1 4436 93 MOLECULAR EVOLUTION OF CHRONIC MYELOID LEUKAEMIA. CHRONIC MYELOID LEUKAEMIA (CML) IS A CLONAL DISORDER OF THE PLURIPOTENT HAEMATOPOIETIC STEM CELL. THE TYPICAL TRIPHASIC COURSE OF CML STARTS WITH THE PREMALIGNANT CHRONIC PHASE INITIATED BY BCR-ABL HYBRID ONCOGENE FORMATION. SECONDARY GENETIC AND EPIGENETIC ABERRATIONS ACCOMPANY THE PROGRESSION TO THE ACCELERATED PHASE AND FATAL BLASTIC CRISIS. PROPERLY TIMED BONE MARROW TRANSPLANTATION IN ELIGIBLE PATIENTS CAN RESULT IN DURABLE REMISSIONS OR CURE. BOTH OF THESE STATES ARE OFTEN ACCOMPANIED BY A LONG-TERM PERSISTENCE OF QUIESCENT LEUKAEMIC CELLS. ACCORDINGLY, A "FUNCTIONAL CURE" (I.E. TUMOUR DORMANCY INDUCTION), RATHER THAN COMPLETE ERADICATION OF THE MALIGNANT CELLS, IS AN ADEQUATE THERAPEUTICAL GOAL. THE LEVEL OF THE RESIDUAL BCR-ABL-POSITIVE CLONES SHOULD BE MONITORED AND SALVAGE TREATMENT INITIATED WHENEVER THESE QUIESCENT LEUKAEMIC CELLS EXIT THEIR DORMANT STATE. 2001 2 6587 23 TUMOR DORMANCY AND RELAPSE: FROM A NATURAL BYPRODUCT OF EVOLUTION TO A DISEASE STATE. SPECIES EVOLVE BY MUTATIONS AND EPIGENETIC CHANGES ACTING ON INDIVIDUALS IN A POPULATION; TUMORS EVOLVE BY SIMILAR MECHANISMS AT A CELLULAR LEVEL IN A TISSUE. THIS ARTICLE REVIEWS GROWING EVIDENCE ABOUT TUMOR DORMANCY AND SUGGESTS THAT (I) CELLULAR MALIGNANCY IS A NATURAL BYPRODUCT OF EVOLUTIONARY MECHANISMS, SUCH AS GENE MUTATIONS AND EPIGENETIC MODIFICATIONS, WHICH IS MANIFESTED IN THE FORM OF TUMOR DORMANCY IN HEALTHY INDIVIDUALS AS WELL AS IN CANCER SURVIVORS; (II) CANCER METASTASIS COULD BE AN EARLY DISSEMINATION EVENT THAT COULD OCCUR DURING MALIGNANT DORMANCY EVEN BEFORE PRIMARY CANCER IS CLINICALLY DETECTABLE; AND (III) CHRONIC INFLAMMATION IS A KEY FACTOR IN AWAKENING DORMANT MALIGNANT CELLS AT THE PRIMARY SITE, LEADING TO PRIMARY CANCER DEVELOPMENT, AND AT DISTANT SITES, LEADING TO ADVANCED STAGE DISEASES. ON THE BASIS OF THIS EVIDENCE, IT IS REASONABLE TO PROPOSE THAT WE ARE ALL CANCER SURVIVORS RATHER THAN CANCER-FREE INDIVIDUALS BECAUSE OF HARBORING DORMANT MALIGNANT CELLS IN OUR ORGANS. A BETTER UNDERSTANDING OF LOCAL AND METASTATIC TUMOR DORMANCY COULD LEAD TO NOVEL CANCER THERAPEUTICS FOR THE PREVENTION OF CANCER. CANCER RES; 77(10); 2564-9. (C)2017 AACR. 2017 3 359 33 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 4 5488 20 REVERSING HEPATOCELLULAR CARCINOMA PROGRESSION BY USING NETWORKED BIOLOGICAL THERAPIES. THE LIVER IS DISTINGUISHED FROM OTHER TISSUES BY (A) ITS DETOXIFYING FUNCTION, (B) ITS RESISTANCE TO APOPTOSIS, AND (C) ITS REGENERATIVE RESPONSE TO DAMAGE. HEPATOCELLULAR CARCINOMA ARISES WHEN CHRONIC INSULTS, SUCH AS HEPATITIS OR IRON OVERLOAD, CONSTITUTIVELY ACTIVATE THIS REGENERATIVE PROGRAM. HERE, WE PROPOSE THAT THE PROLIFERATIVE RESPONSE OF THE LIVER TO DAMAGE UNDERLIES THE RESISTANCE OF HEPATOCELLULAR CARCINOMA TO CYTOTOXIC THERAPY, AND THAT HEPATOCELLULAR CARCINOMA GROWTH SHOULD THEREFORE BE MORE READILY CONTROLLED BY USING A NETWORKED COMBINATION OF NONCYTOTOXIC INTERVENTIONS TO INTERRUPT THE DAMAGE-INDUCIBLE REGENERATIVE PATHWAY. TO THIS END, HEPATOCELLULAR CARCINOMA BOASTS A WEALTH OF POTENTIAL DRUG TARGETS, INCLUDING VIRAL REPLICATION, THE ANTIAPOPTOTIC IMMUNOSUPPRESSANT ALPHA-FETOPROTEIN, HEPATIC IRON OVERLOAD, INFLAMMATORY SIGNALING, EXTRACELLULAR PROTEASES, AND GROWTH FACTORS. BY BLOCKING THESE POSITIVE FEEDBACK LOOPS IN PARALLEL, AND SO RETURNING THE HOST ENVIRONMENT TO A MORE NORMAL STATE, EPIGENETIC REPRESSION OF TUMOR-SUPPRESSOR GENE FUNCTION MAY BE REVERSED AND TUMOR DORMANCY RESTORED. NONCYTOTOXIC MANEUVERS THAT SHORT CIRCUIT DAMAGE RESISTANCE LOOPS MAY THUS REPRESENT AN INDIRECT FORM OF GENE THERAPY MERITING INCORPORATION INTO HEPATOCELLULAR CARCINOMA CLINICAL TRIALS. 2007 5 2115 17 EPIGENETIC HETEROGENEITY IN HIV-1 LATENCY ESTABLISHMENT. DESPITE PROLONGED ANTIRETROVIRAL THERAPY, HIV-1 PERSISTS AS TRANSCRIPTIONALLY INACTIVE PROVIRUSES. THE HIV-1 LATENCY REMAINS A PRINCIPAL OBSTACLE IN CURING AIDS. IT IS IMPORTANT TO UNDERSTAND MECHANISMS BY WHICH HIV-1 LATENCY IS ESTABLISHED TO MAKE THE LATENT RESERVOIR SMALLER. WE PRESENT A MOLECULAR CHARACTERIZATION OF DISTINCT POPULATIONS AT AN EARLY PHASE OF INFECTION. WE DEVELOPED AN ORIGINAL DUAL-COLOR REPORTER VIRUS TO MONITOR LTR KINETICS FROM ESTABLISHMENT TO MAINTENANCE STAGE. WE FOUND THAT THERE ARE TWO WAYS OF LATENCY ESTABLISHMENT I.E., BY IMMEDIATE SILENCING AND SLOW INACTIVATION FROM ACTIVE INFECTION. HISTONE COVALENT MODIFICATIONS, PARTICULARLY POLYCOMB REPRESSIVE COMPLEX 2 (PRC2)-MEDIATED H3K27 TRIMETHYLATION, APPEARED TO DOMINATE VIRAL TRANSCRIPTION AT THE EARLY PHASE. PRC2 ALSO CONTRIBUTES TO TIME-DEPENDENT LTR DORMANCY IN THE CHRONIC PHASE OF THE INFECTION. SIGNIFICANT DIFFERENCES IN SENSITIVITY AGAINST SEVERAL STIMULI WERE OBSERVED BETWEEN THESE TWO DISTINCT POPULATIONS. THESE RESULTS WILL EXPAND OUR UNDERSTANDING OF HETEROGENEOUS ESTABLISHMENT OF HIV-1 LATENCY POPULATIONS. 2015 6 4769 24 NUCLEAR MORPHOMETRY, NUCLEOMICS AND PROSTATE CANCER PROGRESSION. PROSTATE CANCER (PCA) RESULTS FROM A MULTISTEP PROCESS. THIS PROCESS INCLUDES INITIATION, WHICH OCCURS THROUGH VARIOUS AGING EVENTS AND MULTIPLE INSULTS (SUCH AS CHRONIC INFECTION, INFLAMMATION AND GENETIC INSTABILITY THROUGH REACTIVE OXYGEN SPECIES CAUSING DNA DOUBLE-STRAND BREAKS), FOLLOWED BY A MULTISTEP PROCESS OF PROGRESSION. THESE STEPS INCLUDE SEVERAL GENETIC AND EPIGENETIC ALTERATIONS, AS WELL AS ALTERATIONS TO THE CHROMATIN STRUCTURE, WHICH OCCUR IN RESPONSE TO THE CARCINOGENIC STRESS-RELATED EVENTS THAT SUSTAIN PROLIFERATIVE SIGNALING. EVENTS SUCH AS EVADING GROWTH SUPPRESSORS, RESISTING CELL DEATH, ENABLING REPLICATIVE IMMORTALITY, INDUCING ANGIOGENESIS, AND ACTIVATING INVASION AND METASTASIS ARE READILY OBSERVED. IN ADDITION, IN CONJUNCTION WITH THESE CRITICAL DRIVERS OF CARCINOGENESIS, OTHER FACTORS RELATED TO THE ETIOPATHOGENESIS OF PCA, INVOLVING ENERGY METABOLISM AND EVASION OF THE IMMUNE SURVEILLANCE SYSTEM, APPEAR TO BE INVOLVED. IN ADDITION, WHEN CANCER SPREAD AND METASTASIS OCCUR, THE 'TUMOR MICROENVIRONMENT' IN THE BONE OF PCA PATIENTS MAY PROVIDE A WAY TO SUSTAIN DORMANCY OR SENESCENCE AND EVENTUALLY ESTABLISH A 'SEED AND SOIL' SITE WHERE PCA PROLIFERATION AND GROWTH MAY OCCUR OVER TIME. WHEN PCA IS INITIATED AND PROGRESSION ENSUES, SIGNIFICANT ALTERATIONS IN NUCLEAR SIZE, SHAPE AND HETEROCHROMATIN (DNA TRANSCRIPTION) ORGANIZATION ARE FOUND, AND KEY NUCLEAR TRANSCRIPTIONAL AND STRUCTURAL PROTEINS, AS WELL AS MULTIPLE NUCLEAR BODIES CAN LEAD TO PRECANCEROUS AND MALIGNANT CHANGES. THESE SERIES OF CELLULAR AND TISSUE-RELATED MALIGNANCY-ASSOCIATED EVENTS CAN BE QUANTIFIED TO ASSESS DISEASE PROGRESSION AND MANAGEMENT. 2012 7 791 30 CELLULAR AND MOLECULAR NETWORKS IN CHRONIC MYELOID LEUKEMIA: THE LEUKEMIC STEM, PROGENITOR AND STROMAL CELL INTERPLAY. THE USE OF IMATINIB, SECOND AND THIRD GENERATION ABL TYROSINE KINASE INHIBITORS (TKI) (I.E. DASATINIB, NILOTINIB, BOSUTINIB AND PONATINIB) MADE CML A CLINICALLY MANAGEABLE AND, IN A SMALL PERCENTAGE OF CASES, A CURED DISEASE. TKI THERAPY ALSO TURNED CML BLASTIC TRANSFORMATION INTO A RARE EVENT; HOWEVER, DISEASE PROGRESSION STILL OCCURS IN THOSE PATIENTS WHO ARE REFRACTORY, NOT COMPLIANT WITH TKI THERAPY OR DEVELOP RESISTANCE TO MULTIPLE TKIS. IN THE PAST FEW YEARS, IT BECAME CLEAR THAT THE BCRABL1 ONCOGENE DOES NOT OPERATE ALONE TO DRIVE DISEASE EMERGENCE, MAINTENANCE AND PROGRESSION. INDEED, IT SEEMS THAT BONE MARROW (BM) MICROENVIRONMENT-GENERATED SIGNALS AND CELL AUTONOMOUS BCRABL1 KINASE-INDEPENDENT GENETIC AND EPIGENETIC ALTERATIONS ALL CONTRIBUTE TO: I. PERSISTENCE OF A QUIESCENT LEUKEMIC STEM CELL (LSC) RESERVOIR, II. INNATE OR ACQUIRED RESISTANCE TO TKIS, AND III. PROGRESSION INTO THE FATAL BLAST CRISIS STAGE. HEREIN, WE REVIEW THE INTRICATE LEUKEMIC NETWORK IN WHICH ABERRANT, BUT FINELY TUNED, SURVIVAL, MITOGENIC AND SELF-RENEWAL SIGNALS ARE GENERATED BY LEUKEMIC PROGENITORS, STROMAL CELLS, IMMUNE CELLS AND METABOLIC MICROENVIRONMENTAL CONDITIONS (E.G. HYPOXIA) TO PROMOTE LSC MAINTENANCE AND BLASTIC TRANSFORMATION. 2017 8 3702 30 INFLAMMATORY SIGNALING PATHWAYS IN PRELEUKEMIC AND LEUKEMIC STEM CELLS. HEMATOPOIETIC STEM CELLS (HSCS) ARE A RARE SUBSET OF BONE MARROW CELLS THAT USUALLY EXIST IN A QUIESCENT STATE, ONLY ENTERING THE CELL CYCLE TO REPLENISH THE BLOOD COMPARTMENT, THEREBY LIMITING THE POTENTIAL FOR ERRORS IN REPLICATION. INFLAMMATORY SIGNALS THAT ARE RELEASED IN RESPONSE TO ENVIRONMENTAL STRESSORS, SUCH AS INFECTION, TRIGGER ACTIVE CYCLING OF HSCS. THESE INFLAMMATORY SIGNALS CAN ALSO DIRECTLY INDUCE HSCS TO RELEASE CYTOKINES INTO THE BONE MARROW ENVIRONMENT, PROMOTING MYELOID DIFFERENTIATION. AFTER STRESS MYELOPOIESIS IS TRIGGERED, HSCS REQUIRE INTRACELLULAR SIGNALING PROGRAMS TO DEACTIVATE THIS RESPONSE AND RETURN TO STEADY STATE. PROLONGED OR EXCESSIVE EXPOSURE TO INFLAMMATORY CYTOKINES, SUCH AS IN PROLONGED INFECTION OR IN CHRONIC RHEUMATOLOGIC CONDITIONS, CAN LEAD TO CONTINUED HSC CYCLING AND EVENTUAL HSC LOSS. THIS PROMOTES BONE MARROW FAILURE, AND CAN PRECIPITATE PRELEUKEMIC STATES OR LEUKEMIA THROUGH THE ACQUISITION OF GENETIC AND EPIGENETIC CHANGES IN HSCS. THIS CAN OCCUR THROUGH THE INITIATION OF CLONAL HEMATOPOIESIS, FOLLOWED BY THE EMERGENCE PRELEUKEMIC STEM CELLS (PRE-LSCS). IN THIS REVIEW, WE DESCRIBE THE ROLES OF MULTIPLE INFLAMMATORY SIGNALING PATHWAYS IN THE GENERATION OF PRE-LSCS AND IN PROGRESSION TO MYELODYSPLASTIC SYNDROME (MDS), MYELOPROLIFERATIVE NEOPLASMS, AND ACUTE MYELOID LEUKEMIA (AML). IN AML, ACTIVATION OF SOME INFLAMMATORY SIGNALING PATHWAYS CAN PROMOTE THE CYCLING AND DIFFERENTIATION OF LSCS, AND THIS CAN BE EXPLOITED THERAPEUTICALLY. WE ALSO DISCUSS THE THERAPEUTIC POTENTIAL OF MODULATING INFLAMMATORY SIGNALING FOR THE TREATMENT OF MYELOID MALIGNANCIES. 2017 9 953 31 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 10 952 26 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 11 2402 30 EPIGENETIC REPROGRAMMING SENSITIZES CML STEM CELLS TO COMBINED EZH2 AND TYROSINE KINASE INHIBITION. A MAJOR OBSTACLE TO CURING CHRONIC MYELOID LEUKEMIA (CML) IS RESIDUAL DISEASE MAINTAINED BY TYROSINE KINASE INHIBITOR (TKI)-PERSISTENT LEUKEMIC STEM CELLS (LSC). THESE ARE BCR-ABL1 KINASE INDEPENDENT, REFRACTORY TO APOPTOSIS, AND SERVE AS A RESERVOIR TO DRIVE RELAPSE OR TKI RESISTANCE. WE DEMONSTRATE THAT POLYCOMB REPRESSIVE COMPLEX 2 IS MISREGULATED IN CHRONIC PHASE CML LSCS. THIS IS ASSOCIATED WITH EXTENSIVE REPROGRAMMING OF H3K27ME3 TARGETS IN LSCS, THUS SENSITIZING THEM TO APOPTOSIS UPON TREATMENT WITH AN EZH2-SPECIFIC INHIBITOR (EZH2I). EZH2I DOES NOT IMPAIR NORMAL HEMATOPOIETIC STEM CELL SURVIVAL. STRIKINGLY, TREATMENT OF PRIMARY CML CELLS WITH EITHER EZH2I OR TKI ALONE CAUSED SIGNIFICANT UPREGULATION OF H3K27ME3 TARGETS, AND COMBINED TREATMENT FURTHER POTENTIATED THESE EFFECTS AND RESULTED IN SIGNIFICANT LOSS OF LSCS COMPARED TO TKI ALONE, IN VITRO, AND IN LONG-TERM BONE MARROW MURINE XENOGRAFTS. OUR FINDINGS POINT TO A PROMISING EPIGENETIC-BASED THERAPEUTIC STRATEGY TO MORE EFFECTIVELY TARGET LSCS IN PATIENTS WITH CML RECEIVING TKIS. SIGNIFICANCE: IN CML, TKI-PERSISTENT LSCS REMAIN AN OBSTACLE TO CURE, AND APPROACHES TO ERADICATE THEM REMAIN A SIGNIFICANT UNMET CLINICAL NEED. WE DEMONSTRATE THAT EZH2 AND H3K27ME3 REPROGRAMMING IS IMPORTANT FOR LSC SURVIVAL, BUT RENDERS LSCS SENSITIVE TO THE COMBINED EFFECTS OF EZH2I AND TKI. THIS REPRESENTS A NOVEL APPROACH TO MORE EFFECTIVELY TARGET LSCS IN PATIENTS RECEIVING TKI TREATMENT. CANCER DISCOV; 6(11); 1248-57. (C)2016 AACR.SEE RELATED ARTICLE BY XIE ET AL., P. 1237THIS ARTICLE IS HIGHLIGHTED IN THE IN THIS ISSUE FEATURE, P. 1197. 2016 12 5212 29 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 13 955 31 CHRONIC MYELOID LEUKEMIA: MECHANISMS OF BLASTIC TRANSFORMATION. THE BCR-ABL1 ONCOPROTEIN TRANSFORMS PLURIPOTENT HSCS AND INITIATES CHRONIC MYELOID LEUKEMIA (CML). PATIENTS WITH EARLY PHASE (ALSO KNOWN AS CHRONIC PHASE [CP]) DISEASE USUALLY RESPOND TO TREATMENT WITH ABL TYROSINE KINASE INHIBITORS (TKIS), ALTHOUGH SOME PATIENTS WHO RESPOND INITIALLY LATER BECOME RESISTANT. IN MOST PATIENTS, TKIS REDUCE THE LEUKEMIA CELL LOAD SUBSTANTIALLY, BUT THE CELLS FROM WHICH THE LEUKEMIA CELLS ARE DERIVED DURING CP (SO-CALLED LEUKEMIA STEM CELLS [LSCS]) ARE INTRINSICALLY INSENSITIVE TO TKIS AND SURVIVE LONG TERM. LSCS OR THEIR PROGENY CAN ACQUIRE ADDITIONAL GENETIC AND/OR EPIGENETIC CHANGES THAT CAUSE THE LEUKEMIA TO TRANSFORM FROM CP TO A MORE ADVANCED PHASE, WHICH HAS BEEN SUBCLASSIFIED AS EITHER ACCELERATED PHASE OR BLASTIC PHASE DISEASE. THE LATTER RESPONDS POORLY TO TREATMENT AND IS USUALLY FATAL. HERE, WE DISCUSS WHAT IS KNOWN ABOUT THE MOLECULAR MECHANISMS LEADING TO BLASTIC TRANSFORMATION OF CML AND PROPOSE SOME NOVEL THERAPEUTIC APPROACHES. 2010 14 2277 22 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 15 5249 28 PROGRAMMED CELL DEATH-1 PATHWAY INHIBITION IN MYELOID MALIGNANCIES: IMPLICATIONS FOR MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL HEMATOPOIETIC DISEASES THAT BELONG TO THE SPECTRUM OF MYELOID MALIGNANCIES (MYMS), WHICH ALSO INCLUDE MYELODYSPLASTIC SYNDROMES (MDS), ACUTE MYELOID LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). WHILE HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IS A POTENTIALLY CURATIVE THERAPEUTIC APPROACH TO MANY MYMS, THE ASSOCIATED MORBIDITY AND MORTALITY HAVE NECESSITATED THE DEVELOPMENT OF NON-HSCT THERAPEUTICS FOR SYMPTOM MANAGEMENT AND DISEASE COURSE MODIFICATION. IMMUNE CHECKPOINT INHIBITION, IN PARTICULAR ALONG THE PROGRAMMED CELL DEATH PROTEIN 1 (PD-1)/B7-H1 (PD-L1) AXIS, IS AN ESTABLISHED STRATEGY IN SOLID TUMORS WITH POTENTIAL AS AN ADJUNCTIVE THERAPY IN HEMATOLOGIC MALIGNANCIES. SEMINAL STUDIES SUGGEST THAT THE PRO-INFLAMMATORY MICROENVIRONMENT OF MYMS CAN SUPPRESS T LYMPHOCYTE-MEDIATED IMMUNITY VIA PD-1 SIGNALING AND THAT RESPONSE TO MAINSTAY EPIGENETIC THERAPIES FOR MYMS MAY BE GOVERNED BY PD-1 GENE REGULATION. ALTHOUGH THE ROLE OF PD-1 SIGNALING IN MPN PATHOGENESIS AND PROGRESSION IS AS YET UNCLEAR, RESEARCH IN MPN PATIENTS HAS REVEALED EXPANSION OF MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS), WHICH MAY EFFECT HOST IMMUNE TOLERANCE OF TUMOR VIA TEMPORALLY AND SPATIALLY SPECIFIC ACTIVATION OF PD-1/PD-L1 SIGNALING. THE CURRENT UNDERSTANDING OF IMMUNE DYSFUNCTION IN MPNS AND ANALOGOUS MYMS OFFERS A COMPELLING RATIONALE TO STUDY PD-1/PD-L1 INHIBITION IN PATIENTS AS A NOVEL TREATMENT OPTION. 2017 16 5924 24 TARGETING DNMT1 BY DEMETHYLATING AGENT OR-2100 INCREASES TYROSINE KINASE INHIBITORS-SENSITIVITY AND DEPLETES LEUKEMIC STEM CELLS IN CHRONIC MYELOID LEUKEMIA. ABL1 TYROSINE KINASE INHIBITORS (TKIS) DRAMATICALLY IMPROVE THE PROGNOSIS OF CHRONIC MYELOID LEUKEMIA (CML), BUT 10-20% OF PATIENTS ACHIEVE SUBOPTIMAL RESPONSES WITH LOW TKIS SENSITIVITY. FURTHERMORE, RESIDUAL LEUKEMIC STEM CELLS (LSCS) ARE INVOLVED IN THE MOLECULAR RELAPSE AFTER TKIS DISCONTINUATION. ABERRANT DNA HYPERMETHYLATION CONTRIBUTES TO LOW TKIS SENSITIVITY AND THE PERSISTENCE OF LSCS IN CML. DNMT1 IS A KEY REGULATOR OF HEMATOPOIETIC STEM CELLS, SUGGESTING THAT ABERRANT DNA HYPERMETHYLATION TARGETING DNMT1 REPRESENTS A POTENTIAL THERAPEUTIC TARGET FOR CML. WE INVESTIGATED THE EFFICACY OF OR-2100 (OR21), THE FIRST ORALLY AVAILABLE SINGLE-COMPOUND PRODRUG OF DECITABINE. OR21 EXHIBITED ANTI-TUMOR EFFECTS AS A MONOTHERAPY, AND IN COMBINATION THERAPY IT INCREASED TKI-INDUCED APOPTOSIS AND INDUCTION OF TUMOR SUPPRESSOR GENES INCLUDING PTPN6 ENCODING SHP-1 IN CML CELLS. OR21 IN COMBINATION WITH IMATINIB SIGNIFICANTLY SUPPRESSED TUMOR GROWTH IN A XENOTRANSPLANT MODEL. OR21 AND COMBINATION THERAPY DECREASED THE ABUNDANCE OF LSCS AND INHIBITED ENGRAFTMENT IN A BCR-ABL1-TRANSDUCED MOUSE MODEL. THESE RESULTS DEMONSTRATE THAT TARGETING DNMT1 USING OR21 EXERTS ANTI-TUMOR EFFECTS AND IMPAIRS LSCS IN CML. THEREFORE, COMBINATION TREATMENT OF TKIS AND OR21 REPRESENTS A PROMISING TREATMENT STRATEGY IN CML. 2022 17 3158 28 GLYCOGEN SYNTHASE KINASE 3BETA MISSPLICING CONTRIBUTES TO LEUKEMIA STEM CELL GENERATION. RECENT EVIDENCE SUGGESTS THAT A RARE POPULATION OF SELF-RENEWING CANCER STEM CELLS (CSC) IS RESPONSIBLE FOR CANCER PROGRESSION AND THERAPEUTIC RESISTANCE. CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS AN IMPORTANT PARADIGM FOR UNDERSTANDING THE GENETIC AND EPIGENETIC EVENTS INVOLVED IN CSC PRODUCTION. CML PROGRESSES FROM A CHRONIC PHASE (CP) IN HEMATOPOIETIC STEM CELLS (HSC) THAT HARBOR THE BCR-ABL TRANSLOCATION, TO BLAST CRISIS (BC), CHARACTERIZED BY ABERRANT ACTIVATION OF BETA-CATENIN WITHIN GRANULOCYTE-MACROPHAGE PROGENITORS (GMP). A MAJOR BARRIER TO PREDICTING AND INHIBITING BLAST CRISIS TRANSFORMATION HAS BEEN THE IDENTIFICATION OF MECHANISMS DRIVING BETA-CATENIN ACTIVATION. HERE WE SHOW THAT BC CML MYELOID PROGENITORS, IN PARTICULAR GMP, SERIALLY TRANSPLANT LEUKEMIA IN IMMUNOCOMPROMISED MICE AND THUS ARE ENRICHED FOR LEUKEMIA STEM CELLS (LSC). NOTABLY, CDNA SEQUENCING OF WNT/BETA-CATENIN PATHWAY REGULATORY GENES, INCLUDING ADENOMATOUS POLYPOSIS COLI, GSK3BETA, AXIN 1, BETA-CATENIN, LYMPHOID ENHANCER FACTOR-1, CYCLIN D1, AND C-MYC, REVEALED A NOVEL IN-FRAME SPLICE DELETION OF THE GSK3BETA KINASE DOMAIN IN THE GMP OF BC SAMPLES THAT WAS NOT DETECTABLE BY SEQUENCING IN BLASTS OR NORMAL PROGENITORS. MOREOVER, BC CML PROGENITORS WITH MISSPLICED GSK3BETA HAVE ENHANCED BETA-CATENIN EXPRESSION AS WELL AS SERIAL ENGRAFTMENT POTENTIAL WHILE REINTRODUCTION OF FULL-LENGTH GSK3BETA REDUCES BOTH IN VITRO REPLATING AND LEUKEMIC ENGRAFTMENT. WE PROPOSE THAT CP CML IS INITIATED BY BCR-ABL EXPRESSION IN AN HSC CLONE BUT THAT PROGRESSION TO BC MAY INCLUDE MISSPLICING OF GSK3BETA IN GMP LSC, ENABLING UNPHOSPHORYLATED BETA-CATENIN TO PARTICIPATE IN LSC SELF-RENEWAL. MISSPLICING OF GSK3BETA REPRESENTS A UNIQUE MECHANISM FOR THE EMERGENCE OF BC CML LSC AND MIGHT PROVIDE A NOVEL DIAGNOSTIC AND THERAPEUTIC TARGET. 2009 18 1685 30 DRUGGABLE BIOCHEMICAL PATHWAYS AND POTENTIAL THERAPEUTIC ALTERNATIVES TO TARGET LEUKEMIC STEM CELLS AND ELIMINATE THE RESIDUAL DISEASE IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A DISEASE ARISING IN STEM CELLS EXPRESSING THE BCR-ABL ONCOGENIC TYROSINE KINASE THAT TRANSFORMS ONE HEMATOPOIETIC STEM/PROGENITOR CELL INTO A LEUKEMIC STEM CELL (LSC) AT THE ORIGIN OF DIFFERENTIATED AND PROLIFERATING LEUKEMIC CELLS IN THE BONE MARROW (BM). CML-LSCS ARE RECOGNIZED AS BEING RESPONSIBLE FOR RESISTANCES AND RELAPSES THAT OCCUR DESPITE THE ADVENT OF BCR-ABL-TARGETING THERAPIES WITH TYROSINE KINASE INHIBITORS (TKIS). LSCS SHARE A LOT OF FUNCTIONAL PROPERTIES WITH HEMATOPOIETIC STEM CELLS (HSCS) ALTHOUGH SOME PHENOTYPICAL AND FUNCTIONAL DIFFERENCES HAVE BEEN DESCRIBED DURING THE LAST TWO DECADES. SUBVERTED MECHANISMS AFFECTING EPIGENETIC PROCESSES, APOPTOSIS, AUTOPHAGY AND MORE RECENTLY METABOLISM AND IMMUNOLOGY IN THE BONE MARROW MICROENVIRONMENT (BMM) HAVE BEEN REPORTED. THE AIM OF THIS REVIEW IS TO BRING TOGETHER THE MODIFICATIONS AND MOLECULAR MECHANISMS THAT ARE KNOWN TO ACCOUNT FOR TKI RESISTANCE IN PRIMARY CML-LSCS AND TO FOCUS ON THE POTENTIAL SOLUTIONS THAT CAN CIRCUMVENT THESE RESISTANCES, IN PARTICULAR THOSE THAT HAVE BEEN, OR WILL BE TESTED IN CLINICAL TRIALS. 2019 19 2334 21 EPIGENETIC REGULATION OF INFLAMMATORY CYTOKINE-INDUCED EPITHELIAL-TO-MESENCHYMAL CELL TRANSITION AND CANCER STEM CELL GENERATION. THE NEOPLASTIC TRANSFORMATION OF NORMAL TO METASTATIC CANCER CELLS IS A COMPLEX MULTISTEP PROCESS INVOLVING THE PROGRESSIVE ACCUMULATION OF INTERACTING GENETIC AND EPIGENETIC CHANGES THAT ALTER GENE FUNCTION AND AFFECT CELL PHYSIOLOGY AND HOMEOSTASIS. EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND CHANGES IN NONCODING RNA EXPRESSION, AND DEREGULATION OF EPIGENETIC PROCESSES CAN ALTER GENE EXPRESSION DURING THE MULTISTEP PROCESS OF CARCINOGENESIS. CANCER PROGRESSION AND METASTASIS THROUGH AN 'INVASION-METASTASIS CASCADE' INVOLVING AN EPITHELIAL-TO-MESENCHYMAL CELL TRANSITION (EMT), THE GENERATION OF CANCER STEM CELLS (CSCS), INVASION OF ADJACENT TISSUES, AND DISSEMINATION ARE FUELED BY INFLAMMATION, WHICH IS CONSIDERED A HALLMARK OF CANCER. CHRONIC INFLAMMATION IS GENERATED BY INFLAMMATORY CYTOKINES SECRETED BY THE TUMOR AND THE TUMOR-ASSOCIATED CELLS WITHIN THE TUMOR MICROENVIRONMENT. INFLAMMATORY CYTOKINE SIGNALING INITIATES SIGNALING PATHWAYS LEADING TO THE ACTIVATION OF MASTER TRANSCRIPTION FACTORS (TFS) SUCH AS SMADS, STAT3, AND NF-KAPPAB. MOREOVER, THE SAME INFLAMMATORY RESPONSES ALSO ACTIVATE EMT-INDUCING TF (EMT-TF) FAMILIES SUCH AS SNAIL, TWIST, AND ZEB, AND EPIGENETIC REGULATORS INCLUDING DNA AND HISTONE MODIFYING ENZYMES AND MICORNAS, THROUGH COMPLEX INTERCONNECTED POSITIVE AND NEGATIVE FEEDBACK LOOPS TO REGULATE EMT AND CSC GENERATION. HERE, WE REVIEW THE MOLECULAR REGULATORY FEEDBACK LOOPS AND NETWORKS INVOLVED IN INFLAMMATORY CYTOKINE-INDUCED EMT AND CSC GENERATION. 2019 20 4565 17 MYELOID MALIGNANCIES: MUTATIONS, MODELS AND MANAGEMENT. MYELOID MALIGNANT DISEASES COMPRISE CHRONIC (INCLUDING MYELODYSPLASTIC SYNDROMES, MYELOPROLIFERATIVE NEOPLASMS AND CHRONIC MYELOMONOCYTIC LEUKEMIA) AND ACUTE (ACUTE MYELOID LEUKEMIA) STAGES. THEY ARE CLONAL DISEASES ARISING IN HEMATOPOIETIC STEM OR PROGENITOR CELLS. MUTATIONS RESPONSIBLE FOR THESE DISEASES OCCUR IN SEVERAL GENES WHOSE ENCODED PROTEINS BELONG PRINCIPALLY TO FIVE CLASSES: SIGNALING PATHWAYS PROTEINS (E.G. CBL, FLT3, JAK2, RAS), TRANSCRIPTION FACTORS (E.G. CEBPA, ETV6, RUNX1), EPIGENETIC REGULATORS (E.G. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), TUMOR SUPPRESSORS (E.G. TP53), AND COMPONENTS OF THE SPLICEOSOME (E.G. SF3B1, SRSF2). LARGE-SCALE SEQUENCING EFFORTS WILL SOON LEAD TO THE ESTABLISHMENT OF A COMPREHENSIVE REPERTOIRE OF THESE MUTATIONS, ALLOWING FOR A BETTER DEFINITION AND CLASSIFICATION OF MYELOID MALIGNANCIES, THE IDENTIFICATION OF NEW PROGNOSTIC MARKERS AND THERAPEUTIC TARGETS, AND THE DEVELOPMENT OF NOVEL THERAPIES. GIVEN THE IMPORTANCE OF EPIGENETIC DEREGULATION IN MYELOID DISEASES, THE USE OF DRUGS TARGETING EPIGENETIC REGULATORS APPEARS AS A MOST PROMISING THERAPEUTIC APPROACH. 2012