1 2548 95 EPIGENETICS IN MYELOPROLIFERATIVE NEOPLASMS. THE MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE A GROUP OF ACQUIRED CLONAL DISORDERS WHERE MUTATIONS DRIVE PROLIFERATIVE DISEASE RESULTING IN INCREASED BLOOD COUNTS AND IN SOME CASES END-STAGE MYELOFIBROSIS. EPIGENETIC CHANGES ARE THE REVERSIBLE MODIFICATIONS TO DNA- AND RNA-ASSOCIATED PROTEINS THAT IMPACT GENE ACTIVITY WITHOUT CHANGING THE DNA SEQUENCE. THIS REVIEW SUMMARIZES MECHANISMS OF EPIGENETIC CHANGES AND THE NUCLEOSOME. THE DRIVERS AND EPIGENETIC REGULATORS IN MPNS ARE OUTLINED. IN MPNS, DISTINCT PATTERNS OF EPIGENETIC DYSREGULATION HAVE BEEN SEEN IN CHRONIC AND IN ADVANCED PHASES. METHYLATION AGE AND HISTONE MODIFICATION ARE ALTERED IN MPNS AND BY FURTHER TREATMENT. THE ALTERATIONS FOUND IN METHYLATION AGE IN MPNS AND WITH TREATMENT ARE DISCUSSED, AND THE CHANGES IN HISTONE MODIFICATION WITH JANUS KINASE (JAK) INHIBITION ARE EVALUATED. CURRENTLY AVAILABLE THERAPEUTIC AREAS WHERE THE EPIGENOME CAN BE ALTERED ARE OUTLINED. THUS, WE REVIEW THE CURRENT KNOWLEDGE AND UNDERSTANDING OF EPIGENETICS IN MPN AND CONSIDER FURTHER MANAGEMENT OPTIONS. UNDERSTANDING THE EPIGENOME AND ITS ALTERATION IN MPNS AND EPIGENETIC CHANGES ASSOCIATED WITH THE PROGRESSION OF DISEASE WILL LEAD TO ADVANCES IN THERAPEUTIC OPTIONS. 2023 2 5546 23 ROLE OF EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF CHRONIC COMPLICATIONS OF DIABETES. THERE IS GROWING EVIDENCE THAT EPIGENETIC REGULATION OF GENE EXPRESSION INCLUDING POST-TRANSLATIONAL HISTONE MODIFICATIONS (PTHMS), DNA METHYLATION AND MICRORNA (MIRNA)-REGULATION OF MRNA TRANSLATION COULD PLAY A CRUCIAL ROLE IN THE DEVELOPMENT OF CHRONIC, DIABETIC COMPLICATIONS. HYPERGLYCEMIA CAN INDUCE AN ABNORMAL ACTION OF PTHMS AND DNA METHYLTRANSFERASES AS WELL AS ALTER THE LEVELS OF NUMEROUS MIRNAS IN ENDOTHELIAL CELLS, VASCULAR SMOOTH MUSCLE CELLS, CARDIOMYOCYTES, RETINA, AND RENAL CELLS. THESE EPIGENETIC ABNORMALITIES RESULT IN CHANGES IN THE EXPRESSION OF NUMEROUS GENES CONTRIBUTING TO EFFECTS SUCH AS DEVELOPMENT OF CHRONIC INFLAMMATION, IMPAIRED CLEARANCE OF REACTIVE OXYGEN SPECIES (ROS), ENDOTHELIAL CELL DYSFUNCTION AND/OR THE ACCUMULATION OF EXTRACELLULAR MATRIX IN THE KIDNEY, WHICH CAUSING THE DEVELOPMENT OF RETINOPATHY, NEPHROPATHY OR CARDIOMYOPATHY. SOME EPIGENETIC MODIFICATIONS, FOR EXAMPLE PTHMS AND DNA METHYLATION, BECOME IRREVERSIBLE OVER TIME. THEREFORE, THESE PROCESSES HAVE GAINED MUCH ATTENTION IN EXPLAINING THE LONG-LASTING DETRIMENTAL CONSEQUENCES OF HYPERGLYCAEMIA CAUSING THE DEVELOPMENT OF CHRONIC COMPLICATIONS EVEN AFTER IMPROVED GLYCAEMIC CONTROL IS ACHIEVED. OUR REVIEW SUGGESTS THAT THE TREATMENT OF CHRONIC COMPLICATIONS SHOULD FOCUS ON ERASING METABOLIC MEMORY BY TARGETING CHROMATIN MODIFICATION ENZYMES AND BY RESTORING MIRNA LEVELS. 2014 3 733 27 CANCER EPIGENETICS: LINKING BASIC BIOLOGY TO CLINICAL MEDICINE. CANCER EVOLUTION AT ALL STAGES IS DRIVEN BY BOTH EPIGENETIC ABNORMALITIES AS WELL AS GENETIC ALTERATIONS. DYSREGULATION OF EPIGENETIC CONTROL EVENTS MAY LEAD TO ABNORMAL PATTERNS OF DNA METHYLATION AND CHROMATIN CONFIGURATIONS, BOTH OF WHICH ARE CRITICAL CONTRIBUTORS TO THE PATHOGENESIS OF CANCER. THESE EPIGENETIC ABNORMALITIES ARE SET AND MAINTAINED BY MULTIPLE PROTEIN COMPLEXES AND THE INTERPLAY BETWEEN THEIR INDIVIDUAL COMPONENTS INCLUDING DNA METHYLATION MACHINERY, HISTONE MODIFIERS, PARTICULARLY, POLYCOMB (PCG) PROTEINS, AND CHROMATIN REMODELING PROTEINS. RECENT ADVANCES IN GENOME-WIDE TECHNOLOGY HAVE REVEALED THAT THE INVOLVEMENT OF THESE DYSREGULATED EPIGENETIC COMPONENTS APPEARS TO BE EXTENSIVE. MOREOVER, THERE IS A GROWING CONNECTION BETWEEN EPIGENETIC ABNORMALITIES IN CANCER AND CONCEPTS CONCERNING STEM-LIKE CELL SUBPOPULATIONS AS A DRIVING FORCE FOR CANCER. EMERGING DATA SUGGEST THAT ASPECTS OF THE EPIGENETIC LANDSCAPE INHERENT TO NORMAL EMBRYONIC AND ADULT STEM/PROGENITOR CELLS MAY HELP FOSTER, UNDER THE STRESS OF CHRONIC INFLAMMATION OR ACCUMULATING REACTIVE OXYGEN SPECIES, EVOLUTION OF MALIGNANT SUBPOPULATIONS. FINALLY, UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN INITIATION AND MAINTENANCE OF EPIGENETIC ABNORMALITIES IN ALL TYPES OF CANCER HAS GREAT POTENTIAL FOR TRANSLATIONAL PURPOSES. THIS IS ALREADY EVIDENT FOR EPIGENETIC BIOMARKER DEVELOPMENT, AND FOR PHARMACOLOGICAL TARGETING AIMED AT REVERSING CANCER-SPECIFIC EPIGENETIC ALTERATIONS. 2011 4 6168 16 THE GOOD AND BAD OF BETA-CATENIN IN KIDNEY DEVELOPMENT AND RENAL DYSPLASIA. CONGENITAL RENAL MALFORMATIONS ARE A MAJOR CAUSE OF CHILDHOOD AND ADULT ONSET CHRONIC KIDNEY DISEASE. IDENTIFYING THE ETIOLOGY OF THESE RENAL DEFECTS IS OFTEN CHALLENGING SINCE DISRUPTIONS IN THE PROCESSES THAT DRIVE KIDNEY DEVELOPMENT CAN RESULT FROM DISRUPTIONS IN ENVIRONMENTAL, GENETIC, OR EPIGENETIC CUES. BETA-CATENIN IS AN INTRACELLULAR MOLECULE INVOLVED IN CELL ADHESION, CELL SIGNALING, AND REGULATION OF GENE TRANSCRIPTION. IT PLAYS ESSENTIAL ROLES IN KIDNEY DEVELOPMENT AND IN THE PATHOGENESIS OF RENAL DYSPLASIA. HERE, WE REVIEW THE FUNCTION OF BETA-CATENIN DURING KIDNEY DEVELOPMENT AND IN THE GENESIS OF RENAL DYSPLASIA. 2015 5 6308 20 THE REGULATION OF APOPTOSIS IN KIDNEY DEVELOPMENT: IMPLICATIONS FOR NEPHRON NUMBER AND PATTERN? APOPTOSIS IS ESSENTIAL TO REMODEL DEVELOPING STRUCTURES AND ELIMINATE SUPERFLUOUS CELLS IN A CONTROLLED MANNER DURING NORMAL DEVELOPMENT, AND CONTINUES TO BE AN IMPORTANT COMPONENT OF TISSUE REMODELING AND REGENERATION DURING AN ORGANISM'S LIFESPAN, OR AS A RESPONSE TO INJURY. THIS MINI REVIEW WILL DISCUSS RECENT STUDIES THAT HAVE PROVIDED INSIGHTS INTO THE ROLES OF APOPTOSIS IN THE DETERMINATION OF NEPHRON NUMBER AND PATTERN, DURING NORMAL AND ABNORMAL KIDNEY DEVELOPMENT. THE REGULATION OF CONGENITAL NEPHRON ENDOWMENT HAS IMPLICATIONS FOR RISK OF CHRONIC KIDNEY DISEASE IN LATER LIFE, WHEREAS ABNORMALITIES IN NEPHRON PATTERN ARE ASSOCIATED WITH CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (THE LEADING CAUSE OF RENAL DISEASE IN CHILDREN). TIGHT REGULATION OF APOPTOSIS IS REQUIRED IN NORMAL RENAL MORPHOGENESIS, ALTHOUGH MANY QUESTIONS REMAIN REGARDING THE REGULATION OF APOPTOSIS BY GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS, IN ADDITION TO THE FUNCTIONAL REQUIREMENT OF DIFFERENT COMPONENTS OF THE APOPTOTIC PATHWAY. 2014 6 6114 35 THE EPIGENETIC CONTRIBUTION TO THE PATHOGENESIS OF PSORIASIS: RECENT ADVANCES. PSORIASIS IS DEFINED AS A CHRONIC AUTOIMMUNE DISORDER OF THE SKIN IN WHICH ABNORMAL PROLIFERATION AND DIFFERENTIATION OF KERATINOCYTES ARE BLAMED AS THE CENTRAL CULPRIT OF DISEASE ETIOPATHOGENESIS. A COMPLEX INTERPLAY BETWEEN ENVIRONMENTAL FACTORS AND GENETIC RISK FACTORS HAS BEEN SUGGESTED TO TRIGGER THE DISEASE. HOWEVER, EPIGENETIC REGULATION APPEARS TO CONNECT EXTERNAL STIMULI AND GENETIC ABNORMALITIES IN THE DEVELOPMENT OF PSORIASIS. THE DISCORDANCE IN THE PREVALENCE OF PSORIASIS BETWEEN MONOZYGOTIC TWINS AND ENVIRONMENTAL FACTORS THAT CONTRIBUTE TO ITS ONSET HAVE CAUSED A PARADIGM SHIFT REGARDING THE MECHANISMS UNDERLYING THE PATHOGENESIS OF THIS DISEASE. EPIGENETIC DYSREGULATION MAY BE INVOLVED IN ABERRANCIES OF KERATINOCYTE DIFFERENTIATION, T-CELL ACTIVATION, AND OTHER PLAUSIBLE CELLS, LEADING TO THE INITIATION AND PERPETUATION OF PSORIASIS. EPIGENETICS IS CHARACTERIZED BY HERITABLE ALTERATIONS IN THE TRANSCRIPTION OF GENES WITHOUT NUCLEOTIDE CHANGE AND IS COMMONLY CONSIDERED AT THREE LEVELS, I.E., DNA METHYLATION, HISTONE MODIFICATIONS, AND MICRORNAS. TO DATE, SCIENTIFIC EVIDENCE HAS INDICATED ABNORMAL DNA METHYLATION, HISTONE MODIFICATIONS, AND NON-CODING RNA TRANSCRIPTION IN PSORIATIC PATIENTS. IN ORDER TO REVERSE ABERRANT EPIGENETIC CHANGES IN PSORIASIS PATIENTS, SEVERAL COMPOUNDS AND DRUGS (EPI-DRUGS) HAVE BEEN DEVELOPED TO AFFECT THE MAJOR ENZYMES INVOLVED IN THE METHYLATION OF DNA, OR THE ACETYLATION OF HISTONES, WHICH AIM TO CORRECT THE ABERRANT METHYLATION AND ACETYLATION PATTERNS. A NUMBER OF CLINICAL TRIALS HAVE SUGGESTED THE THERAPEUTIC POTENTIAL OF SUCH DRUGS IN THE TREATMENT OF PSORIASIS. IN THE PRESENT REVIEW, WE ATTEMPT TO CLARIFY RECENT FINDINGS WITH RESPECT TO EPIGENETIC IRREGULARITIES IN PSORIASIS AND DISCUSS FUTURE CHALLENGES. 2023 7 6902 24 [THE IMPACT OF CHROMATIN MODIFICATION ON THE DEVELOPMENT OF CHRONIC COMPLICATIONS IN PATIENTS WITH DIABETES]. DIABETES IS A CHRONIC, METABOLIC DISEASE. OVER 347 MILLION PEOPLE WORLDWIDE HAVE DIABETES. CHRONIC COMPLICATIONS (RETINOPATHY, NEPHROPATHY OR NEUROPATHY) ARE THE MAJOR DANGEROUS OUTCOME OF THIS DISEASE. RECENT STUDIES INDICATE A SIGNIFICANT ROLE OF EPIGENETIC REGULATION IN THE DEVELOPMENT OF CHRONIC COMPLICATIONS IN PATIENTS WITH DIABETES. HYPERGLYCEMIA COULD CAUSE ABNORMAL REGULATION OF THE ACTIVITY OF ENZYMES PARTICIPATING IN THE POST-TRANSLATIONAL HISTONE MODIFICATIONS (PTHMS) AND INITIATION OF CHANGES IN PATTERNS OF DNA METHYLATION. IT LEADS TO MODIFICATION OF CHROMATIN STRUCTURE. THESE EPIGENETIC ABNORMALITIES RESULT IN CHANGES IN THE EXPRESSION OF GENES INVOLVED IN DEVELOPMENT OF CHRONIC INFLAMMATION, SUCH AS NF-KAPPAB (NUCLEAR FACTOR KAPPAB GENE), TNFALPHA (TUMOR NECROSIS FACTOR A GENE), IL6 (INTERLEUKIN 6 GENE) OR MCP1 (MONOCYTE CHEMOATTRACTANT PROTEIN 1 GENE). IT ENHANCES ENDOTHELIAL CELL DYSFUNCTION, WHICH PLAYS AN IMPORTANT ROLE IN DEVELOPMENT OF CHRONIC, DIABETIC COMPLICATIONS. IN ADDITION, CAUSED BY HYPERGLYCEMIA EPIGENETIC MODIFICATIONS CHANGES IN STRUCTURE OF CHROMATIN EXPLAINS "METABOLIC MEMORY", A PHENOMENON OF PRESENCE OF PATHOLOGICAL PATHWAYS RELATED TO THE PROLONGED HYPERGLYCEMIA IN THE PAST, DESPITE MAINTAINING GOOD METABOLIC CONTROL LATER ON. 2015 8 6223 24 THE LEADING ROLE OF EPITHELIAL CELLS IN THE PATHOGENESIS OF IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A RELENTLESSLY PROGRESSIVE AND DEVASTATING INTERSTITIAL LUNG DISEASE OF UNKNOWN ETIOLOGY, WHERE THE NORMAL LUNG ARCHITECTURE IS LOST AND REPLACED BY FIBROTIC TISSUE LEADING TO AN IRREVERSIBLE AND PROGRESSIVE RESPIRATORY INSUFFICIENCY. HISTORICALLY, IPF WAS CONSIDERED A CHRONIC INFLAMMATORY DISORDER, WHICH GRADUALLY PROGRESSED TO ESTABLISHED FIBROSIS. HOWEVER, STRONG CLINICAL AND EXPERIMENTAL EVIDENCE INDICATES THAT THE DISEASE REPRESENTS AN EPITHELIAL-DRIVEN DISORDER WHICH RESULTS FROM A COMPLEX INTERPLAY OF GENETIC AND ENVIRONMENTAL RISK FACTORS, AGING-ASSOCIATED PROCESSES AND A PROFIBROTIC EPIGENETIC REPROGRAMMING. THE CONVERGENCE OF THESE FACTORS RESULTS IN THE ABERRANT ACTIVATION OF EPITHELIAL CELLS THAT INITIATE THE DEVELOPMENT OF THE DISEASE, PRODUCING VIRTUALLY ALL THE MEDIATORS THAT PARTICIPATE IN THE MIGRATION, PROLIFERATION AND ACTIVATION OF FIBROBLASTS, THEIR DIFFERENTIATION TO MYOFIBROBLASTS AND THE EXCESSIVE AND CHAOTIC SECRETION OF EXTRACELLULAR MATRIX PROTEINS. ALTHOUGH PROGRESS HAS BEEN MADE IN UNDERSTANDING THE CAUSES AND CONSEQUENCES OF THIS ABNORMAL BEHAVIOR OF DISTAL AIRWAYS AND ALVEOLAR EPITHELIUM, THE MECHANISMS THAT INITIATE AND PERPETUATE THE VICIOUS CIRCLE OF MULTIDIRECTIONAL ABNORMAL COMMUNICATIONS BETWEEN THE EPITHELIUM AND FIBROBLASTS AND OTHER RESIDENT CELLS HAVE NOT BEEN ELUCIDATED. IN THIS REVIEW, WE DISCUSS THE ROLE OF EPITHELIAL CELLS AND THE MECHANISMS UNDERLYING THE FIBROTIC RESPONSE IN IPF, AND HIGHLIGHT SOME PROMISING THERAPEUTIC TARGETS FOR THESE CELLS. 2020 9 4978 28 PATHOPHYSIOLOGY AND NEW ADVANCES IN PULMONARY HYPERTENSION. PULMONARY HYPERTENSION IS A PROGRESSIVE AND OFTEN FATAL CARDIOPULMONARY CONDITION CHARACTERISED BY INCREASED PULMONARY ARTERIAL PRESSURE, STRUCTURAL CHANGES IN THE PULMONARY CIRCULATION, AND THE FORMATION OF VASO-OCCLUSIVE LESIONS. THESE CHANGES LEAD TO INCREASED RIGHT VENTRICULAR AFTERLOAD, WHICH OFTEN PROGRESSES TO MALADAPTIVE RIGHT VENTRICULAR REMODELLING AND EVENTUALLY DEATH. PULMONARY ARTERIAL HYPERTENSION REPRESENTS ONE OF THE MOST SEVERE AND BEST STUDIED TYPES OF PULMONARY HYPERTENSION AND IS CONSISTENTLY TARGETED BY DRUG TREATMENTS. THE UNDERLYING MOLECULAR PATHOGENESIS OF PULMONARY HYPERTENSION IS A COMPLEX AND MULTIFACTORIAL PROCESS, BUT CAN BE CHARACTERISED BY SEVERAL HALLMARKS: INFLAMMATION, IMPAIRED ANGIOGENESIS, METABOLIC ALTERATIONS, GENETIC OR EPIGENETIC ABNORMALITIES, INFLUENCE OF SEX AND SEX HORMONES, AND ABNORMALITIES IN THE RIGHT VENTRICLE. CURRENT TREATMENTS FOR PULMONARY ARTERIAL HYPERTENSION AND SOME OTHER TYPES OF PULMONARY HYPERTENSION TARGET PATHWAYS INVOLVED IN THE CONTROL OF PULMONARY VASCULAR TONE AND PROLIFERATION; HOWEVER, THESE TREATMENTS HAVE LIMITED EFFICACY ON PATIENT OUTCOMES. THIS REVIEW DESCRIBES KEY FEATURES OF PULMONARY HYPERTENSION, DISCUSSES CURRENT AND EMERGING THERAPEUTIC INTERVENTIONS, AND POINTS TO FUTURE DIRECTIONS FOR RESEARCH AND PATIENT CARE. BECAUSE MOST PROGRESS IN THE SPECIALTY HAS BEEN MADE IN PULMONARY ARTERIAL HYPERTENSION, THIS REVIEW FOCUSES ON THIS TYPE OF PULMONARY HYPERTENSION. THE REVIEW HIGHLIGHTS KEY PATHOPHYSIOLOGICAL CONCEPTS AND EMERGING THERAPEUTIC DIRECTIONS, TARGETING INFLAMMATION, CELLULAR METABOLISM, GENETICS AND EPIGENETICS, SEX HORMONE SIGNALLING, BONE MORPHOGENETIC PROTEIN SIGNALLING, AND INHIBITION OF TYROSINE KINASE RECEPTORS. 2023 10 358 27 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML. 2013 11 5998 22 THE ABERRANT EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF PSORIASIS. PSORIASIS IS A CHRONIC AND RECURRENT INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY ABNORMAL KERATINOCYTE PROLIFERATION, VASCULAR HYPERPLASIA, AND INFILTRATION OF INFLAMMATORY CELLS INTO THE DERMIS AND EPIDERMIS. IT IS GENERALLY ACCEPTED THAT THE CENTRAL PATHOGENESIS OF PSORIASIS IS DYSFUNCTION OF T LYMPHOCYTES, WHICH ARE AFFECTED BY THE COMPLEX INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS, INCLUDING TRAUMA, INFECTIONS, STRESS, DRUGS, SMOKING, AND ALCOHOL CONSUMPTION (NESTLE ET AL., 2009). THE ENVIRONMENTALLY INDUCED EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNAS, HAVE BEEN SHOWN TO BE INVOLVED IN THE PATHOGENESIS OF THIS DISEASE (ZHANG ET AL., 2012). 2018 12 2991 26 GENETIC INSTABILITY IN INHERITED AND SPORADIC LEUKEMIAS. GENETIC INSTABILITY DUE TO INCREASED DNA DAMAGE AND ALTERED DNA REPAIR IS OF CENTRAL SIGNIFICANCE IN THE INITIATION AND PROGRESSION OF INHERITED AND SPORADIC HUMAN LEUKEMIAS. ALTHOUGH VERY RARE, SOME INHERITED DNA REPAIR INSUFFICIENCY SYNDROMES (E.G., FANCONI ANEMIA, BLOOM'S SYNDROME) HAVE ADDED SUBSTANTIALLY TO OUR UNDERSTANDING OF CRUCIAL MECHANISMS OF LEUKEMOGENESIS IN RECENT YEARS. CONVERSELY, SPORADIC LEUKEMIAS ACCOUNT FOR THE MAIN PROPORTION OF LEUKEMIAS AND HERE DNA DAMAGING REACTIVE OXYGEN SPECIES (ROS) PLAY A CENTRAL ROLE. ALTHOUGH THE EXACT MECHANISMS OF INCREASED ROS PRODUCTION REMAIN LARGELY UNKNOWN AND NO SINGLE PATHWAY HAS BEEN DETECTED THUS FAR, SOME ONCOGENIC PROTEINS (E.G., THE ACTIVATED TYROSINE KINASES BCR-ABL1 AND FLT3-ITD) SEEM TO PLAY A KEY ROLE IN DRIVING GENETIC INSTABILITY BY INCREASED ROS GENERATION WHICH INFLUENCES THE DISEASE COURSE (E.G., BLAST CRISIS IN CHRONIC MYELOID LEUKEMIA OR RELAPSE IN FLT3-ITD POSITIVE ACUTE MYELOID LEUKEMIA). OF COURSE OTHER MECHANISMS, WHICH PROMOTE GENETIC INSTABILITY IN LEUKEMIA ALSO EXIST. A NEWLY EMERGING MECHANISM IS THE GENOME-WIDE ALTERATION OF EPIGENETIC MARKS (E.G., HYPOMETHYLATION OF HISTONE H3K79), WHICH PROMOTES CHROMOSOMAL INSTABILITY. TAKEN TOGETHER GENETIC INSTABILITY PLAYS A CRITICAL ROLE BOTH IN INHERITED AND SPORADIC LEUKEMIAS AND EMERGES AS A COMMON THEME IN BOTH INHERITED AND SPORADIC LEUKEMIAS. BEYOND ITS THEORETICAL IMPACT, THE ANALYSIS OF GENETIC INSTABILITY MAY LEAD THE WAY TO THE DEVELOPMENT OF INNOVATIVE THERAPY STRATEGIES. 2010 13 1113 24 COMMON PATHWAYS IN IDIOPATHIC PULMONARY FIBROSIS AND CANCER. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS MARKED BY A VERY DISAPPOINTING SURVIVAL RATE AND STILL REPRESENTS A CLINICAL DILEMMA. ACCORDING TO THE CURRENT PATHOGENIC HYPOTHESIS, CHRONIC DAMAGE OF THE ALVEOLAR EPITHELIUM IS FOLLOWED BY ABNORMAL TISSUE REPAIR AND IMPAIRMENT OF THE ALVEOLAR STRUCTURE. THIS PROCESS IS DRIVEN BY PATHOGENIC EVENTS VERY SIMILAR TO CANCER, INCLUDING EPIGENETIC AND GENETIC CHANGES, ALTERED RESPONSE TO REGULATORY SIGNALS, ABNORMAL EXPRESSION OF MICRORNAS AND ACTIVATION OF SPECIFIC SIGNALLING PATHWAYS. IPF ALSO RESEMBLES CANCER WITH REGARD TO ITS POOR RESPONSE TO MEDICAL TREATMENT AND PROGNOSIS, WHICH IS VERY OFTEN WORSE THAN MANY CANCERS. WE HAVE HYPOTHESISED THAT IPF MIGHT BE ASSIMILATED TO A NEOPROLIFERATIVE DISORDER OF THE LUNG. VIEWING IPF AS A CANCER-LIKE DISEASE MAY SATISFY THE NEED FOR A BETTER UNDERSTANDING OF THE PATHOGENESIS OF IPF BY EXPLOITING THE LARGE AMOUNT OF KNOWLEDGE THAT CANCER BIOLOGY EVOKES. THE RECOGNITION OF COMMON PATHOGENIC PATHWAYS BETWEEN THE TWO DISEASES MAY STIMULATE NEW CLINICAL TRIALS WITH CANCER DRUGS, DIFFERENT DRUG COMBINATIONS AND DIFFERENT LINES OF DRUGS, AS ALREADY EXPERIMENTED IN ONCOLOGY. MOREOVER, THE CONCEPT OF IPF AS A CANCER-LIKE DISORDER MAY IMPROVE THE ATTENTION GIVEN TO THIS DREADFUL DISEASE ON A PUBLIC, POLITICAL AND HEALTHCARE LEVEL. 2013 14 5738 22 SMOKING AND LUNG CANCER: THE ROLE OF INFLAMMATION. WORLDWIDE OVER 1 MILLION PEOPLE DIE DUE TO LUNG CANCER EACH YEAR. IT IS ESTIMATED THAT CIGARETTE SMOKING EXPLAINS ALMOST 90% OF LUNG CANCER RISK IN MEN AND 70 TO 80% IN WOMEN. CLINICALLY EVIDENT LUNG CANCERS HAVE MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES. THESE ABNORMALITIES MAY RESULT IN ACTIVATION OF ONCOGENES AND INACTIVATION OF TUMOR-SUPPRESSOR GENES. CHRONIC INFLAMMATION, WHICH IS KNOWN TO PROMOTE CANCER, MAY RESULT BOTH FROM SMOKING AND FROM GENETIC ABNORMALITIES. THESE MEDIATORS IN TURN MAY BE RESPONSIBLE FOR INCREASED MACROPHAGE RECRUITMENT, DELAYED NEUTROPHIL CLEARANCE, AND INCREASE IN REACTIVE OXYGEN SPECIES (ROS). THUS, THE PULMONARY ENVIRONMENT PRESENTS A UNIQUE MILIEU IN WHICH LUNG CARCINOGENESIS PROCEEDS IN COMPLICITY WITH THE HOST CELLULAR NETWORK. THE PULMONARY DISEASES THAT ARE ASSOCIATED WITH THE GREATEST RISK FOR LUNG CANCER ARE CHARACTERIZED BY ABUNDANT AND DEREGULATED INFLAMMATION. PULMONARY DISORDERS SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA ARE CHARACTERIZED BY PROFOUND ABNORMALITIES IN INFLAMMATORY AND FIBROTIC PATHWAYS. THE CYTOKINES AND GROWTH FACTORS ABERRANTLY PRODUCED IN COPD AND THE DEVELOPING TUMOR MICROENVIRONMENT HAVE BEEN FOUND TO HAVE DELETERIOUS PROPERTIES THAT SIMULTANEOUSLY PAVE THE WAY FOR BOTH EPITHELIAL-MESENCHYMAL TRANSITION (EMT) AND DESTRUCTION OF SPECIFIC HOST CELL-MEDIATED IMMUNE RESPONSES. FULL DEFINITION OF THESE PATHWAYS WILL AFFORD THE OPPORTUNITY TO INTERVENE IN SPECIFIC INFLAMMATORY EVENTS MEDIATING LUNG TUMORIGENESIS AND RESISTANCE TO THERAPY. 2008 15 5549 18 ROLE OF EPIGENETICS IN CHRONIC MYELOID LEUKEMIA. THE EFFICACY OF THERAPEUTIC MODALITIES IN CHRONIC MYELOID LEUKEMIA (CML) DEPENDS ON BOTH GENETIC AND EPIGENETIC MECHANISMS. THIS REVIEW FOCUSES ON EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF CML AND IN RESISTANCE OF TUMOR CELLS TO TYROSINE KINASE INHIBITORS LEADING TO THE LEUKEMIC CLONE ESCAPE AND PROPAGATION. REGULATORY EVENTS AT THE LEVELS OF GENE REGULATION BY TRANSCRIPTION FACTORS AND MICRORNAS ARE DISCUSSED IN THE CONTEXT OF CML PATHOGENESIS AND THERAPEUTIC MODALITIES. 2013 16 4124 26 MECHANISMS OF DISEASE PROGRESSION AND RESISTANCE TO TYROSINE KINASE INHIBITOR THERAPY IN CHRONIC MYELOID LEUKEMIA: AN UPDATE. CHRONIC MYELOID LEUKEMIA (CML) IS CHARACTERIZED BY THE PRESENCE OF THE BCR-ABL1 FUSION GENE, WHICH ENCODES A CONSTITUTIVE ACTIVE TYROSINE KINASE CONSIDERED TO BE THE PATHOGENIC DRIVER CAPABLE OF INITIATING AND MAINTAINING THE DISEASE. DESPITE THE REMARKABLE EFFICACY OF TYROSINE KINASE INHIBITORS (TKIS) TARGETING BCR-ABL1, SOME PATIENTS MAY NOT RESPOND (PRIMARY RESISTANCE) OR MAY RELAPSE AFTER AN INITIAL RESPONSE (SECONDARY RESISTANCE). IN A SMALL PROPORTION OF CASES, DEVELOPMENT OF RESISTANCE IS ACCOMPANIED OR SHORTLY FOLLOWED BY PROGRESSION FROM CHRONIC TO BLASTIC PHASE (BP), CHARACTERIZED BY A DISMAL PROGNOSIS. EVOLUTION FROM CP INTO BP IS A MULTIFACTORIAL AND PROBABLY MULTISTEP PHENOMENON. INCREASE IN BCR-ABL1 TRANSCRIPT LEVELS IS THOUGHT TO PROMOTE THE ONSET OF SECONDARY CHROMOSOMAL OR GENETIC DEFECTS, INDUCE DIFFERENTIATION ARREST, PERTURB RNA TRANSCRIPTION, EDITING AND TRANSLATION THAT TOGETHER WITH EPIGENETIC AND METABOLIC CHANGES MAY ULTIMATELY LEAD TO THE EXPANSION OF HIGHLY PROLIFERATING, DIFFERENTIATION-ARRESTED MALIGNANT CELLS. A MULTITUDE OF STUDIES OVER THE PAST TWO DECADES HAVE INVESTIGATED THE MECHANISMS UNDERLYING THE CLOSELY INTERTWINED PHENOMENA OF DRUG RESISTANCE AND DISEASE PROGRESSION. HERE, WE PROVIDE AN UPDATE ON WHAT IS CURRENTLY KNOWN ON THE MECHANISMS UNDERLYING PROGRESSION AND PRESENT THE LATEST ACQUISITIONS ON BCR-ABL1-INDEPENDENT RESISTANCE AND LEUKEMIA STEM CELL PERSISTENCE. 2019 17 1465 21 DISSECTING THE ROLE OF ABERRANT DNA METHYLATION IN HUMAN LEUKAEMIA. CHRONIC MYELOID LEUKAEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY THE GENETIC TRANSLOCATION T(9;22)(Q34;Q11.2) ENCODING FOR THE BCR-ABL FUSION ONCOGENE. HOWEVER, MANY MOLECULAR MECHANISMS OF THE DISEASE PROGRESSION STILL REMAIN POORLY UNDERSTOOD. A GROWING BODY OF EVIDENCE SUGGESTS THAT THE EPIGENETIC ABNORMALITIES ARE INVOLVED IN TYROSINE KINASE RESISTANCE IN CML, LEADING TO LEUKAEMIC CLONE ESCAPE AND DISEASE PROPAGATION. HERE WE SHOW THAT, BY APPLYING CELLULAR REPROGRAMMING TO PRIMARY CML CELLS, ABERRANT DNA METHYLATION CONTRIBUTES TO THE DISEASE EVOLUTION. IMPORTANTLY, USING A BCR-ABL INDUCIBLE MURINE MODEL, WE DEMONSTRATE THAT A SINGLE ONCOGENIC LESION TRIGGERS DNA METHYLATION CHANGES, WHICH IN TURN ACT AS A PRECIPITATING EVENT IN LEUKAEMIA PROGRESSION. 2015 18 4539 24 MULTISTAGE CARCINOGENESIS IN MOUSE SKIN. THE MOUSE SKIN MODEL OF MULTISTAGE CARCINOGENESIS HAS FOR MANY YEARS PROVIDED A CONCEPTUAL FRAMEWORK FOR STUDYING CARCINOGENESIS MECHANISMS AND POTENTIAL MEANS FOR INHIBITING SPECIFIC STAGES OF CARCINOGENESIS. THE PROCESS OF SKIN CARCINOGENESIS INVOLVES THE STEPWISE ACCUMULATION OF GENETIC CHANGE ULTIMATELY LEADING TO MALIGNANCY. INITIATION, THE FIRST STEP IN MULTISTAGE SKIN CARCINOGENESIS INVOLVES CARCINOGEN-INDUCED GENETIC CHANGES. A TARGET GENE IDENTIFIED FOR SOME SKIN TUMOR INITIATORS IS C-HA-RAS. THE SECOND STEP, THE PROMOTION STAGE, INVOLVES PROCESSES WHEREBY INITIATED CELLS UNDERGO SELECTIVE CLONAL EXPANSION TO FORM VISIBLE PREMALIGNANT LESIONS TERMED PAPILLOMAS. THE PROCESS OF TUMOR PROMOTION INVOLVES THE PRODUCTION AND MAINTENANCE OF A SPECIFIC AND CHRONIC HYPERPLASIA CHARACTERIZED BY A SUSTAINED CELLULAR PROLIFERATION OF EPIDERMAL CELLS. THESE CHANGES ARE BELIEVED TO RESULT FROM EPIGENETIC MECHANISMS SUCH AS ACTIVATION OF THE CELLULAR RECEPTOR, PROTEIN KINASE C, BY SOME CLASSES OF TUMOR PROMOTERS. THE PROGRESSION STAGE INVOLVES THE CONVERSION OF PAPILLOMAS TO MALIGNANT TUMORS, SQUAMOUS CELL CARCINOMAS. THE ACCUMULATION OF ADDITIONAL GENETIC CHANGES IN CELLS COMPRISING PAPILLOMAS HAS BEEN CORRELATED WITH TUMOR PROGRESSION, INCLUDING TRISOMIES OF CHROMOSOMES 6 AND 7 AND LOSS OF HETEROZYGOSITY. THE CURRENT REVIEW FOCUSES ON THE MECHANISMS INVOLVED IN MULTISTAGE SKIN CARCINOGENESIS, A SUMMARY OF KNOWN INHIBITORS OF SPECIFIC STAGES AND THEIR PROPOSED MECHANISMS OF ACTION, AND THE RELEVANCE OF THIS MODEL SYSTEM TO HUMAN CANCER. 1992 19 963 24 CHRONIC MYELOMONOCYTIC LEUKEMIA: INSIGHTS INTO BIOLOGY, PROGNOSTIC FACTORS, AND TREATMENT. PURPOSE OF REVIEW: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOLOGICAL MALIGNANCY CHARACTERIZED BY BOTH DYSPLASTIC AND PROLIFERATIVE FEATURES, WITH AN INHERENT RISK FOR LEUKEMIC TRANSFORMATION. WITH THE HELP OF THIS REVIEW, WE AIM TO SUMMARIZE KEY CONCEPTS WITH REGARDS TO CMML BIOLOGY, DIAGNOSIS, RISK STRATIFICATION, AND THERAPEUTICS. RECENT FINDINGS: BASED ON RECENT STUDIES, CMML IS HALLMARKED BY A RELATIVELY LOW GENETIC COMPLEXITY, WHICH CONTRASTS WITH A COMPELLING PHENOTYPICAL HETEROGENEITY, LARGELY DRIVEN BY EPIGENETIC MECHANISMS. RECENT ADVANCES IN THE CHARACTERIZATION OF CMML BIOLOGY HAS LED TO AN IMPROVEMENT IN RISK-STRATIFICATION, BY MEANS OF INCORPORATING PROGNOSTICALLY RELEVANT GENE MUTATIONS. THIS, HOWEVER, HAS NOT SIGNIFICANTLY IMPACTED AVAILABLE THERAPIES AND OUTCOMES CONTINUE TO REMAIN POOR. ADVANCES IN CMML BIOLOGY HAVE BETTER EXPLAINED THE PHENOTYPIC HETEROGENEITY, WHILE CONTINUING TO DEFINE THE GENETIC AND EPIGENETIC LANDSCAPE. IN SPITE OF RECENT ADVANCES, LIMITED EFFECTIVE THERAPIES EXIST AND DEVELOPING RATIONALLY DERIVED THERAPEUTIC APPROACHES IS MUCH NEEDED. 2019 20 6031 23 THE CANCER EPIGENOME: ITS ORIGINS, CONTRIBUTIONS TO TUMORIGENESIS, AND TRANSLATIONAL IMPLICATIONS. EPIGENETIC ABNORMALITIES IN LUNG AND OTHER CANCERS CONTINUE TO BE DEFINED AT A RAPID PACE. WE ARE COMING TO APPRECIATE THAT CANCERS HAVE AN "EPIGENETIC LANDSCAPE" WHEREIN GENES VULNERABLE TO ABNORMALITIES, SUCH AS PROMOTER DNA HYPERMETHYLATION AND ASSOCIATED GENE SILENCING, TEND TO RESIDE IN DEFINED NUCLEAR POSITIONS AND CHROMOSOME DOMAINS AND RELATIONSHIPS TO CHROMATIN REGULATION, WHICH FACILITATES STATES OF STEM CELL RENEWAL. THESE SAME GENES AND DOMAINS ARE ALSO VULNERABLE TO EPIGENETIC ABNORMALITIES INDUCED BY FACTORS TO WHICH CELLS ARE EXPOSED DURING CANCER RISK STATES, SUCH AS CHRONIC INFLAMMATION. WE CAN USE ALL OF THIS BASIC INFORMATION FOR TRANSLATIONAL PURPOSES IN TERMS OF DERIVING BIOMARKERS FOR CANCER RISK STATES AND DETECTION AND THERAPEUTIC STRATEGIES. 2012