGNANCIES, MECHANISM OF DEMETHYLATION THERAPY, THE ADVANCE OF RESEARCH ON THE DEMETHYLATION THERAPY OF HEMATOLOGICAL MALIGNANCIES, SUCH AS ACUTE AND CHRONIC LEUKEMIA, LYMPHOMA, MYELODYSPLASTIC SYNDROME WERE SUMMARIZED. 2009 13 2671 26 ETHANOL CONSUMPTION INDUCES NONSPECIFIC INFLAMMATION AND FUNCTIONAL DEFECTS IN ALVEOLAR MACROPHAGES. CHRONIC ALCOHOL DRINKING IS ASSOCIATED WITH INCREASED SUSCEPTIBILITY TO VIRAL AND BACTERIAL RESPIRATORY PATHOGENS. IN THIS STUDY, WE USE A RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION TO STUDY THE EFFECTS OF LONG-TERM ALCOHOL DRINKING ON THE IMMUNOLOGICAL LANDSCAPE OF THE LUNG. WE REPORT A HEIGHTENED INFLAMMATORY STATE IN ALVEOLAR MACROPHAGES (AMS) OBTAINED FROM ETHANOL (ETOH)-DRINKING ANIMALS THAT IS ACCOMPANIED BY INCREASED CHROMATIN ACCESSIBILITY IN INTERGENIC REGIONS THAT REGULATE INFLAMMATORY GENES AND CONTAIN BINDING MOTIFS FOR TRANSCRIPTION FACTORS AP-1, IRF8, AND NFKB P-65. IN LINE WITH THESE TRANSCRIPTIONAL AND EPIGENETIC CHANGES AT THE BASAL STATE, AMS FROM ETOH-DRINKING ANIMALS GENERATE ELEVATED INFLAMMATORY MEDIATOR RESPONSES TO LIPOPOLYSACCHARIDES AND RESPIRATORY SYNCYTIAL VIRUS. HOWEVER, THE TRANSCRIPTIONAL ANALYSIS REVEALED AN INEFFICIENT INDUCTION OF INTERFERON-STIMULATED GENES WITH ETOH IN RESPONSE TO THE RESPIRATORY SYNCYTIAL VIRUS, SUGGESTING DISRUPTION OF ANTIMICROBIAL DEFENSES. CORRESPONDINGLY, AMS FROM ETOH-DRINKING ANIMALS EXHIBITED TRANSCRIPTIONAL SHIFTS INDICATIVE OF INCREASED OXIDATIVE STRESS AND OXIDATIVE PHOSPHORYLATION, WHICH WAS COUPLED WITH HIGHER CYTOSOLIC REACTIVE OXYGEN SPECIES AND MITOCHONDRIAL POTENTIAL. THIS HEIGHTENED OXIDATIVE STRESS STATE WAS ACCOMPANIED BY DECREASED ABILITY TO PHAGOCYTOSE BACTERIA. BULK RNA AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN SEQUENCING DATA FURTHER REVEALED REDUCED EXPRESSION AND CHROMATIN ACCESSIBILITY OF LOCI ASSOCIATED WITH TISSUE REPAIR AND MAINTENANCE WITH CHRONIC ETOH DRINKING. SIMILARLY, ANALYSIS OF SINGLE-CELL RNA SEQUENCING DATA REVEALED SHIFTS IN CELL STATES FROM TISSUE MAINTENANCE TO INFLAMMATORY RESPONSES WITH ETOH. COLLECTIVELY, THESE DATA PROVIDE NOVEL INSIGHT INTO MECHANISMS BY WHICH CHRONIC ETOH DRINKING INCREASES SUSCEPTIBILITY TO INFECTION IN PATIENTS WITH ALCOHOL USE DISORDERS. 2022 14 2067 26 EPIGENETIC CONTROL OF MACROPHAGE SHAPE TRANSITION TOWARDS AN ATYPICAL ELONGATED PHENOTYPE BY HISTONE DEACETYLASE ACTIVITY. INFLAMMATORY CHRONIC PATHOLOGIES ARE COMPLEX PROCESSES CHARACTERIZED BY AN IMBALANCE BETWEEN THE RESOLUTION OF THE INFLAMMATORY PHASE AND THE ESTABLISHMENT OF TISSUE REPAIR. THE MAIN PLAYERS IN THESE INFLAMMATORY PATHOLOGIES ARE BONE MARROW DERIVED MONOCYTES (BMDMS). HOWEVER, HOW MONOCYTE DIFFERENTIATION IS MODULATED TO GIVE RISE TO SPECIFIC MACROPHAGE SUBPOPULATIONS (M1 OR M2) THAT MAY EITHER MAINTAIN THE CHRONIC INFLAMMATORY PROCESS OR LEAD TO WOUND HEALING IS STILL UNCLEAR. CONSIDERING THAT INHIBITORS OF HISTONE DEACETYLASE (HDAC) HAVE AN ANTI-INFLAMMATORY ACTIVITY, WE ASKED WHETHER THIS ENZYME WOULD PLAY A ROLE ON MONOCYTE DIFFERENTIATION INTO M1 OR M2 PHENOTYPE AND IN THE CELL SHAPE TRANSITION THAT FOLLOWS. WE THEN INDUCED MURINE BONE MARROW PROGENITORS INTO MONOCYTE/MACROPHAGE DIFFERENTIATION PATHWAY USING MEDIA CONTAINING GM-CSF AND THE HDAC BLOCKER, TRICHOSTATIN A (TSA). WE FOUND THAT THE PHARMACOLOGICAL INHIBITION OF HDAC ACTIVITY LED TO A SHAPE TRANSITION FROM THE TYPICAL MACROPHAGE PANCAKE-LIKE SHAPE INTO AN ELONGATED MORPHOLOGY, WHICH WAS CORRELATED TO A MIXED M1/M2 PROFILE OF CYTOKINE AND CHEMOKINE SECRETION. OUR RESULTS PRESENT, FOR THE FIRST TIME, THAT HDAC ACTIVITY ACTS AS A REGULATOR OF MACROPHAGE DIFFERENTIATION IN THE ABSENCE OF LYMPHOCYTE STIMULI. WE PROPOSE THAT HDAC ACTIVITY DOWN REGULATES MACROPHAGE PLASTICITY FAVORING THE PRO-INFLAMMATORY PHENOTYPE. 2015 15 2752 27 EXPRESSION OF ANGIOGENIC FACTORS IN CHRONIC MYELOID LEUKAEMIA: ROLE OF THE BCR/ABL ONCOGENE, BIOCHEMICAL MECHANISMS, AND POTENTIAL CLINICAL IMPLICATIONS. CHRONIC MYELOID LEUKAEMIA (CML) IS A STEM CELL DISEASE CHARACTERIZED BY AN INCREASED PRODUCTION AND ACCUMULATION OF CLONAL BCR/ABL-POSITIVE CELLS IN HAEMATOPOIETIC TISSUES. THE CHRONIC PHASE OF CML IS INEVITABLY FOLLOWED BY AN ACCELERATED PHASE OF THE DISEASE, WITH CONSECUTIVE BLAST CRISIS. HOWEVER, DEPENDING ON GENETIC STABILITY, EPIGENETIC EVENTS, AND SEVERAL OTHER FACTORS, THE CLINICAL COURSE AND SURVIVAL APPEAR TO VARY AMONG PATIENTS. RECENT DATA SUGGEST THAT ANGIOGENIC CYTOKINES SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), ARE UP-REGULATED IN CML, AND PLAY A ROLE IN THE PATHOGENESIS OF THE DISEASE. THESE FACTORS APPEAR TO BE PRODUCED AND RELEASED IN LEUKAEMIC CELLS IN PATIENTS WITH CML. IN LINE WITH THIS NOTION, INCREASED SERUM-LEVELS OF ANGIOGENIC GROWTH FACTORS ARE MEASURABLE IN CML PATIENTS. IN THIS STUDY WE PROVIDE AN OVERVIEW OF ANGIOGENIC GROWTH FACTORS EXPRESSED IN CML CELLS, DISCUSS THE POSSIBLE PATHOGENETIC ROLE OF THESE CYTOKINES, THE BIOCHEMICAL BASIS OF THEIR PRODUCTION IN LEUKAEMIC CELLS, AND THEIR POTENTIAL CLINICAL IMPLICATIONS. 2004 16 6592 34 TUMOR-ASSOCIATED MACROPHAGES IN HEPATOCELLULAR CARCINOMA PATHOGENESIS, PROGNOSIS AND THERAPY. HEPATOCELLULAR CARCINOMA (HCC) CONSTITUTES A MAJOR HEALTH BURDEN GLOBALLY, AND IT IS CAUSED BY INTRINSIC GENETIC MUTATIONS ACTING IN CONCERT WITH A MULTITUDE OF EPIGENETIC AND EXTRINSIC RISK FACTORS. CANCER INDUCES MYELOPOIESIS IN THE BONE MARROW, AS WELL AS THE MOBILIZATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS, WHICH RESIDE IN THE SPLEEN. MONOCYTES PRODUCED IN THE BONE MARROW AND THE SPLEEN FURTHER INFILTRATE TUMORS, WHERE THEY DIFFERENTIATE INTO TUMOR-ASSOCIATED MACROPHAGES (TAMS). THE RELATIONSHIP BETWEEN CHRONIC INFLAMMATION AND HEPATOCARCINOGENESIS HAS BEEN THOROUGHLY INVESTIGATED OVER THE PAST DECADE; HOWEVER, SEVERAL ASPECTS OF THE ROLE OF TAMS IN HCC DEVELOPMENT ARE YET TO BE DETERMINED. IN RESPONSE TO CERTAIN STIMULI AND SIGNALING, MONOCYTES DIFFERENTIATE INTO MACROPHAGES WITH ANTITUMOR PROPERTIES, WHICH ARE CLASSIFIED AS M1-LIKE. ON THE OTHER HAND, UNDER DIFFERENT STIMULI AND SIGNALING, THE POLARIZATION OF MACROPHAGES SHIFTS TOWARDS AN M2-LIKE PHENOTYPE WITH A TUMOR PROMOTING CAPACITY. M2-LIKE MACROPHAGES DRIVE TUMOR GROWTH BOTH DIRECTLY AND INDIRECTLY, VIA THE SUPPRESSION OF CYTOTOXIC CELL POPULATIONS, INCLUDING CD8+ T CELLS AND NK CELLS. THE TUMOR MICROENVIRONMENT AFFECTS THE RESPONSE TO IMMUNOTHERAPIES. THEREFORE, AN ENHANCED UNDERSTANDING OF ITS IMMUNOBIOLOGY IS ESSENTIAL FOR THE DEVELOPMENT OF NEXT-GENERATION IMMUNOTHERAPIES. THE UTILIZATION OF VARIOUS MONOCYTE-CENTERED ANTICANCER TREATMENT MODALITIES HAS BEEN UNDER CLINICAL INVESTIGATION, SELECTIVELY TARGETING AND MODULATING THE PROCESSES OF MONOCYTE RECRUITMENT, ACTIVATION AND MIGRATION. THIS REVIEW SUMMARIZES THE CURRENT EVIDENCE ON THE ROLE OF TAMS IN HCC PATHOGENESIS AND PROGRESSION, AS WELL AS IN THEIR POTENTIAL INVOLVEMENT IN TUMOR THERAPY, SHEDDING LIGHT ON EMERGING ANTICANCER TREATMENT METHODS TARGETING MONOCYTES. 2022 17 2380 24 EPIGENETIC REGULATION OF WNT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. CERTAIN WNT AND WNT NETWORK TARGET GENES ARE EXPRESSED AT HIGHER OR LOWER LEVELS IN CHRONIC LYMPHOCYTIC LEUKEMIA COMPARED WITH NORMAL B-CELLS. THIS INCLUDES UPREGULATION OF NUCLEAR COMPLEX GENES, AS WELL AS GENES FOR CYTOPLASMIC PROTEINS AND WNT LIGANDS AND THEIR COGNATE RECEPTORS. IN ADDITION, EPIGENETIC SILENCING OF SEVERAL NEGATIVE REGULATORS OF THE WNT PATHWAY HAVE BEEN IDENTIFIED. THE BALANCE BETWEEN EPIGENETIC DOWNREGULATION OF NEGATIVE EFFECTOR GENES AND INCREASED EXPRESSION OF POSITIVE EFFECTOR GENES DEMONSTRATE THAT THE EPIGENETIC DOWNREGULATION OF WNT ANTAGONISTS IS ONE MECHANISM, PERHAPS THE MAIN MECHANISM, THAT IS PERMISSIVE TO ACTIVE WNT SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA. MOREOVER, CONSTITUTIVE ACTIVATION OF THE WNT NETWORK AND TARGET GENES IS LIKELY TO IMPACT ON ADDITIONAL INTERACTING SIGNALING PATHWAYS. BASED ON PUBLISHED STUDIES, WE PROPOSE A MODEL OF WNT SIGNALING THAT INVOLVES MAINLY PERMISSIVE EXPRESSION, AND SOMETIMES OVEREXPRESSION, OF POSITIVE EFFECTORS AND DOWNREGULATION OF NEGATIVE REGULATORS IN THE NETWORK. IN THIS MODEL, DNA METHYLATION, HISTONE MODIFICATIONS AND ALTERED EXPRESSION OF MICRORNA MOLECULES INTERACT TO ALLOW CONTINUOUS WNT SIGNALING. 2010 18 4284 23 MICRORNA CIRCUITS REGULATE THE CANCER-INFLAMMATION LINK. GENETIC AND EPIGENETIC PERTURBATIONS ARE REQUIRED TO TRANSFORM NORMAL CELLS INTO CANCER CELLS. INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN VARIOUS CANCERS, LINKING CHRONIC INFLAMMATION TO ONCOGENESIS. HOWEVER, THE MOLECULAR CIRCUITS THAT RESULT IN SUSTAINED ACTIVATION OF THESE INFLAMMATORY FACTORS ARE NOT YET WELL UNDERSTOOD. IN THE 28 JANUARY 2014 ISSUE OF SCIENCE SIGNALING, XIANG ET AL. IDENTIFIED A MICRORNA-MEDIATED ANTI-INFLAMMATORY CIRCUIT THAT IS REPRESSED EPIGENETICALLY IN RECEPTOR-NEGATIVE BREAST CANCERS. A HIGH-THROUGHPUT SCREEN FOR SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3)-REGULATED MICRORNAS REVEALED MICRORNA MIR-146B AS A DIRECT STAT3 TARGET IN MAMMARY EPITHELIAL CELLS, BUT DNA METHYLATION IN ITS PROMOTER AREA SUPPRESSED MIR-146B EXPRESSION IN CANCER CELLS. OVEREXPRESSION OF MIR-146B SUPPRESSED NUCLEAR FACTOR KAPPAB (NF-KAPPAB)-DEPENDENT EXPRESSION OF IL6 AND SUBSEQUENT STAT3 ACTIVATION AND DECREASED THE STAT3-INDUCED INVASIVENESS AND MESENCHYMAL PHENOTYPE OF BREAST CANCER CELLS. OVERALL, THIS STUDY CONTRIBUTES TO OUR UNDERSTANDING OF HOW INFLAMMATION IS INVOLVED IN ONCOGENIC TRANSFORMATION. FURTHER STUDIES COULD EVALUATE THE THERAPEUTIC POTENTIAL OF TARGETING THIS CIRCUIT IN ESTROGEN RECEPTOR-NEGATIVE BREAST CANCERS. 2014 19 1283 24 DECIPHERING THE EPIGENETIC CODE OF T LYMPHOCYTES. THE MULTIPLE LINEAGES AND DIFFERENTIATION STATES THAT CONSTITUTE THE T-CELL COMPARTMENT ALL DERIVE FROM A COMMON THYMIC PRECURSOR. THESE DISTINCT TRANSCRIPTIONAL STATES ARE MAINTAINED BOTH IN TIME AND AFTER MULTIPLE ROUNDS OF CELL DIVISION BY THE CONCERTED ACTIONS OF A SMALL SET OF LINEAGE-DEFINING TRANSCRIPTION FACTORS THAT ACT IN CONJUNCTION WITH A SUITE OF CHROMATIN-MODIFYING ENZYMES TO ACTIVATE, REPRESS, AND FINE-TUNE GENE EXPRESSION. THESE CHROMATIN MODIFICATIONS COLLECTIVELY PROVIDE AN EPIGENETIC CODE THAT ALLOWS THE STABLE AND HERITABLE MAINTENANCE OF THE T-CELL PHENOTYPE. RECENTLY, IT HAS BECOME APPARENT THAT THE EPIGENETIC CODE REPRESENTS A THERAPEUTIC TARGET FOR A VARIETY OF IMMUNE CELL DISORDERS, INCLUDING LYMPHOMA AND ACUTE AND CHRONIC INFLAMMATORY DISEASES. HERE, WE REVIEW THE RECENT ADVANCES IN EPIGENETIC REGULATION OF GENE EXPRESSION, PARTICULARLY AS IT RELATES TO THE T-CELL DIFFERENTIATION AND FUNCTION. 2014 20 1674 31 DRIVER MUTATIONS IN LEUKEMIA PROMOTE DISEASE PATHOGENESIS THROUGH A COMBINATION OF CELL-AUTONOMOUS AND NICHE MODULATION. STUDIES OF PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) HAVE LED TO THE IDENTIFICATION OF MUTATIONS THAT AFFECT DIFFERENT CELLULAR PATHWAYS. SOME OF THESE HAVE BEEN CLASSIFIED AS PRELEUKEMIC, AND A STEPWISE EVOLUTION PROGRAM WHEREBY CELLS ACQUIRE ADDITIONAL MUTATIONS HAS BEEN PROPOSED IN THE DEVELOPMENT OF AML. HOW THE TIMING OF ACQUISITION OF THESE MUTATIONS AND THEIR IMPACT ON TRANSFORMATION AND THE BONE MARROW (BM) MICROENVIRONMENT OCCURS HAS ONLY RECENTLY BEGUN TO BE INVESTIGATED. WE SHOW THAT CONSTITUTIVE AND EARLY LOSS OF THE EPIGENETIC REGULATOR, TET2, WHEN COMBINED WITH CONSTITUTIVE ACTIVATION OF FLT3, RESULTS IN TRANSFORMATION OF CHRONIC MYELOMONOCYTIC LEUKEMIA-LIKE OR MYELOPROLIFERATIVE NEOPLASM-LIKE PHENOTYPE TO AML, WHICH IS MORE PRONOUNCED IN DOUBLE-MUTANT MICE RELATIVE TO MICE CARRYING MUTATIONS IN SINGLE GENES. FURTHERMORE, WE SHOW THAT IN PRELEUKEMIC AND LEUKEMIC MICE THERE ARE ALTERATIONS IN THE BM NICHE AND SECRETED CYTOKINES, WHICH CREATES A PERMISSIVE ENVIRONMENT FOR THE GROWTH OF MUTATION-BEARING CELLS RELATIVE TO NORMAL CELLS. 2020