1 5965 116 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 2 3234 29 HEMATOPOIETIC AND CHRONIC MYELOID LEUKEMIA STEM CELLS: MULTI-STABILITY VERSUS LINEAGE RESTRICTION. THERE IS COMPELLING EVIDENCE TO SUPPORT THE VIEW THAT THE CELL-OF-ORIGIN FOR CHRONIC MYELOID LEUKEMIA IS A HEMATOPOIETIC STEM CELL. UNLIKE NORMAL HEMATOPOIETIC STEM CELLS, THE PROGENY OF THE LEUKEMIA STEM CELLS ARE PREDOMINANTLY NEUTROPHILS DURING THE DISEASE CHRONIC PHASE AND THERE IS A MILD ANEMIA. THE HALLMARK ONCOGENE FOR CHRONIC MYELOID LEUKEMIA IS THE BCR-ABLP210 FUSION GENE. VARIOUS STUDIES HAVE EXCLUDED A ROLE FOR BCR-ABLP210 EXPRESSION IN MAINTAINING THE POPULATION OF LEUKEMIA STEM CELLS. STUDIES OF BCR-ABLP210 EXPRESSION IN EMBRYONAL STEM CELLS THAT WERE DIFFERENTIATED INTO HEMATOPOIETIC STEM CELLS AND OF THE EXPRESSION IN TRANSGENIC MICE HAVE REVEALED THAT BCR-ABLP210 IS ABLE TO VEER HEMATOPOIETIC STEM AND PROGENITOR CELLS TOWARDS A MYELOID FATE. FOR THE TRANSGENIC MICE, GLOBAL CHANGES TO THE EPIGENETIC LANDSCAPE WERE OBSERVED. IN CHRONIC MYELOID LEUKEMIA, THE ABILITY OF THE LEUKEMIA STEM CELLS TO CHOOSE FROM THE MANY FATES THAT ARE AVAILABLE TO NORMAL HEMATOPOIETIC STEM CELLS APPEARS TO BE DEREGULATED BY BCR-ABLP210 AND CHANGES TO THE EPIGENOME ARE ALSO IMPORTANT. EVEN SO, WE STILL DO NOT HAVE A PRECISE PICTURE AS TO WHY NEUTROPHILS ARE ABUNDANTLY PRODUCED IN CHRONIC MYELOID LEUKEMIA. 2022 3 1283 26 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 4 2106 31 EPIGENETIC EVOLUTION AND LINEAGE HISTORIES OF CHRONIC LYMPHOCYTIC LEUKAEMIA. GENETIC AND EPIGENETIC INTRA-TUMORAL HETEROGENEITY COOPERATE TO SHAPE THE EVOLUTIONARY COURSE OF CANCER(1). CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS A HIGHLY INFORMATIVE MODEL FOR CANCER EVOLUTION AS IT UNDERGOES SUBSTANTIAL GENETIC DIVERSIFICATION AND EVOLUTION AFTER THERAPY(2,3). THE CLL EPIGENOME IS ALSO AN IMPORTANT DISEASE-DEFINING FEATURE(4,5), AND GROWING POPULATIONS OF CELLS IN CLL DIVERSIFY BY STOCHASTIC CHANGES IN DNA METHYLATION KNOWN AS EPIMUTATIONS(6). HOWEVER, PREVIOUS STUDIES USING BULK SEQUENCING METHODS TO ANALYSE THE PATTERNS OF DNA METHYLATION WERE UNABLE TO DETERMINE WHETHER EPIMUTATIONS AFFECT CLL POPULATIONS HOMOGENEOUSLY. HERE, TO MEASURE THE EPIMUTATION RATE AT SINGLE-CELL RESOLUTION, WE APPLIED MULTIPLEXED SINGLE-CELL REDUCED-REPRESENTATION BISULFITE SEQUENCING TO B CELLS FROM HEALTHY DONORS AND PATIENTS WITH CLL. WE OBSERVED THAT THE COMMON CLONAL ORIGIN OF CLL RESULTS IN A CONSISTENTLY INCREASED EPIMUTATION RATE, WITH LOW VARIABILITY IN THE CELL-TO-CELL EPIMUTATION RATE. BY CONTRAST, VARIABLE EPIMUTATION RATES ACROSS HEALTHY B CELLS REFLECT DIVERSE EVOLUTIONARY AGES ACROSS THE TRAJECTORY OF B CELL DIFFERENTIATION, CONSISTENT WITH EPIMUTATIONS SERVING AS A MOLECULAR CLOCK. HERITABLE EPIMUTATION INFORMATION ALLOWED US TO RECONSTRUCT LINEAGES AT HIGH-RESOLUTION WITH SINGLE-CELL DATA, AND TO APPLY THIS DIRECTLY TO PATIENT SAMPLES. THE CLL LINEAGE TREE SHAPE REVEALED EARLIER BRANCHING AND LONGER BRANCH LENGTHS THAN IN NORMAL B CELLS, REFLECTING RAPID DRIFT AFTER THE INITIAL MALIGNANT TRANSFORMATION AND A GREATER PROLIFERATIVE HISTORY. INTEGRATION OF SINGLE-CELL BISULFITE SEQUENCING ANALYSIS WITH SINGLE-CELL TRANSCRIPTOMES AND GENOTYPING CONFIRMED THAT GENETIC SUBCLONES MAPPED TO DISTINCT CLADES, AS INFERRED SOLELY ON THE BASIS OF EPIMUTATION INFORMATION. FINALLY, TO EXAMINE POTENTIAL LINEAGE BIASES DURING THERAPY, WE PROFILED SERIAL SAMPLES DURING IBRUTINIB-ASSOCIATED LYMPHOCYTOSIS, AND IDENTIFIED CLADES OF CELLS THAT WERE PREFERENTIALLY EXPELLED FROM THE LYMPH NODE AFTER TREATMENT, MARKED BY DISTINCT TRANSCRIPTIONAL PROFILES. THE SINGLE-CELL INTEGRATION OF GENETIC, EPIGENETIC AND TRANSCRIPTIONAL INFORMATION THUS CHARTS THE LINEAGE HISTORY OF CLL AND ITS EVOLUTION WITH THERAPY. 2019 5 2786 25 EZH2 RESTRICTS THE SMOOTH MUSCLE LINEAGE DURING MOUSE LUNG MESOTHELIAL DEVELOPMENT. DURING DEVELOPMENT, THE LUNG MESODERM GENERATES A VARIETY OF CELL LINEAGES, INCLUDING AIRWAY AND VASCULAR SMOOTH MUSCLE. EPIGENETIC CHANGES IN ADULT LUNG MESODERMAL LINEAGES ARE THOUGHT TO CONTRIBUTE TOWARDS DISEASES SUCH AS IDIOPATHIC PULMONARY FIBROSIS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ALTHOUGH THE FACTORS THAT REGULATE EARLY LUNG MESODERM DEVELOPMENT ARE UNKNOWN. WE SHOW IN MOUSE THAT THE PRC2 COMPONENT EZH2 IS REQUIRED TO RESTRICT SMOOTH MUSCLE DIFFERENTIATION IN THE DEVELOPING LUNG MESOTHELIUM. MESODERMAL LOSS OF EZH2 LEADS TO THE FORMATION OF ECTOPIC SMOOTH MUSCLE IN THE SUBMESOTHELIAL REGION OF THE DEVELOPING LUNG MESODERM. LOSS OF EZH2 SPECIFICALLY IN THE DEVELOPING MESOTHELIUM REVEALS A MESOTHELIAL CELL-AUTONOMOUS ROLE FOR EZH2 IN REPRESSION OF THE SMOOTH MUSCLE DIFFERENTIATION PROGRAM. LOSS OF EZH2 DEREPRESSES EXPRESSION OF MYOCARDIN AND TBX18, WHICH ARE IMPORTANT REGULATORS OF SMOOTH MUSCLE DIFFERENTIATION FROM THE MESOTHELIUM AND RELATED CELL LINEAGES. TOGETHER, THESE FINDINGS UNCOVER AN EZH2-DEPENDENT MECHANISM TO RESTRICT THE SMOOTH MUSCLE GENE EXPRESSION PROGRAM IN THE DEVELOPING MESOTHELIUM AND ALLOW APPROPRIATE CELL FATE DECISIONS TO OCCUR IN THIS MULTIPOTENT MESODERM LINEAGE. 2016 6 2069 22 EPIGENETIC CONTROL OF SKELETAL MUSCLE REGENERATION: INTEGRATING GENETIC DETERMINANTS AND ENVIRONMENTAL CHANGES. DURING EMBRYONIC DEVELOPMENT, PLURIPOTENT CELLS ARE GENETICALLY COMMITTED TO SPECIFIC LINEAGES BY THE EXPRESSION OF CELL-TYPE-SPECIFIC TRANSCRIPTIONAL ACTIVATORS THAT DIRECT THE FORMATION OF SPECIALIZED TISSUES AND ORGANS IN RESPONSE TO DEVELOPMENTAL CUES. CHROMATIN-MODIFYING PROTEINS ARE EMERGING AS ESSENTIAL COMPONENTS OF THE EPIGENETIC MACHINERY, WHICH ESTABLISHES THE NUCLEAR LANDSCAPE THAT ULTIMATELY DETERMINES THE FINAL IDENTITY AND FUNCTIONAL SPECIALIZATION OF ADULT CELLS. RECENT EVIDENCE HAS REVEALED THAT DISCRETE POPULATIONS OF ADULT CELLS CAN RETAIN THE ABILITY TO ADOPT ALTERNATIVE CELL FATES IN RESPONSE TO ENVIRONMENTAL CUES. THESE CELLS INCLUDE CONVENTIONAL ADULT STEM CELLS AND A STILL POORLY DEFINED COLLECTION OF CELL TYPES ENDOWED WITH FACULTATIVE PHENOTYPE AND FUNCTIONAL PLASTICITY. UNDER PHYSIOLOGICAL CONDITIONS OR ADAPTIVE STATES, THESE CELLS COOPERATE TO SUPPORT TISSUE AND ORGAN HOMEOSTASIS, AND TO PROMOTE GROWTH OR COMPENSATORY REGENERATION. HOWEVER, DURING CHRONIC DISEASES AND AGING THESE CELLS CAN ADOPT A PATHOLOGICAL PHENOTYPE AND MEDIATE MALADAPTIVE RESPONSES, SUCH AS THE FORMATION OF FIBROTIC SCARS AND FAT DEPOSITION THAT PROGRESSIVELY REPLACES STRUCTURAL AND FUNCTIONAL UNITS OF TISSUES AND ORGANS. THE MOLECULAR DETERMINANTS OF THESE PHENOTYPIC TRANSITIONS ARE ONLY EMERGING FROM RECENT STUDIES THAT REVEAL HOW DYNAMIC CHROMATIN STATES CAN GENERATE FLEXIBLE EPIGENETIC LANDSCAPES, WHICH CONFER ON CELLS THE ABILITY TO RETAIN PARTIAL PLURIPOTENCY AND ADAPT TO ENVIRONMENTAL CHANGES. THIS REVIEW SUMMARIZES OUR CURRENT KNOWLEDGE ON THE ROLE OF THE EPIGENETIC MACHINERY AS A 'FILTER' BETWEEN GENETIC COMMITMENT AND ENVIRONMENTAL SIGNALS IN CELL TYPES THAT CAN ALTERNATIVELY PROMOTE SKELETAL MUSCLE REGENERATION OR FIBRO-ADIPOGENIC DEGENERATION. 2013 7 1674 32 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 8 5405 35 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 9 3521 37 IKAROS: FROM CHROMATIN ORGANIZATION TO TRANSCRIPTIONAL ELONGATION CONTROL. IKAROS IS A MASTER REGULATOR OF CELL FATE DETERMINATION IN LYMPHOID AND OTHER HEMATOPOIETIC CELLS. THIS TRANSCRIPTION FACTOR ORCHESTRATES THE ASSOCIATION OF EPIGENETIC REGULATORS WITH CHROMATIN, ENSURING THE EXPRESSION PATTERN OF TARGET GENES IN A DEVELOPMENTAL AND LINEAGE-SPECIFIC MANNER. DISRUPTION OF IKAROS FUNCTION HAS BEEN ASSOCIATED WITH THE DEVELOPMENT OF ACUTE LYMPHOCYTIC LEUKEMIA, LYMPHOMA, CHRONIC MYELOID LEUKEMIA AND IMMUNE DISORDERS. PARADOXICALLY, WHILE IKAROS HAS BEEN SHOWN TO BE A TUMOR SUPPRESSOR, IT HAS ALSO BEEN IDENTIFIED AS A KEY THERAPEUTIC TARGET IN THE TREATMENT OF VARIOUS FORMS OF HEMATOLOGICAL MALIGNANCIES, INCLUDING MULTIPLE MYELOMA. INDEED, TARGETED PROTEOLYSIS OF IKAROS IS ASSOCIATED WITH DECREASED PROLIFERATION AND INCREASED DEATH OF MALIGNANT CELLS. ALTHOUGH THE MOLECULAR MECHANISMS HAVE NOT BEEN ELUCIDATED, THE EXPRESSION LEVELS OF IKAROS ARE VARIABLE DURING HEMATOPOIESIS AND COULD THEREFORE BE A KEY DETERMINANT IN EXPLAINING HOW ITS ABSENCE CAN HAVE SEEMINGLY OPPOSITE EFFECTS. MECHANISTICALLY, IKAROS COLLABORATES WITH A VARIETY OF PROTEINS AND COMPLEXES CONTROLLING CHROMATIN ORGANIZATION AT GENE REGULATORY REGIONS, INCLUDING THE NUCLEOSOME REMODELING AND DEACETYLASE COMPLEX, AND MAY FACILITATE TRANSCRIPTIONAL REPRESSION OR ACTIVATION OF SPECIFIC GENES. SEVERAL TRANSCRIPTIONAL REGULATORY FUNCTIONS OF IKAROS HAVE BEEN PROPOSED. AN EMERGING MECHANISM OF ACTION INVOLVES THE ABILITY OF IKAROS TO PROMOTE GENE REPRESSION OR ACTIVATION THROUGH ITS INTERACTION WITH THE RNA POLYMERASE II MACHINERY, WHICH INFLUENCES PAUSING AND PRODUCTIVE TRANSCRIPTION AT SPECIFIC GENES. THIS CONTROL APPEARS TO BE INFLUENCED BY IKAROS EXPRESSION LEVELS AND ISOFORM PRODUCTION. IN HERE, WE SUMMARIZE THE CURRENT STATE OF KNOWLEDGE ABOUT THE BIOLOGICAL ROLES AND MECHANISMS BY WHICH IKAROS REGULATES GENE EXPRESSION. WE HIGHLIGHT THE DYNAMIC REGULATION OF THIS FACTOR BY POST-TRANSLATIONAL MODIFICATIONS. FINALLY, POTENTIAL AVENUES TO EXPLAIN HOW IKAROS DESTRUCTION MAY BE FAVORABLE IN THE TREATMENT OF CERTAIN HEMATOLOGICAL MALIGNANCIES ARE ALSO EXPLORED. 2023 10 384 31 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 11 6383 35 THE ROLE OF PHF6 IN HEMATOPOIESIS AND HEMATOLOGIC MALIGNANCIES. EPIGENETIC REGULATION OF GENE EXPRESSION REPRESENTS AN IMPORTANT MECHANISM IN THE MAINTENANCE OF STEM CELL FUNCTION. ALTERATIONS IN EPIGENETIC REGULATION CONTRIBUTE TO THE PATHOGENESIS OF HEMATOLOGICAL MALIGNANCIES. PLANT HOMEODOMAIN FINGER PROTEIN 6 (PHF6) IS A MEMBER OF THE PLANT HOMEODOMAIN (PHD)-LIKE ZINC FINGER FAMILY OF PROTEINS THAT IS INVOLVED IN TRANSCRIPTIONAL REGULATION THROUGH THE MODIFICATION OF THE CHROMATIN STATE. GERMLINE MUTATION OF PHF6 IS THE CAUSATIVE GENETIC ALTERATION OF THE X-LINKED MENTAL RETARDATION BORJESON-FORSSMAN-LEHMANN SYNDROME (BFLS). SOMATIC MUTATIONS IN PHF6 ARE IDENTIFIED IN HUMAN LEUKEMIA, SUCH AS ADULT T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (T-ALL, ~ 38%), PEDIATRIC T-ALL (~ 16%), ACUTE MYELOID LEUKEMIA (AML, ~ 3%), CHRONIC MYELOID LEUKEMIA (CML, ~ 2.5%), MIXED PHENOTYPE ACUTE LEUKEMIA (MPAL, ~ 20%), AND HIGH-GRADE B-CELL LYMPHOMA (HGBCL, ~ 3%). MORE RECENT STUDIES IMPLY AN ONCOGENIC EFFECT OF PHF6 IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL) AND SOLID TUMORS. THESE DATA DEMONSTRATE THAT PHF6 COULD ACT AS A DOUBLE-EDGED SWORD, EITHER A TUMOR SUPPRESSOR OR AN ONCOGENE, IN A LINEAGE-DEPENDENT MANNER. HOWEVER, THE UNDERLYING MECHANISMS OF PHF6 IN NORMAL HEMATOPOIESIS AND LEUKEMOGENESIS REMAIN LARGELY UNKNOWN. IN THIS REVIEW, WE SUMMARIZE CURRENT KNOWLEDGE OF PHF6, EMPHASIZING THE ROLE OF PHF6 IN HEMATOLOGICAL MALIGNANCIES. EPIGENETIC REGULATION OF PHF6 IN B-ALL. PHF6 MAINTAINS A CHROMATIN STRUCTURE THAT IS PERMISSIVE TO B-CELL IDENTITY GENES, BUT NOT T-CELL-SPECIFIC GENES (LEFT). LOSS OF PHF6 LEADS TO ABERRANT EXPRESSION OF B-CELL- AND T-CELL-SPECIFIC GENES RESULTING FROM LINEAGE PROMISCUITY AND BINDING OF T-CELL TRANSCRIPTION FACTORS (RIGHT). 2023 12 2444 22 EPIGENETIC STATES OF NEPHRON PROGENITORS AND EPITHELIAL DIFFERENTIATION. IN MAMMALS, FORMATION OF NEW NEPHRONS ENDS PERINATALLY DUE TO CONSUMPTION OF MESENCHYMAL PROGENITOR CELLS. PREMATURE DEPLETION OF PROGENITORS DUE TO PREMATURITY OR POSTNATAL LOSS OF NEPHRONS DUE TO INJURY CAUSES CHRONIC KIDNEY DISEASE AND HYPERTENSION. INTENSIVE EFFORTS ARE CURRENTLY INVESTED IN DESIGNING REGENERATIVE STRATEGIES TO FORM NEW NEPHRON PROGENITORS FROM PLURIPOTENT CELLS, WHICH UPON FURTHER DIFFERENTIATION PROVIDE A POTENTIAL SOURCE OF NEW NEPHRONS. TO KNOW IF REPROGRAMED RENAL CELLS CAN MAINTAIN THEIR IDENTITY AND FATE REQUIRES KNOWLEDGE OF THE EPIGENETIC STATES OF NATIVE NEPHRON PROGENITORS AND THEIR PROGENY. IN THIS ARTICLE, WE SUMMARIZE CURRENT KNOWLEDGE AND GAPS IN THE EPIGENOMIC LANDSCAPE OF THE DEVELOPING KIDNEY. WE NOW KNOW THAT PAX2/PTIP/H3K4 METHYLTRANSFERASE ACTIVITY PROVIDES THE INITIAL EPIGENETIC SPECIFICATION SIGNAL TO THE METANEPHRIC MESENCHYME. DURING NEPHROGENESIS, THE CAP MESENCHYME HOUSING NEPHRON PROGENITORS IS ENRICHED IN BIVALENT CHROMATIN MARKS; AS TUBULOGENESIS PROCEEDS, THE TUBULAR EPITHELIUM ACQUIRES H3K79ME2. THE LATTER MARK IS UNIQUELY INDUCED DURING EPITHELIAL DIFFERENTIATION. ANALYSIS OF HISTONE LANDSCAPES IN CLONAL METANEPHRIC MESENCHYME CELL LINES AND IN WILMS TUMOR AND NORMAL FETAL KIDNEY HAS REVEALED THAT PROMOTERS OF POISED NEPHROGENESIS GENES CARRY BIVALENT HISTONE SIGNATURES IN PROGENITORS. DIFFERENTIATION OR STIMULATION OF WNT SIGNALING PROMOTES RESOLUTION OF BIVALENCY; THIS DOES NOT OCCUR IN WILMS TUMOR CELLS CONSISTENT WITH THEIR DEVELOPMENTAL ARREST. THE USE OF SMALL CELL NUMBER CHIP-SEQ SHOULD FACILITATE THE CHARACTERIZATION OF THE CHROMATIN LANDSCAPE OF THE METANEPHRIC MESENCHYME AND VARIOUS NEPHRON COMPARTMENTS DURING NEPHROGENESIS. ONLY THEN WE WILL KNOW IF STEM AND SOMATIC CELL REPROGRAMMING INTO KIDNEY PROGENITORS RECAPITULATES NORMAL DEVELOPMENT. 2015 13 4838 41 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 14 5320 37 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 15 952 31 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 16 5798 26 STEM CELLS AND LUNG REGENERATION. THE ABILITY TO REPLACE DEFECTIVE CELLS IN AN AIRWAY WITH CELLS THAT CAN ENGRAFT, INTEGRATE, AND RESTORE A FUNCTIONAL EPITHELIUM COULD POTENTIALLY CURE A NUMBER OF LUNG DISEASES. PROGRESS TOWARD THE DEVELOPMENT OF STRATEGIES TO REGENERATE THE ADULT LUNG BY EITHER IN VIVO OR EX VIVO TARGETING OF ENDOGENOUS STEM CELLS OR PLURIPOTENT STEM CELL DERIVATIVES IS LIMITED BY OUR FUNDAMENTAL LACK OF UNDERSTANDING OF THE MECHANISMS CONTROLLING HUMAN LUNG DEVELOPMENT, THE PRECISE IDENTITY AND FUNCTION OF HUMAN LUNG STEM AND PROGENITOR CELL TYPES, AND THE GENETIC AND EPIGENETIC CONTROL OF HUMAN LUNG FATE. IN THIS REVIEW, WE INTEND TO DISCUSS THE KNOWN STEM/PROGENITOR CELL POPULATIONS, THEIR RELATIVE DIFFERENCES BETWEEN RODENTS AND HUMANS, THEIR ROLES IN CHRONIC LUNG DISEASE, AND THEIR THERAPEUTIC PROSPECTS. ADDITIONALLY, WE HIGHLIGHT THE RECENT BREAKTHROUGHS THAT HAVE INCREASED OUR UNDERSTANDING OF THESE CELL TYPES. THESE ADVANCEMENTS INCLUDE NOVEL LINEAGE-TRACED ANIMAL MODELS AND SINGLE-CELL RNA SEQUENCING OF HUMAN AIRWAY CELLS, WHICH HAVE PROVIDED CRITICAL INFORMATION ON THE STEM CELL SUBTYPES, TRANSITION STATES, IDENTIFYING CELL MARKERS, AND INTRICATE PATHWAYS THAT COMMIT A STEM CELL TO DIFFERENTIATE OR TO MAINTAIN PLASTICITY. AS OUR CAPACITY TO MODEL THE HUMAN LUNG EVOLVES, SO WILL OUR UNDERSTANDING OF LUNG REGENERATION AND OUR ABILITY TO TARGET ENDOGENOUS STEM CELLS AS A THERAPEUTIC APPROACH FOR LUNG DISEASE. 2020 17 2277 40 EPIGENETIC REGULATION BY ASXL1 IN MYELOID MALIGNANCIES. MYELOID MALIGNANCIES ARE CLONAL HEMATOPOIETIC DISORDERS THAT ARE COMPRISED OF A SPECTRUM OF GENETICALLY HETEROGENEOUS DISORDERS, INCLUDING MYELODYSPLASTIC SYNDROMES (MDS), MYELOPROLIFERATIVE NEOPLASMS (MPN), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), AND ACUTE MYELOID LEUKEMIA (AML). MYELOID MALIGNANCIES ARE CHARACTERIZED BY EXCESSIVE PROLIFERATION, ABNORMAL SELF-RENEWAL, AND/OR DIFFERENTIATION DEFECTS OF HEMATOPOIETIC STEM CELLS (HSCS) AND MYELOID PROGENITOR CELLS HEMATOPOIETIC STEM/PROGENITOR CELLS (HSPCS). MYELOID MALIGNANCIES CAN BE CAUSED BY GENETIC AND EPIGENETIC ALTERATIONS THAT PROVOKE KEY CELLULAR FUNCTIONS, SUCH AS SELF-RENEWAL, PROLIFERATION, BIASED LINEAGE COMMITMENT, AND DIFFERENTIATION. ADVANCES IN NEXT-GENERATION SEQUENCING LED TO THE IDENTIFICATION OF MULTIPLE MUTATIONS IN MYELOID NEOPLASMS, AND MANY NEW GENE MUTATIONS WERE IDENTIFIED AS KEY FACTORS IN DRIVING THE PATHOGENESIS OF MYELOID MALIGNANCIES. THE POLYCOMB PROTEIN ASXL1 WAS IDENTIFIED TO BE FREQUENTLY MUTATED IN ALL FORMS OF MYELOID MALIGNANCIES, WITH MUTATIONAL FREQUENCIES OF 20%, 43%, 10%, AND 20% IN MDS, CMML, MPN, AND AML, RESPECTIVELY. SIGNIFICANTLY, ASXL1 MUTATIONS ARE ASSOCIATED WITH A POOR PROGNOSIS IN ALL FORMS OF MYELOID MALIGNANCIES. THE FACT THAT ASXL1 MUTATIONS ARE ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH CMML, MDS, AND AML, POINTS TO THE POSSIBILITY THAT ASXL1 MUTATION IS A KEY FACTOR IN THE DEVELOPMENT OF MYELOID MALIGNANCIES. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN UNDERSTANDING MYELOID MALIGNANCIES WITH A SPECIFIC FOCUS ON ASXL1 MUTATIONS. 2023 18 2928 24 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 19 6014 20 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 20 359 29 ALWAYS STRESSED BUT NEVER EXHAUSTED: HOW STEM CELLS IN MYELOID NEOPLASMS AVOID EXTINCTION IN INFLAMMATORY CONDITIONS. CHRONIC OR RECURRENT EPISODES OF ACUTE INFLAMMATION CAUSE ATTRITION OF NORMAL HEMATOPOIETIC STEM CELLS (HSCS) THAT CAN LEAD TO HEMATOPOIETIC FAILURE BUT THEY DRIVE PROGRESSION IN MYELOID MALIGNANCIES AND THEIR PRECURSOR CLONAL HEMATOPOIESIS. MECHANISTIC PARALLELS EXIST BETWEEN HEMATOPOIESIS IN CHRONIC INFLAMMATION AND THE CONTINUOUSLY INCREASED PROLIFERATION OF MYELOID MALIGNANCIES, PARTICULARLY MYELOPROLIFERATIVE NEOPLASMS (MPNS). THE ABILITY TO ENTER DORMANCY, A STATE OF DEEP QUIESCENCE CHARACTERIZED BY LOW OXIDATIVE PHOSPHORYLATION, LOW GLYCOLYSIS, REDUCED PROTEIN SYNTHESIS, AND INCREASED AUTOPHAGY IS CENTRAL TO THE PRESERVATION OF LONG-TERM HSCS AND LIKELY MPN SCS. THE METABOLIC FEATURES OF DORMANCY RESEMBLE THOSE OF DIAPAUSE, A STATE OF ARRESTED EMBRYONIC DEVELOPMENT TRIGGERED BY ADVERSE ENVIRONMENTAL CONDITIONS. TO OUTCOMPETE THEIR NORMAL COUNTERPARTS IN THE INFLAMMATORY MPN ENVIRONMENT, MPN SCS CO-OPT MECHANISMS USED BY HSCS TO AVOID EXHAUSTION, INCLUDING SIGNAL ATTENUATION BY NEGATIVE REGULATORS, INSULATION FROM ACTIVATING CYTOKINE SIGNALS, ANTI-INFLAMMATORY SIGNALING, AND EPIGENETIC REPROGRAMMING. WE PROPOSE THAT NEW THERAPEUTIC STRATEGIES MAY BE DERIVED FROM CONCEPTUALIZING MYELOID MALIGNANCIES AS AN ECOSYSTEM OUT OF BALANCE, IN WHICH RESIDUAL NORMAL AND MALIGNANT HEMATOPOIETIC CELLS INTERACT IN MULTIPLE WAYS, ONLY FEW OF WHICH HAVE BEEN CHARACTERIZED IN DETAIL. DISRUPTING MPN SC INSULATION TO OVERCOME DORMANCY, INTERFERING WITH ABERRANT CYTOKINE CIRCUITS THAT FAVOR MPN CELLS, AND DIRECTLY BOOSTING RESIDUAL NORMAL HSCS ARE POTENTIAL STRATEGIES TO TIP THE BALANCE IN FAVOR OF NORMAL HEMATOPOIESIS. ALTHOUGH ERADICATING THE MALIGNANT CELL CLONES REMAINS THE GOAL OF THERAPY, REBALANCING THE ECOSYSTEM MAY BE A MORE ATTAINABLE OBJECTIVE IN THE SHORT TERM. 2023