1 937 58 CHRONIC LYMPHOCYTIC LEUKAEMIA GENOMICS AND THE PRECISION MEDICINE ERA. MASSIVE GENOMIC ANALYSES HAVE UNDERSCORED THE DIVERSITY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) BETWEEN PATIENTS. GENETIC HETEROGENEITY OF TUMOUR CLONES WITHIN A PATIENT MAY FUEL TUMOUR EVOLUTION. SEVERAL RECURRENTLY DEREGULATED INTRA-CELLULAR PATHWAYS ARE CANDIDATES FOR TARGETED THERAPIES THAT ARE VERY PROMISING AND ARE DRAMATICALLY CHANGING CLINICAL PATIENTS' PERSPECTIVES. IN THIS REVIEW WE PRESENT AN OVERVIEW OF THE GENETIC AND EPIGENETIC FEATURES OF CLL AND THEIR CLINICAL AND BIOLOGICAL IMPLICATIONS. 2017 2 4178 15 MEMORY T-CELL HETEROGENEITY AND TERMINOLOGY. IMMUNOLOGICAL MEMORY AND EXHAUSTION ARE FUNDAMENTAL FEATURES OF ADAPTIVE IMMUNITY. RECENT ADVANCES REVEAL INCREASING HETEROGENEITY AND DIVERSITY AMONG CD8 T-CELL SUBSETS, RESULTING IN NEW SUBSETS TO ANNOTATE AND UNDERSTAND. HERE, WE REVIEW OUR CURRENT KNOWLEDGE OF DIFFERENTIATION AND MAINTENANCE OF MEMORY AND EXHAUSTED CD8 T CELLS, INCLUDING PHENOTYPIC CLASSIFICATION, DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS. ADDITIONALLY, WE USE THIS OUTLINE TO DISCUSS THE NOMENCLATURE OF EFFECTOR, MEMORY, AND EXHAUSTED CD8 T CELLS. FINALLY, WE DISCUSS HOW NEW FINDINGS ABOUT THESE CELL TYPES MAY IMPACT THE THERAPEUTIC EFFICACY AND DEVELOPMENT OF IMMUNOTHERAPIES TARGETING EFFECTOR, MEMORY, AND/OR EXHAUSTED CD8 T CELLS IN CHRONIC INFECTIONS AND CANCER. 2021 3 1482 14 DIVERSITY, MECHANISMS, AND SIGNIFICANCE OF MACROPHAGE PLASTICITY. MACROPHAGES ARE A DIVERSE SET OF CELLS PRESENT IN ALL BODY COMPARTMENTS. THIS DIVERSITY IS IMPRINTED BY THEIR ONTOGENETIC ORIGIN (EMBRYONAL VERSUS ADULT BONE MARROW-DERIVED CELLS); THE ORGAN CONTEXT; BY THEIR ACTIVATION OR DEACTIVATION BY VARIOUS SIGNALS IN THE CONTEXTS OF MICROBIAL INVASION, TISSUE DAMAGE, AND METABOLIC DERANGEMENT; AND BY POLARIZATION OF ADAPTIVE T CELL RESPONSES. CLASSIC ADAPTIVE RESPONSES OF MACROPHAGES INCLUDE TOLERANCE, PRIMING, AND A WIDE SPECTRUM OF ACTIVATION STATES, INCLUDING M1, M2, OR M2-LIKE. MOREOVER, MACROPHAGES CAN RETAIN LONG-TERM IMPRINTING OF MICROBIAL ENCOUNTERS (TRAINED INNATE IMMUNITY). SINGLE-CELL ANALYSIS OF MONONUCLEAR PHAGOCYTES IN HEALTH AND DISEASE HAS ADDED A NEW DIMENSION TO OUR UNDERSTANDING OF THE DIVERSITY OF MACROPHAGE DIFFERENTIATION AND ACTIVATION. EPIGENETIC LANDSCAPES, TRANSCRIPTION FACTORS, AND MICRORNA NETWORKS UNDERLIE THE ADAPTABILITY OF MACROPHAGES TO DIFFERENT ENVIRONMENTAL CUES. MACROPHAGE PLASTICITY, AN ESSENTIAL COMPONENT OF CHRONIC INFLAMMATION, AND ITS INVOLVEMENT IN DIVERSE HUMAN DISEASES, MOST NOTABLY CANCER, IS DISCUSSED HERE AS A PARADIGM. 2020 4 3811 18 INTRATUMORAL HETEROGENEITY: CLONAL COOPERATION IN EPITHELIAL-TO-MESENCHYMAL TRANSITION AND METASTASIS. ALTHOUGH PHENOTYPIC INTRATUMORAL HETEROGENEITY WAS FIRST DESCRIBED MANY DECADES AGO, THE ADVENT OF NEXT-GENERATION SEQUENCING HAS PROVIDED CONCLUSIVE EVIDENCE THAT IN ADDITION TO PHENOTYPIC DIVERSITY, SIGNIFICANT GENOTYPIC DIVERSITY EXISTS WITHIN TUMORS. TUMOR HETEROGENEITY LIKELY ARISES BOTH FROM CLONAL EXPANSIONS, AS WELL AS FROM DIFFERENTIATION HIERARCHIES EXISTENT IN THE TUMOR, SUCH AS THAT ESTABLISHED BY CANCER STEM CELLS (CSCS) AND NON-CSCS. THESE DIFFERENTIATION HIERARCHIES MAY ARISE DUE TO GENETIC MUTATIONS, EPIGENETIC ALTERATIONS, OR MICROENVIRONMENTAL INFLUENCES. AN ADDITIONAL DIFFERENTIATION HIERARCHY WITHIN EPITHELIAL TUMORS MAY ARISE WHEN ONLY A FEW TUMOR CELLS TRANS-DIFFERENTIATE INTO MESENCHYMAL-LIKE CELLS, A PROCESS KNOWN AS EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT). AGAIN, THIS PROCESS CAN BE INFLUENCED BY BOTH GENETIC AND NON-GENETIC FACTORS. IN THIS REVIEW WE DISCUSS THE EVIDENCE FOR CLONAL INTERACTION AND COOPERATION FOR TUMOR MAINTENANCE AND PROGRESSION, PARTICULARLY WITH RESPECT TO EMT, AND FURTHER ADDRESS THE FAR-REACHING EFFECTS THAT TUMOR HETEROGENEITY MAY HAVE ON CANCER THERAPY. 2015 5 6014 13 THE ARCHITECTURAL DESIGN OF CD8+ T CELL RESPONSES IN ACUTE AND CHRONIC INFECTION: PARALLEL STRUCTURES WITH DIVERGENT FATES. IN RESPONSE TO INFECTION, T CELLS ADOPT A RANGE OF DIFFERENTIATION STATES, CREATING NUMEROUS HETEROGENEOUS SUBSETS THAT EXHIBIT DIFFERENT PHENOTYPES, FUNCTIONS, AND MIGRATION PATTERNS. THIS T CELL HETEROGENEITY IS A UNIVERSAL FEATURE OF T CELL IMMUNITY, NEEDED TO EFFECTIVELY CONTROL PATHOGENS IN A CONTEXT-DEPENDENT MANNER AND GENERATE LONG-LIVED IMMUNITY TO THOSE PATHOGENS. HERE, WE REVIEW NEW INSIGHTS INTO DIFFERENTIATION STATE DYNAMICS AND POPULATION HETEROGENEITY OF CD8+ T CELLS IN ACUTE AND CHRONIC VIRAL INFECTIONS AND CANCER AND HIGHLIGHT THE PARALLELS AND DISTINCTIONS BETWEEN ACUTE AND CHRONIC ANTIGEN STIMULATION SETTINGS. WE FOCUS ON TRANSCRIPTIONAL AND EPIGENETIC NETWORKS THAT MODULATE THE PLASTICITY AND TERMINAL DIFFERENTIATION OF ANTIGEN-SPECIFIC CD8+ T CELLS AND GENERATE FUNCTIONALLY DIVERSE T CELL SUBSETS WITH DIFFERENT ROLES TO COMBAT INFECTION AND CANCER. 2021 6 6588 25 TUMOR HETEROGENEITY IN LYMPHOMAS: A DIFFERENT BREED. THE FACTS THAT CANCER REPRESENTS TISSUES CONSISTING OF HETEROGENEOUS NEOPLASTIC, AS WELL AS REACTIVE, CELL POPULATIONS AND THAT CANCERS OF THE SAME HISTOTYPE MAY SHOW PROFOUND DIFFERENCES IN CLINICAL BEHAVIOR HAVE LONG BEEN RECOGNIZED. WITH THE ADVENT OF NEW TECHNOLOGIES AND THE DEMANDS OF PRECISION MEDICINE, THE INVESTIGATION OF TUMOR HETEROGENEITY HAS GAINED MUCH INTEREST. AN UNDERSTANDING OF INTERTUMORAL HETEROGENEITY IN PATIENTS WITH THE SAME DISEASE ENTITY IS NECESSARY TO OPTIMALLY GUIDE PERSONALIZED TREATMENT. IN ADDITION, INCREASING EVIDENCE INDICATES THAT DIFFERENT TUMOR AREAS OR PRIMARY TUMORS AND METASTASES IN AN INDIVIDUAL PATIENT CAN SHOW SIGNIFICANT INTRATUMORAL HETEROGENEITY ON DIFFERENT LEVELS. THIS PHENOMENON CAN BE DRIVEN BY GENOMIC INSTABILITY, EPIGENETIC EVENTS, THE TUMOR MICROENVIRONMENT, AND STOCHASTIC VARIATIONS IN CELLULAR FUNCTION AND ANTITUMORAL THERAPIES. THESE MECHANISMS MAY LEAD TO BRANCHED SUBCLONAL EVOLUTION FROM A COMMON PROGENITOR CLONE, RESULTING IN SPATIAL VARIATION BETWEEN DIFFERENT TUMOR SITES, DISEASE PROGRESSION, AND TREATMENT RESISTANCE. THIS REVIEW ADDRESSES TUMOR HETEROGENEITY IN LYMPHOMAS FROM A PATHOLOGIST'S VIEWPOINT. THE RELATIONSHIP BETWEEN MORPHOLOGIC, IMMUNOPHENOTYPIC, AND GENETIC HETEROGENEITY IS EXEMPLIFIED IN DIFFERENT LYMPHOMA ENTITIES AND REVIEWED IN THE CONTEXT OF HIGH-GRADE TRANSFORMATION AND TRANSDIFFERENTIATION. IN ADDITION, FACTORS DRIVING HETEROGENEITY, AS WELL AS CLINICAL AND THERAPEUTIC IMPLICATIONS OF LYMPHOMA HETEROGENEITY, WILL BE DISCUSSED. 2018 7 6054 19 THE CURRENT STATE AND FUTURE OF T-CELL EXHAUSTION RESEARCH. 'EXHAUSTION' IS A TERM USED TO DESCRIBE A STATE OF NATIVE AND REDIRECTED T-CELL HYPO-RESPONSIVENESS RESULTING FROM PERSISTENT ANTIGEN EXPOSURE DURING CHRONIC VIRAL INFECTIONS OR CANCER. ALTHOUGH A WELL-ESTABLISHED PHENOTYPE ACROSS MICE AND HUMANS, EXHAUSTION AT THE MOLECULAR LEVEL REMAINS POORLY DEFINED AND INCONSISTENT ACROSS THE LITERATURE. THIS IS, IN PART, DUE TO AN OVERRELIANCE ON SURFACE RECEPTORS TO DEFINE THESE CELLS AND EXPLAIN EXHAUSTIVE BEHAVIOURS, AN INCOMPLETE UNDERSTANDING OF HOW EXHAUSTION ARISES, AND A LACK OF CLARITY OVER WHETHER EXHAUSTION IS THE SAME ACROSS CONTEXTS, E.G. CHRONIC VIRAL INFECTIONS VERSUS CANCER. WITH THE DEVELOPMENT OF SYSTEMS-BASED GENETIC APPROACHES SUCH AS SINGLE-CELL RNA-SEQ AND CRISPR SCREENS APPLIED TO IN VIVO DATA, WE ARE MOVING CLOSER TO A CONSENSUS VIEW OF EXHAUSTION, ALTHOUGH UNDERSTANDING HOW IT ARISES REMAINS CHALLENGING GIVEN THE DIFFICULTY IN MANIPULATING THE IN VIVO SETTING. ACCORDINGLY, PRODUCING AND STUDYING EXHAUSTED T-CELLS EX VIVO ARE BURGEONING, ALLOWING EXPERIMENTS TO BE CONDUCTED AT SCALE UP AND WITH HIGH THROUGHPUT. HERE, WE FIRST REVIEW WHAT IS CURRENTLY KNOWN ABOUT T-CELL EXHAUSTION AND HOW IT'S BEING STUDIED. WE THEN DISCUSS HOW IMPROVEMENTS IN THEIR METHOD OF ISOLATION/PRODUCTION AND EXAMINING THE IMPACT OF DIFFERENT MICROENVIRONMENTAL SIGNALS AND CELL INTERACTIONS HAVE NOW BECOME AN ACTIVE AREA OF RESEARCH. FINALLY, WE DISCUSS WHAT THE FUTURE HOLDS FOR THE ANALYSIS OF THIS PHYSIOLOGICAL CONDITION AND, GIVEN THE DIVERSITY OF WAYS IN WHICH EXHAUSTED CELLS ARE NOW BEING GENERATED, PROPOSE THE ADOPTION OF A UNIFIED APPROACH TO CLEARLY DEFINING EXHAUSTION USING A SET OF METABOLIC-, EPIGENETIC-, TRANSCRIPTIONAL-, AND ACTIVATION-BASED PHENOTYPIC MARKERS, THAT WE CALL 'M.E.T.A'. 2023 8 5898 15 T(H)2 CELL DEVELOPMENT AND FUNCTION. T HELPER 2 (T(H)2) CELLS ORCHESTRATE PROTECTIVE TYPE 2 IMMUNE RESPONSES, SUCH AS THOSE THAT TARGET HELMINTHS AND FACILITATE TISSUE REPAIR, BUT ALSO CONTRIBUTE TO CHRONIC INFLAMMATORY DISEASES, SUCH AS ASTHMA AND ALLERGY. HERE, WE REVIEW RECENT INSIGHTS INTO HOW DIVERSE MOLECULAR SIGNALS FROM CELLULAR SOURCES, INCLUDING DENDRITIC CELLS, INNATE LYMPHOID CELLS AND THE EPITHELIUM, ARE INTEGRATED BY T CELLS TO GUIDE THE TRANSCRIPTIONAL AND EPIGENETIC CHANGES NECESSARY FOR T(H)2 CELL DIFFERENTIATION. OUR IMPROVED UNDERSTANDING OF THESE PATHWAYS HAS OPENED NEW AVENUES FOR THERAPEUTICALLY TARGETING T(H)2 CELLS IN ASTHMA AND ALLERGY. THE ADVENT OF COMPREHENSIVE SINGLE-CELL TRANSCRIPTOMICS ALONG WITH IMPROVEMENTS IN SINGLE-CELL PROTEOMICS AND THE GENERATION OF NOVEL IN VIVO CELL FATE MAPPING TECHNIQUES PROMISE TO EXPAND OUR UNDERSTANDING OF T CELL DIVERSITY AND OFFER NEW INSIGHT INTO DISEASE-RELATED HETEROGENEITY AND PLASTICITY OF T(H) CELL RESPONSES. 2018 9 4340 14 MIGRATION OF STEM-LIKE CD8 T CELLS BETWEEN TISSUE MICROENVIRONMENTS UNDERPINS SUCCESSFUL ANTI-TUMOUR IMMUNE RESPONSES. THE CLINICAL SUCCESS OF IMMUNE CHECKPOINT BLOCKADE IN SOME PATIENTS HAS TRANSFORMED TREATMENT APPROACHES IN CANCER AND OFFERS THE HOPE OF DURABLE CURATIVE RESPONSES. BUILDING FROM STUDIES OF CHRONIC INFECTION, THE COMPOSITION OF TUMOUR INFILTRATING LYMPHOCYTES AND IN PARTICULAR, THE SPECTRUM OF EXHAUSTED CD8 T CELLS HAS NOW BEEN CHARACTERIZED IN DETAIL, PROFILING THE PHENOTYPE, FUNCTION, TRANSCRIPTIONAL REGULATION AND EVEN THE EPIGENETIC CHANGES. HOWEVER, WHAT REMAINS LESS CLEAR IS HOW INTRATUMOURAL IMMUNE CELLS INTERFACE WITH POPULATIONS IN THE PERIPHERY, BOTH IN TERMS OF SUSTAINING THE RESPONSE IN CANCER, BUT ALSO IN ESTABLISHING SYSTEMIC MEMORY RESPONSES THAT CAN PROVIDE LONG-TERM PROTECTION. HERE WE WILL SUCCINCTLY REVIEW THE CURRENT UNDERSTANDING OF THE ANTI-TUMOUR RESPONSE, CONSIDER THE TISSUE MICROENVIRONMENTS THAT SUPPORT KEY CELLULAR SUBSETS AND THE EXTENT TO WHICH CELLULAR MIGRATION BETWEEN THESE SITES IMPACTS THE RESPONSE. 2023 10 127 14 A TRANSCRIPTIONAL PERSPECTIVE ON HUMAN MACROPHAGE BIOLOGY. MACROPHAGES ARE A MAJOR CELL TYPE IN TISSUE HOMEOSTASIS AND CONTRIBUTE TO BOTH PATHOLOGY AND RESOLUTION IN ALL ACUTE AND CHRONIC INFLAMMATORY DISEASES RANGING FROM INFECTIONS, CANCER, OBESITY, ATHEROSCLEROSIS, AUTOIMMUNE DISORDERS TO NEURODEGENERATIVE DISEASES SUCH AS ALZHEIMER'S DISEASE. THE CELLULAR AND FUNCTIONAL DIVERSITY OF MACROPHAGES DEPENDS UPON TIGHTLY REGULATED TRANSCRIPTION. THE INNATE IMMUNE SYSTEM IS UNDER PROFOUND EVOLUTIONARY SELECTION. THERE IS INCREASING RECOGNITION THAT HUMAN MACROPHAGE BIOLOGY DIFFERS VERY SIGNIFICANTLY FROM THAT OF COMMONLY STUDIED ANIMAL MODELS, WHICH THEREFORE CAN HAVE A LIMITED PREDICTIVE VALUE. HERE WE REPORT ON THE NEWEST FINDINGS ON TRANSCRIPTIONAL CONTROL OF MACROPHAGE ACTIVATION, AND HOW WE ENVISION INTEGRATING STUDIES ON TRANSCRIPTIONAL AND EPIGENETIC REGULATION, AND MORE CLASSICAL APPROACHES IN MURINE MODELS. MOREOVER, WE PROVIDE NEW INSIGHTS INTO HOW WE CAN LEARN ABOUT TRANSCRIPTIONAL REGULATION IN THE HUMAN SYSTEM FROM LARGER EFFORTS SUCH AS THE FANTOM (FUNCTIONAL ANNOTATION OF THE MAMMALIAN GENOME) CONSORTIUM. 2015 11 944 25 CHRONIC LYMPHOCYTIC LEUKEMIA: FROM MOLECULAR PATHOGENESIS TO NOVEL THERAPEUTIC STRATEGIES. CHRONIC LYMPHOCYTIC LEUKEMIA IS A WELL-DEFINED LYMPHOID NEOPLASM WITH VERY HETEROGENEOUS BIOLOGICAL AND CLINICAL BEHAVIOR. THE LAST DECADE HAS BEEN REMARKABLY FRUITFUL IN NOVEL FINDINGS ELUCIDATING MULTIPLE ASPECTS OF THE PATHOGENESIS OF THE DISEASE INCLUDING MECHANISMS OF GENETIC SUSCEPTIBILITY, INSIGHTS INTO THE RELEVANCE OF IMMUNOGENETIC FACTORS DRIVING THE DISEASE, PROFILING OF GENOMIC ALTERATIONS, EPIGENETIC SUBTYPES, GLOBAL EPIGENOMIC TUMOR CELL REPROGRAMMING, MODULATION OF TUMOR CELL AND MICROENVIRONMENT INTERACTIONS, AND DYNAMICS OF CLONAL EVOLUTION FROM EARLY STEPS IN MONOCLONAL B CELL LYMPHOCYTOSIS TO PROGRESSION AND TRANSFORMATION INTO DIFFUSE LARGE B-CELL LYMPHOMA. ALL THIS KNOWLEDGE HAS OFFERED NEW PERSPECTIVES THAT ARE BEING EXPLOITED THERAPEUTICALLY WITH NOVEL TARGET AGENTS AND MANAGEMENT STRATEGIES. IN THIS REVIEW WE PROVIDE AN OVERVIEW OF THESE NOVEL ADVANCES AND HIGHLIGHT QUESTIONS AND PERSPECTIVES THAT NEED FURTHER PROGRESS TO TRANSLATE INTO THE CLINICS THE BIOLOGICAL KNOWLEDGE AND IMPROVE THE OUTCOME OF THE PATIENTS. 2020 12 5896 17 T CELLS IN HEALTH AND DISEASE. T CELLS ARE CRUCIAL FOR IMMUNE FUNCTIONS TO MAINTAIN HEALTH AND PREVENT DISEASE. T CELL DEVELOPMENT OCCURS IN A STEPWISE PROCESS IN THE THYMUS AND MAINLY GENERATES CD4(+) AND CD8(+) T CELL SUBSETS. UPON ANTIGEN STIMULATION, NAIVE T CELLS DIFFERENTIATE INTO CD4(+) HELPER AND CD8(+) CYTOTOXIC EFFECTOR AND MEMORY CELLS, MEDIATING DIRECT KILLING, DIVERSE IMMUNE REGULATORY FUNCTION, AND LONG-TERM PROTECTION. IN RESPONSE TO ACUTE AND CHRONIC INFECTIONS AND TUMORS, T CELLS ADOPT DISTINCT DIFFERENTIATION TRAJECTORIES AND DEVELOP INTO A RANGE OF HETEROGENEOUS POPULATIONS WITH VARIOUS PHENOTYPE, DIFFERENTIATION POTENTIAL, AND FUNCTIONALITY UNDER PRECISE AND ELABORATE REGULATIONS OF TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS. ABNORMAL T-CELL IMMUNITY CAN INITIATE AND PROMOTE THE PATHOGENESIS OF AUTOIMMUNE DISEASES. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF T CELL DEVELOPMENT, CD4(+) AND CD8(+) T CELL CLASSIFICATION, AND DIFFERENTIATION IN PHYSIOLOGICAL SETTINGS. WE FURTHER ELABORATE THE HETEROGENEITY, DIFFERENTIATION, FUNCTIONALITY, AND REGULATION NETWORK OF CD4(+) AND CD8(+) T CELLS IN INFECTIOUS DISEASE, CHRONIC INFECTION AND TUMOR, AND AUTOIMMUNE DISEASE, HIGHLIGHTING THE EXHAUSTED CD8(+) T CELL DIFFERENTIATION TRAJECTORY, CD4(+) T CELL HELPER FUNCTION, T CELL CONTRIBUTIONS TO IMMUNOTHERAPY AND AUTOIMMUNE PATHOGENESIS. WE ALSO DISCUSS THE DEVELOPMENT AND FUNCTION OF GAMMADELTA T CELLS IN TISSUE SURVEILLANCE, INFECTION, AND TUMOR IMMUNITY. FINALLY, WE SUMMARIZED CURRENT T-CELL-BASED IMMUNOTHERAPIES IN BOTH CANCER AND AUTOIMMUNE DISEASES, WITH AN EMPHASIS ON THEIR CLINICAL APPLICATIONS. A BETTER UNDERSTANDING OF T CELL IMMUNITY PROVIDES INSIGHT INTO DEVELOPING NOVEL PROPHYLACTIC AND THERAPEUTIC STRATEGIES IN HUMAN DISEASES. 2023 13 940 26 CHRONIC LYMPHOCYTIC LEUKEMIA AND MANTLE CELL LYMPHOMA: CROSSROADS OF GENETIC AND MICROENVIRONMENT INTERACTIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND MANTLE CELL LYMPHOMA (MCL) ARE 2 WELL-DEFINED ENTITIES THAT DIVERGE IN THEIR BASIC PATHOGENIC MECHANISMS AND CLINICAL EVOLUTION BUT THEY SHARE EPIDEMIOLOGICAL CHARACTERISTICS, CELLS OF ORIGIN, MOLECULAR ALTERATIONS, AND CLINICAL FEATURES THAT DIFFER FROM OTHER LYMPHOID NEOPLASMS. CLL AND MCL ARE CLASSICALLY CONSIDERED INDOLENT AND AGGRESSIVE NEOPLASMS, RESPECTIVELY. HOWEVER, THE CLINICAL EVOLUTION OF BOTH TUMORS IS VERY HETEROGENEOUS, WITH SUBSETS OF PATIENTS HAVING STABLE DISEASE FOR A LONG TIME WHEREAS OTHERS REQUIRE IMMEDIATE INTERVENTION. BOTH CLL AND MCL INCLUDE 2 MAJOR MOLECULAR SUBTYPES THAT SEEM TO DERIVE FROM ANTIGEN-EXPERIENCED CD5(+) B CELLS THAT RETAIN A NAIVE OR MEMORY-LIKE EPIGENETIC SIGNATURE AND CARRY A VARIABLE LOAD OF IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE REGION SOMATIC MUTATIONS FROM TRULY UNMUTATED TO HIGHLY MUTATED, RESPECTIVELY. THESE 2 SUBTYPES OF TUMORS DIFFER IN THEIR MOLECULAR PATHWAYS, GENOMIC ALTERATIONS, AND CLINICAL BEHAVIOR, BEING MORE AGGRESSIVE IN NAIVE-LIKE THAN MEMORY-LIKE-DERIVED TUMORS IN BOTH CLL AND MCL. THE PATHOGENESIS OF THE 2 ENTITIES INTEGRATES THE RELEVANT INFLUENCE OF B-CELL RECEPTOR SIGNALING, TUMOR CELL MICROENVIRONMENT INTERACTIONS, GENOMIC ALTERATIONS, AND EPIGENOME MODIFICATIONS THAT CONFIGURE THE EVOLUTION OF THE TUMORS AND OFFER NEW POSSIBILITIES FOR THERAPEUTIC INTERVENTION. THIS REVIEW WILL FOCUS ON THE SIMILARITIES AND DIFFERENCES OF THESE 2 TUMORS BASED ON RECENT STUDIES THAT ARE ENHANCING THE UNDERSTANDING OF THEIR PATHOGENESIS AND CREATING SOLID BASES FOR NEW MANAGEMENT STRATEGIES. 2018 14 384 23 AN EVOLUTIONARY PERSPECTIVE ON CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) SHARES WITH OTHER MYELOID DISEASES A NUMBER OF SOMATIC GENE MUTATIONS. THESE MUTATIONS CAN NOW BE INTEGRATED WITHIN THE FRAMEWORK OF EVOLUTION THEORY TO ADDRESS THE MECHANISMS OF THE DISEASE. SEVERAL EVIDENCES INDICATE THAT THE DISEASE EMERGES IN ADULT HEMATOPOIETIC STEM CELLS (HSC) THROUGH THE AGE-DEPENDENT ACCUMULATION OF DNA DAMAGE, LEADING STOCHASTICALLY TO A DRIVER MUTATION THAT CONFERS A COMPETITIVE ADVANTAGE TO THE CELL. A MUTATION IN TET2 GENE COULD BE ONE OF THESE DRIVER MUTATIONS PROVOKING THE EMERGENCE OF CLONALITY. AFTER A LONG LATENCY, SECONDARY LESIONS, SUCH AS MUTATIONS IN THE SRSF2 GENE, CONTRIBUTE TO PROGRESSION TO FULL-BLOWN MALIGNANCY, WITH ABNORMAL DIFFERENTIATION. ADDITIONAL MUTATIONS ACCUMULATE AND BRANCHING ARISING MOSTLY THROUGH MITOTIC RECOMBINATION GENERATES CLONAL HETEROGENEITY. MODIFICATIONS IN THE MICROENVIRONMENT PROBABLY AFFECT THIS CLONAL DYNAMICS, WHEREAS EPIGENETIC ALTERATIONS, SUCH AS HYPERMETHYLATION OF THE TIF1GAMMA GENE PROMOTER, MAY GENERATE PHENOTYPIC DIVERSIFICATION OF OTHERWISE CLONAL POPULATIONS. THE PRESERVED ALTHOUGH DEREGULATED MYELOID DIFFERENTIATION THAT CHARACTERIZES CMML, WITH GRANULOMONOCYTE EXPANSION AND VARIOUS CYTOPENIAS, MAY DEPEND ON EARLY CLONAL DOMINANCE IN THE HEMATOPIETIC CELL HIERARCHY. PROGRESSION TO ACUTE MYELOID LEUKEMIA OBSERVED IN 25-30% OF THE PATIENTS MAY ARISE FROM THE MASSIVE EXPANSION OF A CLONE WITH NOVEL GENETIC LESIONS, PROVIDING A HIGH FITNESS TO PREVIOUSLY MINOR SUBCLONES WHEN IN CHRONIC PHASE OF THE DISEASE. THIS REVIEW DISCUSSES THE VARIOUS MODELS OF DISEASE EMERGENCE AND PROGRESSION AND HOW THIS RECENT KNOWLEDGE COULD DRIVE RATIONAL THERAPEUTIC STRATEGIES. 2013 15 6571 16 TRANSPOSABLE ELEMENTS CROSS KINGDOM BOUNDARIES AND CONTRIBUTE TO INFLAMMATION AND AGEING: SOMATIC ACQUISITION OF FOREIGN TRANSPOSABLE ELEMENTS AS A CATALYST OF GENOME INSTABILITY, EPIGENETIC DYSREGULATION, INFLAMMATION, SENESCENCE, AND AGEING. THE DE-REPRESSION OF TRANSPOSABLE ELEMENTS (TES) IN MAMMALIAN GENOMES IS THOUGHT TO CONTRIBUTE TO GENOME INSTABILITY, INFLAMMATION, AND AGEING, YET IS VIEWED AS A CELL-AUTONOMOUS EVENT. IN CONTRAST TO MAMMALIAN CELLS, PROKARYOTES CONSTANTLY EXCHANGE GENETIC MATERIAL THROUGH TES, CROSSING BOTH CELL AND SPECIES BARRIERS, CONTRIBUTING TO RAPID MICROBIAL EVOLUTION AND DIVERSITY IN COMPLEX COMMUNITIES SUCH AS THE MAMMALIAN GUT. HERE, IT IS PROPOSED THAT TES RELEASED FROM PROKARYOTES IN THE MICROBIOME OR FROM PATHOGENIC INFECTIONS REGULARLY CROSS THE KINGDOM BARRIER TO THE SOMATIC CELLS OF THEIR EUKARYOTIC HOSTS. IT IS PROPOSED THIS HORIZONTAL TRANSFER OF TES FROM MICROBE TO HOST IS A STOCHASTIC, ONGOING CATALYST OF GENOME DESTABILIZATION, RESULTING IN STRUCTURAL AND EPIGENETIC VARIATIONS, AND ACTIVATION OF WELL-EVOLVED HOST DEFENSE MECHANISMS CONTRIBUTING TO INFLAMMATION, SENESCENCE, AND BIOLOGICAL AGEING. IT IS PROPOSED THAT INNATE IMMUNITY PATHWAYS DEFEND AGAINST THE HORIZONTAL ACQUISITION OF MICROBIAL TES, AND THAT ACTIVATION OF THIS PATHWAY DURING HORIZONTAL TRANSPOSON TRANSFER PROMOTES CHRONIC INFLAMMATION DURING AGEING. FINALLY, IT IS SUGGESTED THAT HORIZONTAL ACQUISITION OF PROKARYOTIC TES INTO MAMMALIAN GENOMES HAS BEEN MASKED AND SUBSEQUENTLY UNDER-REPORTED DUE TO FLAWS IN CURRENT SEQUENCING PIPELINES, AND NEW STRATEGIES TO UNCOVER THESE EVENTS ARE PROPOSED. 2020 16 5901 16 T-CELL HETEROGENEITY, PROGENITOR-PROGENY RELATIONSHIPS, AND FUNCTION DURING LATENT AND CHRONIC VIRAL INFECTIONS. UPON RESOLUTION OF AN ACUTE VIRAL INFECTION, DURING LATENT-REACTIVATING INFECTION AND DURING CHRONIC ACTIVE INFECTIONS VIRUS-SPECIFIC T-CELLS DIFFERENTIATE INTO DISTINCT SUBSETS THAT DIFFER IN PHENOTYPE, LONGEVITY, TRANSCRIPTIONAL, METABOLIC, AND EPIGENETIC PROFILES, AND EFFECTOR FUNCTIONS. WITH RECENT ADVANCES IN SINGLE-CELL PROFILING, THIS SUBSTANTIAL HETEROGENEITY HAS BECOME APPARENT AND NEW SUBSETS OF VIRUS-SPECIFIC T CELLS, EITHER OF STABLE OR TRANSITORY NATURE, ARE BEING IDENTIFIED. A UNIFYING PRINCIPLE OF T CELLS EMERGING IN THESE DIFFERENT CONDITIONS IS THEIR PRECURSOR-PROGENY RELATIONSHIP. FOR ACUTE AND RESOLVED VIRAL INFECTIONS, THIS RELATIONSHIP BECOMES APPARENT DURING RE-CHALLENGE, WHEREAS A CONSTANT DIFFERENTIATION OF PROGENITOR T CELLS INTO MORE DIFFERENTIATED CELLS OCCURS DURING LATENT-REACTIVATING AND ACTIVE CHRONIC VIRAL INFECTIONS. IN THIS REVIEW, WE SUMMARIZE AND DISCUSS CURRENT KNOWLEDGE ABOUT T-CELL HETEROGENEITY AND PROGENITOR-PROGENY RELATIONSHIPS IN THE SETTING OF PERSISTENT VIRAL INFECTIONS. 2023 17 6101 13 THE EMERGING ROLE OF EPIGENETICS IN THE IMMUNE RESPONSE TO VACCINATION AND INFECTION: A SYSTEMATIC REVIEW. EXTENSIVE RESEARCH HAS HIGHLIGHTED THE ROLE OF INFECTION-INDUCED EPIGENETIC EVENTS IN THE DEVELOPMENT OF CANCER. MORE RECENTLY, ATTENTION HAS FOCUSED ON THE ABILITY OF NON-CARCINOGENIC INFECTIONS, AS WELL AS VACCINES, TO MODIFY THE HUMAN EPIGENOME AND MODULATE THE IMMUNE RESPONSE. THIS REVIEW EXPLORES THIS RAPIDLY EVOLVING AREA OF INVESTIGATION AND OUTLINES THE MANY AND VARIED WAYS IN WHICH VACCINATION AND NATURAL INFECTION CAN INFLUENCE THE HUMAN EPIGENOME FROM MODULATION OF THE INNATE AND ADAPTIVE IMMUNE RESPONSE, TO BIOLOGICAL AGEING AND MODIFICATION OF DISEASE RISK. THE IMPLICATIONS OF THESE EPIGENETIC CHANGES ON IMMUNE REGULATION AND THEIR POTENTIAL APPLICATION TO THE DIAGNOSIS AND TREATMENT OF CHRONIC INFECTION AND VACCINE DEVELOPMENT ARE ALSO DISCUSSED. 2020 18 2906 18 GENE EDITING FOR INFLAMMATORY DISORDERS. TECHNOLOGY FOR PRECISE AND EFFICIENT GENETIC EDITING IS CONSTANTLY EVOLVING AND IS NOW CAPABLE OF HUMAN CLINICAL APPLICATIONS. AUTOIMMUNE AND INFLAMMATORY DISEASES ARE CHRONIC, DISABLING, SOMETIMES LIFE-THREATENING, CONDITIONS THAT FEATURE HERITABLE COMPONENTS. BOTH PRIMARY GENETIC LESIONS AND THE INFLAMMATORY PATHOBIOLOGY UNDERLYING THESE DISEASES REPRESENT FERTILE SOIL FOR NEW THERAPIES BASED ON THE CAPABILITIES OF GENE EDITING. THE ABILITY TO ORCHESTRATE PRECISE TARGETED MODIFICATIONS TO THE GENOME WILL LIKELY ENABLE CELL-BASED THERAPIES FOR INFLAMMATORY DISEASES SUCH AS MONOGENIC AUTOINFLAMMATORY DISEASE, ACQUIRED AUTOIMMUNE DISEASE AND FOR REGENERATIVE MEDICINE IN THE SETTING OF AN INFLAMMATORY ENVIRONMENT. HERE, WE DISCUSS RECENT ADVANCES IN GENOME EDITING AND THEIR EVOLVING APPLICATIONS IN IMMUNOINFLAMMATORY DISEASES. STRENGTHS AND LIMITATIONS OF OLDER GENETIC MODIFICATION TOOLS ARE COMPARED WITH CRISPR/CAS9, BASE EDITING, RNA EDITING, TARGETED ACTIVATORS AND REPRESSORS OF TRANSCRIPTION AND TARGETED EPIGENETIC MODIFIERS. COMMONLY EMPLOYED DELIVERY VEHICLES TO TARGET CELLS OR TISSUES OF INTEREST WITH GENETIC MODIFICATION MACHINERY, INCLUDING VIRAL, NON-VIRAL AND CELLULAR VECTORS, ARE DESCRIBED. FINALLY, APPLICATIONS IN ANIMAL AND HUMAN MODELS OF INFLAMMATORY DISEASES ARE DISCUSSED. USE OF CHIMERIC AUTOANTIGEN RECEPTOR T CELLS, CORRECTION OF MONOGENIC DISEASES WITH GENETICALLY EDITED HAEMATOPOIETIC STEM AND PROGENITOR CELLS, ENGINEERING OF INDUCED PLURIPOTENT STEM CELLS AND EX VIVO EXPANSION AND MODIFICATION OF REGULATORY T CELLS FOR A RANGE OF CHRONIC INFLAMMATORY DISEASES ARE REVIEWED. 2019 19 4726 11 NOT-SO-OPPOSITE ENDS OF THE SPECTRUM: CD8(+) T CELL DYSFUNCTION ACROSS CHRONIC INFECTION, CANCER AND AUTOIMMUNITY. CD8(+) T CELLS ARE CRITICAL MEDIATORS OF CYTOTOXIC EFFECTOR FUNCTION IN INFECTION, CANCER AND AUTOIMMUNITY. IN CANCER AND CHRONIC VIRAL INFECTION, CD8(+) T CELLS UNDERGO A PROGRESSIVE LOSS OF CYTOKINE PRODUCTION AND CYTOTOXICITY, A STATE TERMED T CELL EXHAUSTION. IN AUTOIMMUNITY, AUTOREACTIVE CD8(+) T CELLS RETAIN THE CAPACITY TO EFFECTIVELY MEDIATE THE DESTRUCTION OF HOST TISSUES. ALTHOUGH THE CLINICAL OUTCOME DIFFERS IN EACH CONTEXT, CD8(+) T CELLS ARE CHRONICALLY EXPOSED TO ANTIGEN IN ALL THREE. THESE CHRONICALLY STIMULATED CD8(+) T CELLS SHARE SOME COMMON PHENOTYPIC FEATURES, AS WELL AS TRANSCRIPTIONAL AND EPIGENETIC PROGRAMMING, ACROSS DISEASE CONTEXTS. A BETTER UNDERSTANDING OF THESE CD8(+) T CELL STATES MAY REVEAL NOVEL STRATEGIES TO AUGMENT CLEARANCE OF CHRONIC VIRAL INFECTION AND CANCER AND TO MITIGATE SELF-REACTIVITY LEADING TO TISSUE DAMAGE IN AUTOIMMUNITY. 2021 20 6157 18 THE GENETICS AND EPIGENETICS OF ALTERED PROLIFERATIVE HOMEOSTASIS IN AGEING AND CANCER. AGEING MAMMALS ARE SUBJECT TO AN AMAZING ARRAY OF ABERRATIONS IN PROLIFERATIVE HOMEOSTASIS. THESE ARE OF TWO BASIC TYPES: THE POST-MATURATIONAL FAILURE TO ADEQUATELY REPLACE EFFETE SOMATIC CELLS (ATROPHIES) AND EXCESSIVE PROLIFERATIONS OF SOMATIC CELLS (HYPERPLASIAS). TO A SURPRISING DEGREE, THESE OCCUR SIDE BY SIDE WITHIN THE SAME TISSUES AND ARE FEATURES OF NUMEROUS MAMMALIAN GERIATRIC DISORDERS. ATROPHY IS THE LIKELY USUAL INITIAL EVENT, THE PROLIFERATIVE RESPONSE PERHAPS DEVELOPING AS A SECONDARY, COMPENSATORY, INITIALLY ADAPTIVE REACTION. WE HAVE LITTLE UNDERSTANDING OF WHY THIS PUTATIVE COMPENSATORY REACTION SO OFTEN FAILS TO BE APPROPRIATELY REGULATED IN AGEING MAMMALS, LEADING TO SUCH PATHOLOGIES AS CHRONIC INFLAMMATION, FIBROSIS, METAPLASIA AND NEOPLASIA. ADVANCES IN FORMAL GENETIC ANALYSIS, MUTAGENESIS, STEM CELL BIOLOGY AND EPIGENETICS ARE LIKELY TO PROVIDE MAJOR NEW UNDERSTANDING. STOCHASTIC EPIGENETIC SHIFTS IN GENE EXPRESSION ARE OF GROWING INTEREST, PARTICULARLY IN EXPLAINING INTRA-SPECIFIC VARIATIONS ON RATES AND PATTERNS OF AGEING. NATURE MAY WELL HAVE EVOLVED SUCH RANDOM FLUCTUATIONS IN GENE EXPRESSION AS A TYPE OF GROUP-SELECTIONIST ADAPTIVE STRATEGY TO COPE WITH DIVERSE STOCHASTIC ENVIRONMENTAL CHALLENGES. ALTERNATIVELY, SUCH BACKGROUND "NOISE" IN TRANSCRIPTION AND TRANSLATION MAY SIMPLY REFLECT A TYPE OF INFORMATIONAL ENTROPY. 2007