1 5015 106 PERSISTENCE OF SELF-REACTIVE CD8+ T CELLS IN THE CNS REQUIRES TOX-DEPENDENT CHROMATIN REMODELING. SELF-REACTIVE CD8(+) T CELLS ARE IMPORTANT MEDIATORS OF PROGRESSIVE TISSUE DAMAGE IN AUTOIMMUNE DISEASES, BUT THE MOLECULAR PROGRAM UNDERLYING THESE CELLS' FUNCTIONAL ADAPTATION IS UNCLEAR. HERE WE CHARACTERIZE THE TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPE OF SELF-REACTIVE CD8(+) T CELLS IN A MOUSE MODEL OF PROTRACTED CENTRAL NERVOUS SYSTEM (CNS) AUTOIMMUNITY AND COMPARE IT TO POPULATIONS OF CNS-RESIDENT MEMORY CD8(+) T CELLS EMERGING FROM ACUTE VIRAL INFECTION. WE FIND THAT AUTOIMMUNE CD8(+) T CELLS PERSISTING AT SITES OF SELF-ANTIGEN EXHIBIT CHARACTERISTIC TRANSCRIPTIONAL REGULATION TOGETHER WITH DISTINCT EPIGENETIC REMODELING. THIS SELF-REACTIVE CD8(+) T CELL FATE DEPENDS ON THE TRANSCRIPTIONAL REGULATION BY THE DNA-BINDING HMG-BOX PROTEIN TOX WHICH REMODELS MORE THAN 400 GENOMIC REGIONS INCLUDING LOCI SUCH AS TCF7, WHICH IS CENTRAL TO STEMNESS OF CD8(+) T CELLS. CONTINUOUS EXPOSURE TO CNS SELF-ANTIGEN SUSTAINS TOX LEVELS IN SELF-REACTIVE CD8(+) T CELLS, WHEREAS GENETIC ABLATION OF TOX IN CD8(+) T CELLS RESULTS IN SHORTENED PERSISTENCE OF SELF-REACTIVE CD8(+) T CELLS IN THE INFLAMED CNS. OUR STUDY ESTABLISHES AND CHARACTERIZES THE GENETIC DIFFERENTIATION PROGRAM ENABLING CHRONIC T CELL-DRIVEN IMMUNOPATHOLOGY IN CNS AUTOIMMUNITY. 2021 2 2421 40 EPIGENETIC SIGNATURE OF PD-1+ TCF1+ CD8 T CELLS THAT ACT AS RESOURCE CELLS DURING CHRONIC VIRAL INFECTION AND RESPOND TO PD-1 BLOCKADE. WE HAVE RECENTLY DEFINED A NOVEL POPULATION OF PD-1 (PROGRAMMED CELL DEATH 1)+ TCF1 (T CELL FACTOR 1)+ VIRUS-SPECIFIC CD8 T CELLS THAT FUNCTION AS RESOURCE CELLS DURING CHRONIC LCMV INFECTION AND PROVIDE THE PROLIFERATIVE BURST SEEN AFTER PD-1 BLOCKADE. SUCH CD8 T CELLS HAVE BEEN FOUND IN OTHER CHRONIC INFECTIONS AND ALSO IN CANCER IN MICE AND HUMANS. THESE CD8 T CELLS EXHIBIT STEM-LIKE PROPERTIES UNDERGOING SELF-RENEWAL AND ALSO DIFFERENTIATING INTO THE TERMINALLY EXHAUSTED CD8 T CELLS. HERE WE COMPARED THE EPIGENETIC SIGNATURE OF STEM-LIKE CD8 T CELLS WITH EXHAUSTED CD8 T CELLS. ATAC-SEQ ANALYSIS SHOWED THAT STEM-LIKE CD8 T CELLS HAD A UNIQUE SIGNATURE IMPLICATING ACTIVITY OF HMG (TCF) AND RHD (NF-KAPPAB) TRANSCRIPTION FACTOR FAMILY MEMBERS IN CONTRAST TO HIGHER ACCESSIBILITY TO ETS AND RUNX MOTIFS IN EXHAUSTED CD8 T CELLS. IN ADDITION, REGULATORY REGIONS OF THE TRANSCRIPTION FACTORS TCF7 AND ID3 WERE MORE ACCESSIBLE IN STEM-LIKE CELLS WHEREAS PRDM1 AND ID2 WERE MORE ACCESSIBLE IN EXHAUSTED CD8 T CELLS. WE ALSO COMPARED THE EPIGENETIC SIGNATURES OF THE 2 CD8 T CELL SUBSETS FROM CHRONICALLY INFECTED MICE WITH EFFECTOR AND MEMORY CD8 T CELLS GENERATED AFTER AN ACUTE LCMV INFECTION. BOTH CD8 T CELL SUBSETS GENERATED DURING CHRONIC INFECTION WERE STRIKINGLY DIFFERENT FROM CD8 T CELL SUBSETS FROM ACUTE INFECTION. INTERESTINGLY, THE STEM-LIKE CD8 T CELL SUBSET FROM CHRONIC INFECTION, DESPITE SHARING KEY FUNCTIONAL PROPERTIES WITH MEMORY CD8 T CELLS, HAD A VERY DISTINCT EPIGENETIC PROGRAM. THESE RESULTS SHOW THAT THE CHRONIC STEM-LIKE CD8 T CELL PROGRAM REPRESENTS A SPECIFIC ADAPTATION OF THE T CELL RESPONSE TO PERSISTENT ANTIGENIC STIMULATION. 2019 3 4838 27 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 4 1759 32 EARLY PRECURSOR T CELLS ESTABLISH AND PROPAGATE T CELL EXHAUSTION IN CHRONIC INFECTION. CD8(+) T CELLS RESPONDING TO CHRONIC INFECTIONS OR TUMORS ACQUIRE AN 'EXHAUSTED' STATE ASSOCIATED WITH ELEVATED EXPRESSION OF INHIBITORY RECEPTORS, INCLUDING PD-1, AND IMPAIRED CYTOKINE PRODUCTION. EXHAUSTED T CELLS ARE CONTINUOUSLY REPLENISHED BY T CELLS WITH PRECURSOR CHARACTERISTICS THAT SELF-RENEW AND DEPEND ON THE TRANSCRIPTION FACTOR TCF1; HOWEVER, THEIR DEVELOPMENTAL REQUIREMENTS ARE POORLY UNDERSTOOD. IN THE PRESENT STUDY, WE DEMONSTRATE THAT HIGH ANTIGEN LOAD PROMOTED THE DIFFERENTIATION OF PRECURSOR T CELLS, WHICH ACQUIRED HALLMARKS OF EXHAUSTION WITHIN DAYS OF INFECTION, WHEREAS EARLY EFFECTOR CELLS RETAINED POLYFUNCTIONAL FEATURES. EARLY PRECURSOR T CELLS SHOWED EPIGENETIC IMPRINTING CHARACTERISTIC OF T CELL RECEPTOR-DEPENDENT TRANSCRIPTION FACTOR BINDING AND WERE RESTRICTED TO THE GENERATION OF CELLS DISPLAYING EXHAUSTION CHARACTERISTICS. TRANSCRIPTION FACTORS BACH2 AND BATF WERE KEY REGULATORS WITH OPPOSING FUNCTIONS IN THE GENERATION OF EARLY PRECURSOR T CELLS. OVERALL, WE DEMONSTRATE THAT EXHAUSTION MANIFESTS FIRST IN TCF1(+) PRECURSOR T CELLS AND IS PROPAGATED SUBSEQUENTLY TO THE POOL OF ANTIGEN-SPECIFIC T CELLS. 2020 5 953 23 CHRONIC MYELOID LEUKEMIA STEM CELLS. ALTHOUGH RARE, CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS AN IMPORTANT PARADIGM FOR UNDERSTANDING THE MOLECULAR EVENTS LEADING TO MALIGNANT TRANSFORMATION OF PRIMITIVE HEMATOPOIETIC PROGENITORS. CML WAS THE FIRST CANCER TO BE ASSOCIATED WITH A DEFINED GENETIC ABNORMALITY, BCR-ABL, THAT IS NECESSARY AND SUFFICIENT FOR INITIATING CHRONIC PHASE DISEASE AS WELL AS THE FIRST CANCER TO BE TREATED WITH MOLECULAR TARGETED THERAPY. MALIGNANT PROGENITORS OR LEUKEMIA STEM CELLS (LSCS) EVOLVE AS A RESULT OF BOTH EPIGENETIC AND GENETIC EVENTS THAT ALTER HEMATOPOIETIC PROGENITOR DIFFERENTIATION, PROLIFERATION, SURVIVAL, AND SELF-RENEWAL. LSCS ARE RARE AND DIVIDE LESS FREQUENTLY, AND THUS, REPRESENT A RESERVOIR FOR RELAPSE AND RESISTANCE TO A MOLECULARLY TARGETED SINGLE AGENT. ON SUBVERTING DEVELOPMENTAL PROCESSES NORMALLY RESPONSIBLE FOR MAINTAINING ROBUST LIFE-LONG HEMATOPOIESIS, THE LSCS ARE ABLE TO EVADE THE MAJORITY OF CURRENT CANCER TREATMENTS THAT TARGET RAPIDLY DIVIDING CELLS. ENTHUSIASM FOR THE ENORMOUS SUCCESS OF TYROSINE KINASE INHIBITORS AT CONTROLLING THE CHRONIC PHASE DISEASE IS TEMPERED SOMEWHAT BY THE PERSISTENCE OF THE LSC POOL IN THE MAJORITY OF THE PATIENTS. COMBINED THERAPIES TARGETING ABERRANT PROPERTIES OF LSC MAY OBVIATE THERAPEUTIC RESISTANCE AND RELAPSE IN ADVANCED PHASE AND THERAPEUTICALLY RECALCITRANT CML. 2008 6 559 32 BACH2 ENFORCES THE TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS OF STEM-LIKE CD8(+) T CELLS. DURING CHRONIC INFECTION AND CANCER, A SELF-RENEWING CD8(+) T CELL SUBSET MAINTAINS LONG-TERM IMMUNITY AND IS CRITICAL TO THE EFFECTIVENESS OF IMMUNOTHERAPY. THESE STEM-LIKE CD8(+) T CELLS DIVERGE FROM OTHER CD8(+) SUBSETS EARLY AFTER CHRONIC VIRAL INFECTION. HOWEVER, PATHWAYS GUARDING STEM-LIKE CD8(+) T CELLS AGAINST TERMINAL EXHAUSTION REMAIN UNCLEAR. HERE, WE SHOW THAT THE GENE ENCODING TRANSCRIPTIONAL REPRESSOR BACH2 IS TRANSCRIPTIONALLY AND EPIGENETICALLY ACTIVE IN STEM-LIKE CD8(+) T CELLS BUT NOT TERMINALLY EXHAUSTED CELLS EARLY AFTER INFECTION. BACH2 OVEREXPRESSION ENFORCED STEM-LIKE CELL FATE, WHEREAS BACH2 DEFICIENCY IMPAIRED STEM-LIKE CD8(+) T CELL DIFFERENTIATION. SINGLE-CELL TRANSCRIPTOMIC AND EPIGENOMIC APPROACHES REVEALED THAT BACH2 ESTABLISHED THE TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS OF STEM-LIKE CD8(+) T CELLS. IN ADDITION, BACH2 SUPPRESSED THE MOLECULAR PROGRAM DRIVING TERMINAL EXHAUSTION THROUGH TRANSCRIPTIONAL REPRESSION AND EPIGENETIC SILENCING. THUS, OUR STUDY REVEALS A NEW PATHWAY THAT ENFORCES COMMITMENT TO STEM-LIKE CD8(+) LINEAGE AND PREVENTS AN ALTERNATIVE TERMINALLY EXHAUSTED CELL FATE. 2021 7 952 29 CHRONIC MYELOID LEUKEMIA STEM CELL BIOLOGY. LEUKEMIA PROGRESSION AND RELAPSE IS FUELED BY LEUKEMIA STEM CELLS (LSC) THAT ARE RESISTANT TO CURRENT TREATMENTS. IN THE PROGRESSION OF CHRONIC MYELOID LEUKEMIA (CML), BLAST CRISIS PROGENITORS ARE CAPABLE OF ADOPTING MORE PRIMITIVE BUT DEREGULATED STEM CELL FEATURES WITH ACQUIRED RESISTANCE TO TARGETED THERAPIES. THIS IN TURN PROMOTES LSC BEHAVIOR CHARACTERIZED BY ABERRANT SELF-RENEWAL, DIFFERENTIATION, AND SURVIVAL CAPACITY. MULTIPLE REPORTS SUGGEST THAT CELL CYCLE ALTERATIONS, ACTIVATION OF CRITICAL SIGNALING PATHWAYS, ABERRANT MICROENVIRONMENTAL CUES FROM THE HEMATOPOIETIC NICHE, AND ABERRANT EPIGENETIC EVENTS AND DEREGULATION OF RNA PROCESSING MAY FACILITATE THE ENHANCED SURVIVAL AND MALIGNANT TRANSFORMATION OF CML PROGENITORS. HERE WE REVIEW THE MOLECULAR EVOLUTION OF CML LSC THAT PROMOTES CML PROGRESSION AND RELAPSE. RECENT ADVANCES IN THESE AREAS HAVE IDENTIFIED NOVEL TARGETS THAT REPRESENT IMPORTANT AVENUES FOR FUTURE THERAPEUTIC APPROACHES AIMED AT SELECTIVELY ERADICATING THE LSC POPULATION WHILE SPARING NORMAL HEMATOPOIETIC PROGENITORS IN PATIENTS SUFFERING FROM CHRONIC MYELOID MALIGNANCIES. 2012 8 5704 37 SINGLE-CELL RNA-SEQ REVEALS TOX AS A KEY REGULATOR OF CD8(+) T CELL PERSISTENCE IN CHRONIC INFECTION. PROGENITOR-LIKE CD8(+) T CELLS MEDIATE LONG-TERM IMMUNITY TO CHRONIC INFECTION AND CANCER AND RESPOND POTENTLY TO IMMUNE CHECKPOINT BLOCKADE. THESE CELLS SHARE TRANSCRIPTIONAL REGULATORS WITH MEMORY PRECURSOR CELLS, INCLUDING T CELL-SPECIFIC TRANSCRIPTION FACTOR 1 (TCF1), BUT IT IS UNCLEAR WHETHER THEY ADOPT DISTINCT PROGRAMS TO ADAPT TO THE IMMUNOSUPPRESSIVE ENVIRONMENT. BY COMPARING THE SINGLE-CELL TRANSCRIPTOMES AND EPIGENETIC PROFILES OF CD8(+) T CELLS RESPONDING TO ACUTE AND CHRONIC VIRAL INFECTIONS, WE FOUND THAT PROGENITOR-LIKE CD8(+) T CELLS BECAME DISTINCT FROM MEMORY PRECURSOR CELLS BEFORE THE PEAK OF THE T CELL RESPONSE. WE DISCOVERED A COEXPRESSION GENE MODULE CONTAINING TOX THAT EXHIBITED HIGHER TRANSCRIPTIONAL ACTIVITY ASSOCIATED WITH MORE ABUNDANT ACTIVE HISTONE MARKS IN PROGENITOR-LIKE CELLS THAN MEMORY PRECURSOR CELLS. MOREOVER, THYMOCYTE SELECTION-ASSOCIATED HIGH MOBILITY GROUP BOX PROTEIN TOX (TOX) PROMOTED THE PERSISTENCE OF ANTIVIRAL CD8(+) T CELLS AND WAS REQUIRED FOR THE PROGRAMMING OF PROGENITOR-LIKE CD8(+) T CELLS. THUS, LONG-TERM CD8(+) T CELL IMMUNITY TO CHRONIC VIRAL INFECTION REQUIRES UNIQUE TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS ASSOCIATED WITH THE TRANSCRIPTION FACTOR TOX. 2019 9 5965 27 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 10 5212 22 PRESERVATION OF QUIESCENT CHRONIC MYELOGENOUS LEUKEMIA STEM CELLS BY THE BONE MARROW MICROENVIRONMENT. THE MAJORITY OF LEUKEMIA PATIENTS ACHIEVING REMISSION ULTIMATELY RELAPSE. PERSISTENCE OF LEUKEMIA STEM CELLS (LSC) CAPABLE OF REGENERATING LEUKEMIA IS A MAJOR CAUSE OF RELAPSE. THERE IS A PRESSING NEED TO BETTER UNDERSTAND MECHANISMS OF LSC REGULATION AND THEIR RESISTANCE TO THERAPY IN ORDER TO IMPROVE OUTCOMES FOR LEUKEMIA. CHRONIC MYELOGENOUS LEUKEMIA (CML) IS A LETHAL MYELOPROLIFERATIVE DISORDER THAT THAT IS CAUSED BY HEMATOPOIETIC STEM CELL (HSC) TRANSFORMATION BY THE BCR-ABL TYROSINE KINASE. TREATMENT WITH TYROSINE KINASE INHIBITORS (TKI) HAS REVOLUTIONIZED CML TREATMENT, BUT FAILS TO ELIMINATE LSC RESPONSIBLE FOR PROPAGATING AND REGENERATING LEUKEMIA. THEREFORE, PATIENTS REQUIRE CONTINUED TREATMENT TO PREVENT RELAPSE. LEUKEMIC AND NORMAL STEM CELLS SHARE PROPERTIES OF QUIESCENCE AND SELF-RENEWAL, THAT ARE SUPPORTED BY BONE MARROW NICHES. PERSISTENCE OF LSC AFTER TKI TREATMENT IS RELATED TO TYROSINE KINASE INDEPENDENT MECHANISMS WHICH INCLUDE INTRINSIC PROPERTIES OF LSCS DETERMINED BY EPIGENETIC ALTERATIONS, ALTERED TRANSCRIPTIONAL REGULATORY NETWORKS OR MITOCHONDRIAL/METABOLIC CHANGES. IN ADDITION TO CELL INTRINSIC CHANGES, SIGNALS FROM THE BONE MARROW MICROENVIRONMENT (BMM) PLAY A CRITICAL ROLE IN PROTECTING LSC FROM TKI TREATMENT. EACH TYPE OF ALTERATION MAY OFFER POTENTIAL POINTS OF INTERVENTION FOR THERAPEUTIC TARGETING OF LSC. 2018 11 1306 37 DEFINING 'T CELL EXHAUSTION'. 'T CELL EXHAUSTION' IS A BROAD TERM THAT HAS BEEN USED TO DESCRIBE THE RESPONSE OF T CELLS TO CHRONIC ANTIGEN STIMULATION, FIRST IN THE SETTING OF CHRONIC VIRAL INFECTION BUT MORE RECENTLY IN RESPONSE TO TUMOURS. UNDERSTANDING THE FEATURES OF AND PATHWAYS TO EXHAUSTION HAS CRUCIAL IMPLICATIONS FOR THE SUCCESS OF CHECKPOINT BLOCKADE AND ADOPTIVE T CELL TRANSFER THERAPIES. IN THIS VIEWPOINT ARTICLE, 18 EXPERTS IN THE FIELD TELL US WHAT EXHAUSTION MEANS TO THEM, RANGING FROM COMPLETE LACK OF EFFECTOR FUNCTION TO ALTERED FUNCTIONALITY TO PREVENT IMMUNOPATHOLOGY, WITH POTENTIAL DIFFERENCES BETWEEN CANCER AND CHRONIC INFECTION. THEIR RESPONSES HIGHLIGHT THE DICHOTOMY BETWEEN TERMINALLY DIFFERENTIATED EXHAUSTED T CELLS THAT ARE TCF1(-) AND THE SELF-RENEWING TCF1(+) POPULATION FROM WHICH THEY DERIVE. THESE TCF1(+) CELLS ARE CONSIDERED BY SOME TO HAVE STEM CELL-LIKE PROPERTIES AKIN TO MEMORY T CELL POPULATIONS, BUT THE DEVELOPMENTAL RELATIONSHIPS ARE UNCLEAR AT PRESENT. RECENT STUDIES HAVE ALSO HIGHLIGHTED AN IMPORTANT ROLE FOR THE TRANSCRIPTIONAL REGULATOR TOX IN DRIVING THE EPIGENETIC ENFORCEMENT OF EXHAUSTION, BUT KEY QUESTIONS REMAIN ABOUT THE POTENTIAL TO REVERSE THE EPIGENETIC PROGRAMME OF EXHAUSTION AND HOW THIS MIGHT AFFECT THE PERSISTENCE OF T CELL POPULATIONS. 2019 12 1379 29 DEVELOPMENTAL RELATIONSHIPS OF FOUR EXHAUSTED CD8(+) T CELL SUBSETS REVEALS UNDERLYING TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPE CONTROL MECHANISMS. CD8(+) T CELL EXHAUSTION IS A MAJOR BARRIER TO CURRENT ANTI-CANCER IMMUNOTHERAPIES. DESPITE THIS, THE DEVELOPMENTAL BIOLOGY OF EXHAUSTED CD8(+) T CELLS (TEX) REMAINS POORLY DEFINED, RESTRAINING IMPROVEMENT OF STRATEGIES AIMED AT "RE-INVIGORATING" TEX CELLS. HERE, WE DEFINED A FOUR-CELL-STAGE DEVELOPMENTAL FRAMEWORK FOR TEX CELLS. TWO TCF1(+) PROGENITOR SUBSETS WERE IDENTIFIED, ONE TISSUE RESTRICTED AND QUIESCENT AND ONE MORE BLOOD ACCESSIBLE, THAT GRADUALLY LOST TCF1 AS IT DIVIDED AND CONVERTED TO A THIRD INTERMEDIATE TEX SUBSET. THIS INTERMEDIATE SUBSET RE-ENGAGED SOME EFFECTOR BIOLOGY AND INCREASED UPON PD-L1 BLOCKADE BUT ULTIMATELY CONVERTED INTO A FOURTH, TERMINALLY EXHAUSTED SUBSET. BY USING TRANSCRIPTIONAL AND EPIGENETIC ANALYSES, WE IDENTIFIED THE CONTROL MECHANISMS UNDERLYING SUBSET TRANSITIONS AND DEFINED A KEY INTERPLAY BETWEEN TCF1, T-BET, AND TOX IN THE PROCESS. THESE DATA REVEAL A FOUR-STAGE DEVELOPMENTAL HIERARCHY FOR TEX CELLS AND DEFINE THE MOLECULAR, TRANSCRIPTIONAL, AND EPIGENETIC MECHANISMS THAT COULD PROVIDE OPPORTUNITIES TO IMPROVE CANCER IMMUNOTHERAPY. 2020 13 737 30 CANCER STEM CELLS. THERE IS AN INCREASING EVIDENCE SUPPORTING THE CANCER STEM CELL HYPOTHESIS. NORMAL STEM CELLS IN THE ADULT ORGANISM ARE RESPONSIBLE FOR TISSUE RENEWAL AND REPAIR OF AGED OR DAMAGED TISSUE. A SUBSTANTIAL CHARACTERISTIC OF STEM CELLS IS THEIR ABILITY FOR SELF-RENEWAL WITHOUT LOSS OF PROLIFERATION CAPACITY WITH EACH CELL DIVISION. THE STEM CELLS ARE IMMORTAL, AND RATHER RESISTANT TO ACTION OF DRUGS. THEY ARE ABLE TO DIFFERENTIATE AND FORM SPECIFIC TYPES OF TISSUE DUE TO THE INFLUENCE OF MICROENVIRONMENTAL AND SOME OTHER FACTORS. STEM CELLS DIVIDE ASYMMETRICALLY PRODUCING TWO DAUGHTER CELLS -- ONE IS A NEW STEM CELL AND THE SECOND IS PROGENITOR CELL, WHICH HAS THE ABILITY FOR DIFFERENTIATION AND PROLIFERATION, BUT NOT THE CAPABILITY FOR SELF-RENEWAL. CANCER STEM CELLS ARE IN MANY ASPECTS SIMILAR TO THE STEM CELLS. IT HAS BEEN PROVEN THAT TUMOR CELLS ARE HETEROGENEOUS COMPRISING RARE TUMOR INITIATING CELLS AND ABUNDANT NON-TUMOR INITIATING CELLS. TUMOR INITIATING CELLS -- CANCER STEM CELLS HAVE THE ABILITY OF SELF-RENEWAL AND PROLIFERATION, ARE RESISTANT TO DRUGS, AND EXPRESS TYPICAL MARKERS OF STEM CELLS. IT IS NOT CLEAR WHETHER CANCER STEM CELLS ORIGINATE FROM NORMAL STEM CELLS IN CONSEQUENCE OF GENETIC AND EPIGENETIC CHANGES AND/OR BY REDIFFERENTIATION FROM SOMATIC TUMOR CELLS TO THE STEM-LIKE CELLS. PROBABLY BOTH MECHANISMS ARE INVOLVED IN THE ORIGIN OF CANCER STEM CELLS. DYSREGULATION OF STEM CELL SELF-RENEWAL IS A LIKELY REQUIREMENT FOR THE DEVELOPMENT OF CANCER. ISOLATION AND IDENTIFICATION OF CANCER STEM CELLS IN HUMAN TUMORS AND IN TUMOR CELL LINES HAS BEEN SUCCESSFUL. TO DATE, THE EXISTENCE OF CANCER STEM CELLS HAS BEEN PROVEN IN ACUTE AND CHRONIC MYELOID LEUKEMIA, IN BREAST CANCER, IN BRAIN TUMORS, IN LUNG CANCER AND GASTROINTESTINAL TUMORS. CANCER STEM CELL MODEL IS ALSO CONSISTENT WITH SOME CLINICAL OBSERVATIONS. ALTHOUGH STANDARD CHEMOTHERAPY KILLS MOST CELLS IN A TUMOR, CANCER STEM CELLS REMAIN VIABLE. DESPITE THE SMALL NUMBER OF SUCH CELLS, THEY MIGHT BE THE CAUSE OF TUMOR RECURRENCE, SOMETIMES MANY YEARS AFTER THE "SUCCESSFUL" TREATMENT OF PRIMARY TUMOR. GROWTH OF METASTASES IN DISTINCT AREAS OF BODY AND THEIR CELLULAR HETEROGENEITY MIGHT BE CONSEQUENCE OF CANCER STEM CELL DIFFERENTIATION AND/OR DEDIFFERENTIATION AND ASYMMETRIC DIVISION OF CANCER STEM CELLS. FURTHER CHARACTERIZATION OF CANCER STEM CELLS IS NEEDED IN ORDER TO FIND WAYS TO DESTROY THEM, WHICH MIGHT CONTRIBUTE SIGNIFICANTLY TO THE THERAPEUTIC MANAGEMENT OF MALIGNANT TUMORS. 2005 14 6319 40 THE ROAD LESS TAKEN: LESS APPRECIATED PATHWAYS FOR MANIPULATING CD8(+) T CELL EXHAUSTION. EXHAUSTED CD8(+) T (TEX) CELLS ARE A DISTINCT CELL POPULATION THAT ARISE DURING PERSISTENT ANTIGEN EXPOSURE IN THE CONTEXT OF CHRONIC INFECTIONS AND CANCERS. ALTHOUGH CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS, HIGH AND SUSTAINED INHIBITORY RECEPTOR EXPRESSION AND DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS, TEX CELLS ARE HETEROGENEOUS. AMONG THESE, A SELF-RENEWING TCF-1(+) TEX POPULATION, HAVING UNIQUE CHARACTERISTICS AND THE ABILITY TO RESPOND TO IMMUNE-CHECKPOINT BLOCKADE, GIVES RISE TO TCF-1(-) TERMINALLY TEX CELLS. THESE TCF-1(+) CELLS HAVE STEM CELL-LIKE PROPERTIES SIMILAR TO MEMORY T CELL POPULATIONS, BUT THE SIGNALS THAT REGULATE THE DEVELOPMENTAL PATHWAYS AND RELATIONSHIPS AMONG EXHAUSTED CELL POPULATIONS ARE STILL UNCLEAR. HERE, WE REVIEW OUR CURRENT UNDERSTANDING OF TEX CELL BIOLOGY, AND DISCUSS SOME LESS APPRECIATED MOLECULES AND PATHWAYS AFFECTING T CELL EXHAUSTION. WE HIGHLIGHT TWO CO-STIMULATORY RECEPTORS, CD226 AND CD137, AND THEIR ROLE IN INDUCING OR RESTRAINING T CELL EXHAUSTION, AS WELL AS SIGNALING PATHWAYS THAT MAY BE AMENABLE TO PHARMACOLOGICAL INHIBITION WITH A FOCUS ON PHOSPHOINOSITIDE-3 KINASE AND IL-2 PARTIAL AGONISTS. FINALLY, WE DISCUSS NOVEL METHODS THAT MAY INCREASE TCF-1(+) POPULATIONS AND THEREFORE IMPROVE IMMUNOTHERAPY RESPONSIVENESS. UNDERSTANDING FEATURES OF AND PATHWAYS TO EXHAUSTION HAS IMPORTANT IMPLICATIONS FOR THE SUCCESS OF IMMUNOTHERAPY, INCLUDING CHECKPOINT BLOCKADE AND ADOPTIVE T-CELL TRANSFER THERAPIES. 2022 15 5050 30 PHARMACOLOGICAL MIMICKING OF CALORIC RESTRICTION ELICITS EPIGENETIC REPROGRAMMING OF DIFFERENTIATED CELLS TO STEM-LIKE SELF-RENEWAL STATES. NETWORKS OF ONCOGENES AND TUMOR SUPPRESSOR GENES THAT CONTROL CANCER CELL PROLIFERATION ALSO REGULATE STEM CELL RENEWAL AND POSSIBLY STEM CELL AGING. BECAUSE (DE)DIFFERENTIATION PROCESSES MIGHT DICTATE TUMOR CELLS TO RETROGRESS TO A MORE STEM-LIKE STATE IN RESPONSE TO AGING-RELEVANT EPIGENETIC AND/OR ENVIRONMENTAL PLAYERS, WE RECENTLY ENVISIONED THAT CULTURED HUMAN CANCER CELLS MIGHT BE USED AS RELIABLE MODELS TO TEST THE ABILITY OF ANTIAGING INTERVENTIONS FOR PROMOTING THE INITIATION AND MAINTENANCE OF SELF-RENEWING DIVISIONS. CANCER CELL LINES NATURALLY BEARING UNDETECTABLE AMOUNTS OF STEM/PROGENITOR-LIKE CELL POPULATIONS WERE CONTINUOUSLY CULTURED IN THE PRESENCE OF THE CALORIC RESTRICTION MIMETIC METFORMIN FOR SEVERAL MONTHS. MICROARRAY TECHNOLOGY WAS EMPLOYED TO PROFILE EXPRESSION OF GENES RELATED TO THE IDENTIFICATION, GROWTH, AND DIFFERENTIATION OF STEM CELLS. DETECTION OF FUNCTIONALLY RELATED GENE GROUPS USING A PATHWAY ANALYSIS PACKAGE PROVIDED ANNOTATED GENETIC SIGNATURES OVER- AND UNDEREXPRESSED IN RESPONSE TO PHARMACOLOGICAL MIMICKING OF CALORIC RESTRICTION. BY FOLLOWING THIS METHODOLOGICAL APPROACH, WE RECENTLY OBTAINED DATA FITTING A MODEL IN WHICH, IN RESPONSE TO CHRONIC IMPAIRMENT OF CELLULAR BIOENERGETICS IMPOSED BY METFORMIN-INDUCED MITOCHONDRIAL UNCOUPLING AS ASSESSED BY THE PHOSPHORYLATION STATE OF CAMP-RESPONSE ELEMENT BINDING PROTEIN (CREB), TUMOR CELLS CAN RETROGRESS FROM A DIFFERENTIATED STATE TO A MORE CD44(+) STEM-LIKE PRIMITIVE STATE EPIGENETICALLY GOVERNED BY THE POLYCOMB-GROUP SUPPRESSOR BMI1-A CRUCIAL "STEMNESS" GENE INVOLVED IN THE EPIGENETIC MAINTENANCE OF ADULT STEM CELLS. THESE FINDINGS MIGHT PROVIDE A NOVEL MOLECULAR AVENUE TO INVESTIGATE IF ANTIAGING BENEFITS FROM CALORIC RESTRICTION MIMETICS MIGHT RELATE TO THEIR ABILITY TO EPIGENETICALLY REPROGRAM STEMNESS WHILE PROLONGING THE CAPACITY OF STEM-LIKE CELL STATES TO PROLIFERATE, DIFFERENTIATE, AND REPLACE MATURE CELLS IN ADULT AGING TISSUES. 2010 16 5405 28 REGULATED EXPRESSION OF P210 BCR-ABL DURING EMBRYONIC STEM CELL DIFFERENTIATION STIMULATES MULTIPOTENTIAL PROGENITOR EXPANSION AND MYELOID CELL FATE. P210 BCR-ABL IS AN ACTIVATED TYROSINE KINASE ONCOGENE ENCODED BY THE PHILADELPHIA CHROMOSOME ASSOCIATED WITH HUMAN CHRONIC MYELOGENOUS LEUKEMIA (CML). THE DISEASE REPRESENTS A CLONAL DISORDER ARISING IN THE PLURIPOTENT HEMATOPOIETIC STEM CELL. DURING THE CHRONIC PHASE, PATIENTS PRESENT WITH A DRAMATIC EXPANSION OF MYELOID CELLS AND A MILD ANEMIA. RETROVIRAL GENE TRANSFER AND TRANSGENIC EXPRESSION IN RODENTS HAVE DEMONSTRATED THE ABILITY OF BCR-ABL TO INDUCE VARIOUS TYPES OF LEUKEMIA. HOWEVER, STUDY OF HUMAN CML OR RODENT MODELS HAS NOT DETERMINED THE DIRECT AND IMMEDIATE EFFECTS OF BCR-ABL ON HEMATOPOIETIC CELLS FROM THOSE REQUIRING SECONDARY GENETIC OR EPIGENETIC CHANGES SELECTED DURING THE PATHOGENIC PROCESS. WE UTILIZED TETRACYCLINE-REGULATED EXPRESSION OF BCR-ABL FROM A PROMOTER ENGINEERED FOR ROBUST EXPRESSION IN PRIMITIVE STEM CELLS THROUGH MULTILINEAGE BLOOD CELL DEVELOPMENT IN COMBINATION WITH THE IN VITRO DIFFERENTIATION OF EMBRYONAL STEM CELLS INTO HEMATOPOIETIC ELEMENTS. OUR RESULTS DEMONSTRATE THAT BCR-ABL EXPRESSION ALONE IS SUFFICIENT TO INCREASE THE NUMBER OF MULTIPOTENT AND MYELOID LINEAGE COMMITTED PROGENITORS IN A DOSE-DEPENDENT MANNER WHILE SUPPRESSING THE DEVELOPMENT OF COMMITTED ERYTHROID PROGENITORS. THESE EFFECTS ARE REVERSIBLE UPON EXTINGUISHING BCR-ABL EXPRESSION. THESE FINDINGS ARE CONSISTENT WITH BCR-ABL BEING THE SOLE GENETIC CHANGE NEEDED FOR THE ESTABLISHMENT OF THE CHRONIC PHASE OF CML AND PROVIDE A POWERFUL SYSTEM FOR THE ANALYSIS OF ANY GENETIC CHANGE THAT ALTERS CELL GROWTH AND LINEAGE CHOICES OF THE HEMATOPOIETIC STEM CELL. 2000 17 5620 41 SCHRODINGER'S T CELLS: MOLECULAR INSIGHTS INTO STEMNESS AND EXHAUSTION. T CELL STEMNESS AND EXHAUSTION COEXIST AS TWO KEY CONTRASTING PHENOMENA DURING CHRONIC ANTIGEN STIMULATION, SUCH AS INFECTION, TRANSPLANT, CANCER, AND AUTOIMMUNITY. T CELL EXHAUSTION REFERS TO THE PROGRESSIVE LOSS OF EFFECTOR FUNCTION CAUSED BY CHRONIC ANTIGEN EXPOSURE. EXHAUSTED T (T(EX)) CELLS HIGHLY EXPRESS MULTIPLE INHIBITORY RECEPTORS AND EXHIBIT SEVERE DEFECTS IN CELL PROLIFERATION AND CYTOKINE PRODUCTION. THE TERM T CELL STEMNESS DESCRIBES THE STEM CELL-LIKE BEHAVIORS OF T CELLS, INCLUDING SELF-RENEWAL, MULTIPOTENCY, AND FUNCTIONAL PERSISTENCE. IT IS WELL ACCEPTED THAT NAIVE AND SOME MEMORY T CELL SUBSETS HAVE STEM CELL-LIKE PROPERTIES. WHEN INVESTIGATING THE EXHAUSTIVE DIFFERENTIATION OF T CELLS IN CHRONIC INFECTION AND CANCER, RECENT STUDIES HIGHLIGHTED THE STEMNESS OF "PRECURSORS OF EXHAUSTED" T (T(PEX)) CELLS PRIOR TO THEIR TERMINAL DIFFERENTIATION TO T(EX) CELLS. CLINICALLY SUCCESSFUL CHECKPOINT BLOCKADES FOR CANCER TREATMENT APPEAR TO INVIGORATE ANTITUMOR T(PEX) CELLS BUT NOT T(EX) CELLS. HERE WE DISCUSS THE TRANSCRIPTIONAL AND EPIGENETIC REGULATIONS OF T CELL STEMNESS AND EXHAUSTION, WITH A FOCUS ON HOW SYSTEMS IMMUNOLOGY WAS AND WILL BE UTILIZED TO DEFINE THE MOLECULAR BASIS UNDERLYING THE TRANSITION OF T(PEX) TO T(EX) CELLS. WE SUGGEST A "STEPWISE MODEL" OF T CELL STEMNESS AND EXHAUSTION, IN WHICH LOSS OF STEMNESS AND EXHAUSTION PROGRESSION ARE GRADUAL MULTI-STEP PROCESSES. WE PROVIDE PERSPECTIVES ON THE RESEARCH NEEDED TO DEFINE T CELL STEMNESS AND EXHAUSTION IN THE TRANSPLANTATION SETTING, IN WHICH ALLOGENIC T CELLS ARE ALSO CHRONICALLY EXPOSED TO ALLOANTIGENS. A BETTER UNDERSTANDING OF T CELL STEMNESS AND EXHAUSTION WILL SHED LIGHT ON DEVELOPING NOVEL STRATEGIES FOR IMMUNOTHERAPIES. 2021 18 2878 42 FUNCTIONAL T CELLS ARE CAPABLE OF SUPERNUMERARY CELL DIVISION AND LONGEVITY. DIFFERENTIATED SOMATIC MAMMALIAN CELLS PUTATIVELY EXHIBIT SPECIES-SPECIFIC DIVISION LIMITS THAT IMPEDE CANCER BUT MAY CONSTRAIN LIFESPANS(1-3). TO PROVIDE IMMUNITY, TRANSIENTLY STIMULATED CD8(+) T CELLS UNDERGO UNUSUALLY RAPID BURSTS OF NUMEROUS CELL DIVISIONS, AND THEN FORM QUIESCENT LONG-LIVED MEMORY CELLS THAT REMAIN POISED TO REPROLIFERATE FOLLOWING SUBSEQUENT IMMUNOLOGICAL CHALLENGES. HERE WE ADDRESSED WHETHER T CELLS ARE INTRINSICALLY CONSTRAINED BY CHRONOLOGICAL OR CELL-DIVISION LIMITS. WE ACTIVATED MOUSE T CELLS IN VIVO USING ACUTE HETEROLOGOUS PRIME-BOOST-BOOST VACCINATIONS(4), TRANSFERRED EXPANDED CELLS TO NEW MICE, AND THEN REPEATED THIS PROCESS ITERATIVELY. OVER 10 YEARS (GREATLY EXCEEDING THE MOUSE LIFESPAN)(5) AND 51 SUCCESSIVE IMMUNIZATIONS, T CELLS REMAINED COMPETENT TO RESPOND TO VACCINATION. CELLS REQUIRED SUFFICIENT REST BETWEEN STIMULATION EVENTS. DESPITE DEMONSTRATING THE POTENTIAL TO EXPAND THE STARTING POPULATION AT LEAST 10(40)-FOLD, CELLS DID NOT SHOW LOSS OF PROLIFERATION CONTROL AND RESULTS WERE NOT DUE TO CONTAMINATION WITH YOUNG CELLS. PERSISTENT STIMULATION BY CHRONIC INFECTIONS OR CANCER CAN CAUSE T CELL PROLIFERATIVE SENESCENCE, FUNCTIONAL EXHAUSTION AND DEATH(6). WE FOUND THAT ALTHOUGH ITERATIVE ACUTE STIMULATIONS ALSO INDUCED SUSTAINED EXPRESSION AND EPIGENETIC REMODELLING OF COMMON EXHAUSTION MARKERS (INCLUDING PD1, WHICH IS ALSO KNOWN AS PDCD1, AND TOX) IN THE CELLS, THEY COULD STILL PROLIFERATE, EXECUTE ANTIMICROBIAL FUNCTIONS AND FORM QUIESCENT MEMORY CELLS. THESE OBSERVATIONS PROVIDE A MODEL TO BETTER UNDERSTAND MEMORY CELL DIFFERENTIATION, EXHAUSTION, CANCER AND AGEING, AND SHOW THAT FUNCTIONALLY COMPETENT T CELLS CAN RETAIN THE POTENTIAL FOR EXTRAORDINARY POPULATION EXPANSION AND LONGEVITY WELL BEYOND THEIR ORGANISMAL LIFESPAN. 2023 19 1142 28 CONCISE REVIEW: CHRONIC MYELOID LEUKEMIA: STEM CELL NICHE AND RESPONSE TO PHARMACOLOGIC TREATMENT. NOWADAYS, MORE THAN 90% OF PATIENTS AFFECTED BY CHRONIC MYELOID LEUKEMIA (CML) SURVIVE WITH A GOOD QUALITY OF LIFE, THANKS TO THE CLINICAL EFFICACY OF TYROSINE KINASE INHIBITORS (TKIS). NEVERTHELESS, POINT MUTATIONS OF THE ABL1 POCKET OCCURRING DURING TREATMENT MAY REDUCE BINDING OF TKIS, BEING RESPONSIBLE OF ABOUT 20% OF CASES OF RESISTANCE AMONG CML PATIENTS. IN ADDITION, THE PRESENCE OF LEUKEMIC STEM CELLS (LSCS) REPRESENTS THE MOST IMPORTANT EVENT IN LEUKEMIA PROGRESSION RELATED TO TKI RESISTANCE. LSCS EXPRESS STEM CELL MARKERS, INCLUDING ACTIVE EFFLUX PUMPS AND GENETIC AND EPIGENETIC ALTERATIONS TOGETHER WITH DEREGULATED CELL SIGNALING PATHWAYS INVOLVED IN SELF-RENEWAL, SUCH AS WNT/BETA-CATENIN, NOTCH, AND HEDGEHOG. MOREOVER, THE INTERACTION WITH THE BONE MARROW MICROENVIRONMENT, ALSO KNOWN AS HEMATOPOIETIC NICHE, MAY INFLUENCE THE PHENOTYPE OF SURROUNDING CELLS, WHICH EVADE MECHANISMS CONTROLLING CELL PROLIFERATION AND ARE LESS SENSITIVE OR FRANKLY RESISTANT TO TKIS. THIS REVIEW FOCUSES ON THE ROLE OF LSCS AND STEM CELL NICHE IN RELATION TO RESPONSE TO PHARMACOLOGICAL TREATMENTS. A LITERATURE SEARCH FROM PUBMED DATABASE WAS PERFORMED UNTIL APRIL 30, 2017, AND IT HAS BEEN ANALYZED ACCORDING TO KEYWORDS SUCH AS CHRONIC MYELOID LEUKEMIA, STEM CELL, LEUKEMIC STEM CELLS, HEMATOPOIETIC NICHE, TYROSINE KINASE INHIBITORS, AND DRUG RESISTANCE. STEM CELLS TRANSLATIONAL MEDICINE 2018;7:305-314. 2018 20 769 36 CD8 T CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION AND CANCER. EXHAUSTED CD8 T (TEX) CELLS ARE A DISTINCT CELL LINEAGE THAT ARISE DURING CHRONIC INFECTIONS AND CANCERS IN ANIMAL MODELS AND HUMANS. TEX CELLS ARE CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS, HIGH AND SUSTAINED INHIBITORY RECEPTOR EXPRESSION, METABOLIC DYSREGULATION, POOR MEMORY RECALL AND HOMEOSTATIC SELF-RENEWAL, AND DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS. THE ABILITY TO REINVIGORATE TEX CELLS THROUGH INHIBITORY RECEPTOR BLOCKADE, SUCH AS ALPHAPD-1, HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF TARGETING THIS POPULATION. EMERGING INSIGHTS INTO THE MECHANISMS OF EXHAUSTION ARE INFORMING IMMUNOTHERAPIES FOR CANCER AND CHRONIC INFECTIONS. HOWEVER, LIKE OTHER IMMUNE CELLS, TEX CELLS ARE HETEROGENEOUS AND INCLUDE PROGENITOR AND TERMINAL SUBSETS WITH UNIQUE CHARACTERISTICS AND RESPONSES TO CHECKPOINT BLOCKADE. HERE, WE REVIEW OUR CURRENT UNDERSTANDING OF TEX CELL BIOLOGY, INCLUDING THE DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS CONTRIBUTING TO EXHAUSTION AND HOW THIS KNOWLEDGE MAY INFORM THERAPEUTIC TARGETING OF TEX CELLS IN CHRONIC INFECTIONS, AUTOIMMUNITY, AND CANCER. 2019