1 953 112 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 2 1685 43 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 3 791 36 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 4 5212 41 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 5 955 35 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 6 570 41 BCR-ABL INDEPENDENT MECHANISMS OF RESISTANCE IN CHRONIC MYELOID LEUKEMIA. NOT ALL CHRONIC MYELOID LEUKEMIA (CML) PATIENTS ARE CURED WITH TYROSINE KINASE INHIBITORS (TKIS), AND A PROPORTION OF THEM DEVELOP RESISTANCE. RECENTLY, CONTINUOUS BCR-ABL GENE EXPRESSION HAS BEEN FOUND IN RESISTANT CELLS WITH UNDETECTABLE BCR-ABL PROTEIN EXPRESSION, INDICATING THAT RESISTANCE MAY OCCUR THROUGH KINASE INDEPENDENT MECHANISMS, MAINLY DUE TO THE PERSISTENCE OF LEUKEMIA STEM CELLS (LSCS). LSCS RESIDE IN THE BONE MARROW NICHE IN A QUIESCENT STATE, AND ARE CHARACTERIZED BY A HIGH HETEROGENEITY IN GENETIC, EPIGENETIC, AND TRANSCRIPTIONAL MECHANISMS. NEW APPROACHES BASED ON SINGLE CELL GENOMICS HAVE OFFERED THE OPPORTUNITY TO IDENTIFY DISTINCT SUBPOPULATIONS OF LSCS AT DIAGNOSIS AND DURING TREATMENT. IN THE ONE HAND, TKIS ARE NOT ABLE TO EFFICIENTLY KILL CML-LSCS, BUT THEY MAY BE RESPONSIBLE FOR THE MODIFICATION OF SOME LSCS CHARACTERISTICS, THUS CONTRIBUTING TO HETEROGENEITY WITHIN THE TUMOR. IN THE OTHER HAND, THE BONE MARROW NICHE IS RESPONSIBLE FOR THE INTERACTIONS BETWEEN SURROUNDING STROMAL CELLS AND LSCS, RESULTING IN THE GENERATION OF SPECIFIC SIGNALS WHICH COULD FAVOR LSCS CELL CYCLE ARREST AND ALLOW THEM TO PERSIST DURING TREATMENT WITH TKIS. ADDITIONALLY, LSCS MAY THEMSELVES ALTER THE NICHE BY EXPRESSING VARIOUS COSTIMULATORY MOLECULES AND SECRETING SUPPRESSIVE CYTOKINES, ABLE TO TARGET METABOLIC PATHWAYS, CREATE AN ANTI-APOPTOTIC ENVIRONMENT, AND ALTER IMMUNE SYSTEM FUNCTIONS. ACCORDINGLY, THE PRODUCTION OF AN IMMUNOSUPPRESSANT MILIEU MAY FACILITATE TUMOR ESCAPE FROM IMMUNE SURVEILLANCE AND INDUCE CHEMO-RESISTANCE. IN THIS REVIEW WE WILL FOCUS ON BCR-ABL-INDEPENDENT MECHANISMS, ANALYZING ESPECIALLY THOSE WITH A POTENTIAL CLINICAL IMPACT IN THE MANAGEMENT OF CML PATIENTS. 2019 7 4430 31 MOLECULAR BIOLOGY OF ONCOGENIC INFLAMMATORY PROCESSES. I. NON-ONCOGENIC AND ONCOGENIC PATHOGENS, INTRINSIC INFLAMMATORY REACTIONS WITHOUT PATHOGENS, AND MICRORNA/DNA INTERACTIONS (REVIEW). IN SOME INFLAMMASOMES TUMOR CELLS ARE GENERATED. THE INTERNAL ENVIRONMENT OF THE INFLAMMASOME IS CONDUCIVE TO THE INDUCTION OF MALIGNANT TRANSFORMATION. EPIGENETIC CHANGES INITIATE THIS PROCESS. THE SUBVERTED STROMAL CONNECTIVE TISSUE CELLS ACT TO PROMOTE AND SUSTAIN THE PROCESS OF MALIGNANT TRANS-FORMATION. IN ITS EARLY STAGES, THE PREMALIGNANT CELLS DEPEND ON PARACRINE CIRCUITRIES FOR THE RECEPTION OF GROWTH FACTORS. THE LIGANDS ARE DERIVED FROM THE CONNECTIVE TISSUE, AND THE RECEPTORS ARE EXPRESSED ON THE RECIPIENT PREMALIGNANT CELLS. THE INITIAL EVENTS ARE NOT A DIRECT ATTACK ON THE PROTO-ONCOGENES, AND THUS IT MAY BE ENTIRELY REVERSIBLE. EPIGENETIC PROCESSES OF HYPERMETHYLATION OF THE GENES AT THE PROMOTERS OF TUMOR SUPPRESSOR GENES (TO SILENCE THEM), AND DEACETYLATION OF THE HISTONES AIMED AT THE PROMOTERS OF PROTO-ONCOGENES (TO ACTIVATE THEM) ARE ON-GOING. A LARGE NUMBER OF SHORT RNA SEQUENCES (INTERFERING, MICRO-, SHORT HAIRPIN, NON-CODING RNAS) SILENCE TUMOR SUPPRESSOR GENES, BY NEUTRALIZING THEIR MRNAS. IN A SERIAL SEQUENCE ONCOGENES UNDERGO AMPLIFICATIONS, POINT-MUTATIONS, TRANSLOCATIONS AND FUSIONS. IN ITS EARLIEST STAGE, THE PROCESS IS REVERSIBLE BY DEMETHYLATION OF THE SILENCED SUPPRESSOR GENE PROMOTERS (TO REACTIVATE THEM), OR RE-ACETYLATION OF THE HISTONES OF THE ONCOGENE PROMOTERS, THUS DE-ACTIVATING THEM. THE EXTERNAL ADMINISTRATION OF HISTONE DEACETYLASE INHIBITORS USUALLY LEADS TO THE RESTORATION OF HISTONE ACETYLATION. IN TIME, THE UNCORRECTED PROCESSES SOLIDIFY INTO CONSTITUTIVE AND IRREVERSIBLE GENE MUTATIONS. SOME OF THE PATHOGENS INDUCING INFLAMMATIONS WITH CONSQUENTIAL MALIGNANT TRANSFORMATION CONTAIN ONCOGENIC GENE SEQUENCES (PAPILLOMA VIRUSES, EPSTEIN-BARR VIRUS, KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS, HEPATITIS B AND C VIRUSES, MERKEL CELL POLYOMA VIRUS, HELICOBACTER PYLORI, ENTEROTOXIGENIC BACTEROIDES FRAGILIS). THESE INDUCED MALIGNANCIES MAY BE MULTIFOCAL. OTHER PATHOGENS ARE DEVOID OF ANY KNOWN ONCOGENIC GENOMIC SEQUENCES (MYCOPLASMA VAV-CARCINOGENESIS, CHLAMYDIA MALT-LYMPHOMA GENESIS). IN THESE CASES THE HOST'S INFLAMMATORY REACTIONS INDUCE THE MALIGNANT TRANSFORMATION IN SERIAL SEQUENCES OF GENE ALTERATIONS INITIATED BY HYPOXIA AND REACTIVE OXYGEN AND NITROGEN SPECIES GENERATION. CARCINOGENIC INTRINSIC INFLAMMATORY PROCESSES ENDOGENOUSLY INITIATED WITHOUT A PATHOGEN ARE RECOGNIZED. CHRONIC INFLAMMATORY PROCESSES SIGNAL THE RNA/DNA COMPLEX. IN RESPONSE, THE DNA MAY REVERT INTO ITS ANCIENT PRIMORDIAL 'IMMORTAL' FORMAT, WHICH THE CLINICS RECOGNIZE AS 'ONCOGENESIS'. THE DNA REMAINS THE ULTIMATE MASTER OF BIOENGINEERING IN ORDER TO SUSTAIN LIFE. A DISCUSSION ON THE MOST VERSATILE AND RESISTANT PRIMORDIAL RNA/DNA COMPLEX AND THE PRE-, PROTO-, AND UNICELLULAR WORLD IN WHICH THEY CO-EXISTED IS INCLUDED. 2012 8 952 43 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 9 4533 41 MULTIPLE GENE KNOCKDOWN STRATEGIES FOR INVESTIGATING THE PROPERTIES OF HUMAN LEUKEMIA STEM CELLS AND EXPLORING NEW THERAPIES. THE PAST TWO DECADES HAVE WITNESSED SIGNIFICANT STRIDES IN LEUKEMIA THERAPIES THROUGH APPROVAL OF THERAPEUTIC INHIBITORS TARGETING ONCOGENE-DRIVING DYSREGULATED TYROSINE KINASE ACTIVITIES AND KEY EPIGENETIC AND APOPTOSIS REGULATORS. ALTHOUGH THESE DRUGS HAVE BROUGHT ABOUT COMPLETE REMISSION IN THE MAJORITY OF PATIENTS, MANY PATIENTS FACE RELAPSE OR HAVE REFRACTORY DISEASE. THE MAIN FACTOR CONTRIBUTING TO RELAPSE IS THE PRESENCE OF A SMALL SUBPOPULATION OF DORMANT DRUG-RESISTANT LEUKEMIA CELLS THAT POSSESS STEM CELL FEATURES (TERMED AS LEUKEMIA STEM CELLS OR LSCS). THUS, OVERCOMING DRUG RESISTANCE AND TARGETING LSCS REMAIN MAJOR CHALLENGES FOR CURATIVE TREATMENT OF HUMAN LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A GOOD EXAMPLE, WITH RARE, PROPAGATING LSCS AND DRUG-RESISTANT CELLS THAT CANNOT BE ERADICATED BY BCR-ABL-DIRECTED TYROSINE KINASE INHIBITOR (TKI) MONOTHERAPY AND THAT ARE RESPONSIBLE FOR DISEASE RELAPSE/PROGRESSION. THEREFORE, IT IS IMPERATIVE TO IDENTIFY KEY PLAYERS IN REGULATING BCR-ABL1-DEPENDENT AND INDEPENDENT DRUG-RESISTANCE MECHANISMS, AND THEIR KEY PATHWAYS, SO THAT CML LSCS CAN BE SELECTIVELY TARGETED OR SENSITIZED TO TKIS. HERE, WE DESCRIBE SEVERAL EASILY ADAPTABLE GENE KNOCKDOWN APPROACHES IN CD34(+) CML STEM/PROGENITOR CELLS THAT CAN BE USED TO INVESTIGATE THE BIOLOGICAL PROPERTIES OF LSCS AND MOLECULAR EFFECTS OF GENES OF INTEREST (GOI), WHICH CAN BE FURTHER EXPLORED AS THERAPEUTIC MODALITIES AGAINST LSCS IN THE CONTEXT OF HUMAN LEUKEMIA. 2022 10 1142 38 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 11 572 40 BCR-ABL1 KINASE-DEPENDENT ALTERATION OF MRNA METABOLISM: POTENTIAL ALTERNATIVES FOR THERAPEUTIC INTERVENTION. THE USE OF FIRST- AND SECOND-GENERATION TYROSINE KINASE INHIBITORS (TKIS) SIGNIFICANTLY IMPROVES PROGNOSIS FOR PATIENTS WITH EARLY CHRONIC PHASE CHRONIC MYELOID LEUKEMIA (CML) AND EFFICIENTLY COUNTERACTS LEUKEMIA IN MOST PATIENTS WITH CML BEARING A DISEASE CHARACTERIZED BY THE EXPRESSION OF BCR-ABL1 MUTANTS. HOWEVER, THE SO-CALLED 'TINIB' TKIS (E.G. IMATINIB, NILOTINIB, DASATINIB, AND BOSUTINIB) ARE BOTH INEFFECTIVE IN PATIENTS WHO UNDERGO BLASTIC TRANSFORMATION AND UNABLE TO ERADICATE CML AT THE STEM CELL LEVEL. THIS RAISES A FEW IMPORTANT QUESTIONS. IS BCR-ABL1 EXPRESSION AND/OR ACTIVITY ESSENTIAL FOR BLASTIC TRANSFORMATION? IS BLASTIC TRANSFORMATION THE RESULT OF GENETIC OR EPIGENETIC EVENTS THAT OCCUR AT THE STEM CELL LEVEL WHICH ONLY BECOME APPARENT IN THE GRANULOCYTE-MACROPHAGE PROGENITOR (GMP) CELL POOL, OR DOES IT ARISE DIRECTLY AT THE GMP LEVEL? AS ALTERED MRNA METABOLISM CONTRIBUTES TO THE PHENOTYPE OF BLAST CRISIS CML PROGENITORS (DECREASED TRANSLATION OF TUMOR SUPPRESSOR GENES AND TRANSCRIPTION FACTORS ESSENTIAL FOR TERMINAL DIFFERENTIATION AND INCREASED TRANSLATION OF ANTI-APOPTOTIC GENES), ONE ATTRACTIVE CONCEPT IS TO RESTORE LEVELS OF THESE ESSENTIAL MOLECULES TO THEIR NORMAL LEVELS. IN THIS REVIEW, WE DISCUSS THE MECHANISMS BY WHICH MRNA PROCESSING, TRANSLATION, AND DEGRADATION ARE DEREGULATED IN BCR-ABL1 MYELOID BLAST CRISIS CML PROGENITORS, AND PRESENT ENCOURAGING RESULTS FROM STUDIES WITH PHARMACOLOGIC INHIBITORS WHICH SUPPORT THEIR INCLUSION IN THE CLINIC. 2011 12 4436 31 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 13 2085 40 EPIGENETIC DYSREGULATION IN CHRONIC MYELOID LEUKAEMIA: A MYRIAD OF MECHANISMS AND THERAPEUTIC OPTIONS. THE ONSET OF GLOBAL EPIGENETIC CHANGES IN CHROMATIN THAT DRIVE TUMOR PROLIFERATION AND HETEROGENEITY IS A HALLMARK OF MANY FORMS OF CANCER. IDENTIFYING THE EPIGENETIC MECHANISMS THAT GOVERN THESE CHANGES AND DEVELOPING THERAPEUTIC APPROACHES TO MODULATE THEM, IS A WELL-ESTABLISHED AVENUE PURSUED IN TRANSLATIONAL CANCER MEDICINE. CHRONIC MYELOID LEUKEMIA (CML) ARISES CLONALLY WHEN A HEMATOPOIETIC STEM CELL (HSC) ACQUIRES THE CAPACITY TO PRODUCE THE CONSTITUTIVELY ACTIVE TYROSINE KINASE BCR-ABL1 FUSION PROTEIN WHICH DRIVES TUMOR DEVELOPMENT. TREATMENT WITH TYROSINE KINASE INHIBITORS (TKI) THAT TARGET BCR-ABL1 HAS BEEN TRANSFORMATIVE IN CML MANAGEMENT BUT IT DOES NOT LEAD TO CURE IN THE VAST MAJORITY OF PATIENTS. THUS NOVEL THERAPEUTIC APPROACHES ARE REQUIRED AND THESE MUST TARGET CHANGES TO BIOLOGICAL PATHWAYS THAT ARE ABERRANT IN CML - INCLUDING THOSE THAT OCCUR WHEN EPIGENETIC MECHANISMS ARE ALTERED. THESE CHANGES MAY BE DUE TO ALTERATIONS IN DNA OR HISTONES, THEIR BIOCHEMICAL MODIFICATIONS AND REQUISITE 'WRITER' PROTEINS, OR TO DYSREGULATION OF VARIOUS TYPES OF NON-CODING RNAS THAT COLLECTIVELY FUNCTION AS MODULATORS OF TRANSCRIPTIONAL CONTROL AND DNA INTEGRITY. HERE, WE REVIEW THE EVIDENCE FOR SUBVERTED EPIGENETIC MECHANISMS IN CML AND HOW THESE IMPACT ON A DIVERSE SET OF BIOLOGICAL PATHWAYS, ON DISEASE PROGRESSION, PROGNOSIS AND DRUG RESISTANCE. WE WILL ALSO DISCUSS RECENT PROGRESS TOWARDS DEVELOPING EPIGENETIC THERAPIES THAT SHOW PROMISE TO IMPROVE CML PATIENT CARE AND MAY LEAD TO IMPROVED CURE RATES. 2018 14 3516 32 IDO1 AND INFLAMMATORY NEOVASCULARIZATION: BRINGING NEW BLOOD TO TUMOR-PROMOTING INFLAMMATION. IN PARALLEL WITH THE GENETIC AND EPIGENETIC CHANGES THAT ACCUMULATE IN TUMOR CELLS, CHRONIC TUMOR-PROMOTING INFLAMMATION ESTABLISHES A LOCAL MICROENVIRONMENT THAT FOSTERS THE DEVELOPMENT OF MALIGNANCY. WHILE KNOWLEDGE OF THE SPECIFIC FACTORS THAT DISTINGUISH TUMOR-PROMOTING FROM NON-TUMOR-PROMOTING INFLAMMATION REMAINS INCHOATE, NEVERTHELESS, AS HIGHLIGHTED IN THIS SERIES ON THE 'HALLMARKS OF CANCER', IT IS CLEAR THAT TUMOR-PROMOTING INFLAMMATION IS ESSENTIAL TO NEOPLASIA AND METASTATIC PROGRESSION MAKING IDENTIFICATION OF SPECIFIC FACTORS CRITICAL. STUDIES OF IMMUNOMETABOLISM AND INFLAMOMETABOLISM HAVE REVEALED A ROLE FOR THE TRYPTOPHAN CATABOLIZING ENZYME IDO1 AS A CORE ELEMENT IN TUMOR-PROMOTING INFLAMMATION. AT ONE LEVEL, IDO1 EXPRESSION PROMOTES IMMUNE TOLERANCE TO TUMOR ANTIGENS, THEREBY HELPING TUMORS EVADE ADAPTIVE IMMUNE CONTROL. ADDITIONALLY, RECENT FINDINGS INDICATE THAT IDO1 ALSO PROMOTES TUMOR NEOVASCULARIZATION BY SUBVERTING LOCAL INNATE IMMUNITY. THIS NEWLY RECOGNIZED FUNCTION FOR IDO1 IS MEDIATED BY A UNIQUE MYELOID CELL POPULATION TERMED IDVCS (IDO1-DEPENDENT VASCULARIZING CELLS). INITIALLY IDENTIFIED IN METASTATIC LESIONS, IDVCS MAY EXERT BROADER EFFECTS ON PATHOLOGIC NEOVASCULARIZATION IN VARIOUS DISEASE SETTINGS. MECHANISTICALLY, INDUCTION OF IDO1 EXPRESSION IN IDVCS BY THE INFLAMMATORY CYTOKINE IFNGAMMA BLOCKS THE ANTAGONISTIC EFFECT OF IFNGAMMA ON NEOVASCULARIZATION BY STIMULATING THE EXPRESSION OF IL6, A POWERFUL PRO-ANGIOGENIC CYTOKINE. BY CONTRIBUTING TO VASCULAR ACCESS, THIS NEWLY ASCRIBED FUNCTION FOR IDO1 ALIGNS WITH ITS INVOLVEMENT IN OTHER CANCER HALLMARK FUNCTIONALITIES, (TUMOR-PROMOTING INFLAMMATION, IMMUNE ESCAPE, ALTERED CELLULAR METABOLISM, METASTASIS), WHICH MAY STEM FROM AN UNDERLYING ROLE IN NORMAL PHYSIOLOGICAL FUNCTIONS SUCH AS WOUND HEALING AND PREGNANCY. UNDERSTANDING THE NUANCES OF HOW IDO1 INVOLVEMENT IN THESE CANCER HALLMARK FUNCTIONALITIES VARIES BETWEEN DIFFERENT TUMOR SETTINGS WILL BE CRUCIAL TO THE FUTURE DEVELOPMENT OF SUCCESSFUL IDO1-DIRECTED THERAPIES. 2023 15 954 26 CHRONIC MYELOID LEUKEMIA: CURRENT PERSPECTIVES. CHRONIC MYELOID LEUKEMIA (CML), CHARACTERIZED BY THE T(9;22) AND BCR/ABL1 FUSION, IS A DISEASE MODEL FOR STUDYING THE MECHANISMS OF GENETIC ABNORMALITIES IN LEUKEMOGENESIS. THE DETECTION OF THE T(9;22), CHARACTERIZATION OF THE BCR/ABL FUSION, AND THE DISCOVERY OF IMATINIB HAVE ELEGANTLY REFLECTED THE SUCCESS OF OUR RESEARCH EFFORTS IN CML. HOWEVER, GENOMIC INSTABILITIES THAT LEAD TO THE FORMATION OF THE BCR/ ABL1 FUSION ARE NOT FULLY UNDERSTOOD. IT IS IMPORTANT TO UNDERSTAND HOW VARIOUS GENES THAT ARE INVOLVED IN REGULATING THE SIGNALING PATHWAY AND EPIGENETIC DEREGULATION COOPERATE WITH THE BCR/ABL1 FUSION IN THE INITIATION AND PROGRESSION OF CML. 2011 16 1082 36 CML - NOT ONLY BCR-ABL1 MATTERS. BCR-ABL1 IS IN THE CENTER OF CHRONIC MYELOID LEUKEMIA (CML) PATHOLOGY, DIAGNOSIS AND TREATMENT, AS CONFIRMED BY THE SUCCESS OF TYROSINE KINASE INHIBITOR (TKI) THERAPY. HOWEVER, ADDITIONAL MECHANISMS AND EVENTS, MANY OF WHICH FUNCTION INDEPENDENTLY OF BCR-ABL1, PLAY IMPORTANT ROLES, PARTICULARLY IN TERMS OF LEUKEMIC STEM CELL (LSC) PERSISTENCE, PRIMARY AND SECONDARY RESISTANCE, AND DISEASE PROGRESSION. PROMISING THERAPEUTIC APPROACHES AIM TO DISRUPT PATHWAYS WHICH MEDIATE LSC SURVIVAL DURING SUCCESSFUL TKI TREATMENT, IN THE HOPE OF IMPROVING LONG-TERM TREATMENT-FREE-REMISSION AND PERHAPS PROVIDE A FUNCTIONAL CURE FOR SOME PATIENTS. OVER THE YEARS THROUGH ADVANCES IN SEQUENCING TECHNOLOGY FREQUENT MOLECULAR ABERRATIONS IN ADDITION TO BCR-ABL1 HAVE BEEN IDENTIFIED NOT ONLY IN ADVANCED DISEASE BUT ALSO IN CHRONIC PHASE CML, OFTEN AFFECTING EPIGENETIC REGULATORS SUCH AS ASXL1, DNMT3A AND TET2. ANALYSES OF SERIAL SAMPLES HAVE REVEALED VARIOUS PATTERNS OF CLONAL EVOLUTION WITH SOME MUTATIONS PRECEDING THE BCR-ABL1 ACQUISITION. SUCH MUTATIONS CAN BE CONSIDERED TO BE IMPORTANT CO-FACTORS IN THE PATHOGENESIS OF CML AND COULD POTENTIALLY INFLUENCE THERAPEUTIC STRATEGIES IN THE FUTURE. 2020 17 6609 37 TYROSINE KINASE INHIBITORS IN PH+ CHRONIC MYELOID LEUKEMIA THERAPY: A REVIEW. CHRONIC MYELOID LEUKAEMIA (CML) IS A CLONAL MYELOPROLIFERATIVE HEMATOPOIETIC STEM CELL DISORDER. DEREGULATED BCRABL FUSION TYROSINE KINASE ACTIVITY IS THE MAIN CAUSE OF CML DISEASE PATHOGENESIS, MAKING BCRABL AN IDEAL TARGET FOR INHIBITION. CURRENT TYROSINE KINASE INHIBITORS (TKIS) DESIGNED TO INHIBIT BCRABL ONCOPROTEIN ACTIVITY, HAVE COMPLETELY TRANSFORMED THE PROGNOSIS OF CML. INTERRUPTION OF TKI TREATMENT LEADS TO MINIMAL RESIDUAL DISEASE RESIDE (MRD), THOUGHT TO RESIDE IN TKIINSENSITIVE LEUKAEMIA STEM CELLS WHICH REMAIN A POTENTIAL RESERVOIR FOR DISEASE RELAPSE. THIS HIGHLIGHTS THE NEED TO DEVELOP NEW THERAPEUTIC STRATEGIES FOR CML EITHER AS SMALL MOLECULE MASTER TKIS OR PHYTOPHARMACEUTICALS DERIVED FROM NATURE TO ACHIEVE CHRONIC MOLECULAR REMISSION. THIS REVIEW OUTLINES THE PAST, PRESENT AND FUTURE THERAPEUTIC APPROACHES FOR CML INCLUDING COVERAGE OF RELEVANT MECHANISMS, WHETHER ABL DEPENDENT OR INDEPENDENT, AND EPIGENETIC FACTORS RESPONSIBLE FOR DEVELOPING RESISTANCE AGAINST TKIS. APPEARANCE OF MUTANT CLONES ALONG THE COURSE OF THERAPY EITHER PREEXISTING OR INDUCED DUE TO THERAPY IS STILL A CHALLENGE FOR THE CLINICIAN. A PROPOSED INVITRO MODEL OF GENERATING COLONY FORMING UNITS FROM CML STEM CELLS DERIVED FROM DIAGNOSTIC SAMPLES SEEMS TO BE ACHIEVABLE IN THE ERA OF HIGH THROUGHPUT TECHNOLOGY WHICH CAN TAKE CARE OF SINGLE CELL GENOMIC PROFILING. 2016 18 3158 49 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 19 4552 36 MUTATIONAL LANDSCAPE OF CHRONIC MYELOID LEUKEMIA: MORE THAN A SINGLE ONCOGENE LEUKEMIA. THE BCR-ABL1 FUSION GENE, WHICH CAUSES ABERRANT KINASE ACTIVITY AND UNCONTROLLED CELL PROLIFERATION, IS THE HALLMARK OF CHRONIC MYELOID LEUKEMIA (CML). THE DEVELOPMENT OF TYROSINE KINASE INHIBITORS (TKI) THAT TARGET THE BCR-ABL ONCOPROTEIN HAS LED TO DRAMATIC IMPROVEMENT IN CML MANAGEMENT. HOWEVER, SOME CHALLENGES REMAIN TO BE ADDRESSED IN THE TKI ERA, INCLUDING PATIENT STRATIFICATION AND THE SELECTION OF FRONTLINE TKIS AND CML PROGRESSION. ADDITIONALLY, WITH THE EMERGING GOAL OF TREATMENT-FREE REMISSION (TFR) IN CML MANAGEMENT, BIOMARKERS THAT PREDICT THE OUTCOMES OF STOPPING TKI REMAIN TO BE IDENTIFIED. NOTABLY, RECENT REPORTS HAVE REVEALED THE POWER OF GENOME SCREENING IN UNDERSTANDING THE ROLE OF GENOME ABERRATIONS OTHER THAN BCR-ABL1 IN CML PATHOGENESIS. THESE STUDIES HAVE DISCOVERED THE PRESENCE OF DISEASE-PHASE SPECIFIC MUTATIONS AND LINKED CERTAIN MUTATIONS TO INFERIOR RESPONSES TO TKI TREATMENT AND CML PROGRESSION. A PERSONALIZED APPROACH THAT INCORPORATES GENETIC DATA IN TAILORING TREATMENT STRATEGIES HAS BEEN SUCCESSFULLY IMPLEMENTED IN ACUTE LEUKEMIA, AND IT REPRESENTS A PROMISING APPROACH FOR THE MANAGEMENT OF HIGH-RISK CML PATIENTS. IN THIS ARTICLE, WE WILL REVIEW CURRENT KNOWLEDGE ABOUT THE MUTATIONAL PROFILE IN DIFFERENT PHASES OF CML AS WELL AS PATTERNS OF MUTATIONAL DYNAMICS IN PATIENTS HAVING DIFFERENT OUTCOMES. WE HIGHLIGHT THE EFFECTS OF SOMATIC MUTATIONS INVOLVING CERTAIN GENES (E.G. EPIGENETIC MODIFIERS) ON THE OUTCOMES OF TKI TREATMENT. WE ALSO DISCUSS THE POTENTIAL VALUE OF INCORPORATING GENETIC DATA IN TREATMENT DECISIONS AND THE ROUTINE CARE OF CML PATIENTS AS A FUTURE DIRECTION FOR OPTIMIZING CML MANAGEMENT. 2021 20 690 34 BRD4 DEGRADATION BLOCKS EXPRESSION OF MYC AND MULTIPLE FORMS OF STEM CELL RESISTANCE IN PH(+) CHRONIC MYELOID LEUKEMIA. IN MOST PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) CLONAL CELLS CAN BE KEPT UNDER CONTROL BY BCR::ABL1 TYROSINE KINASE INHIBITORS (TKI). HOWEVER, OVERT RESISTANCE OR INTOLERANCE AGAINST THESE TKI MAY OCCUR. WE IDENTIFIED THE EPIGENETIC READER BRD4 AND ITS DOWNSTREAM-EFFECTOR MYC AS GROWTH REGULATORS AND THERAPEUTIC TARGETS IN CML CELLS. BRD4 AND MYC WERE FOUND TO BE EXPRESSED IN PRIMARY CML CELLS, CD34(+) /CD38(-) LEUKEMIC STEM CELLS (LSC), AND IN THE CML CELL LINES KU812, K562, KCL22, AND KCL22(T315I) . THE BRD4-TARGETING DRUG JQ1 WAS FOUND TO SUPPRESS PROLIFERATION IN KU812 CELLS AND PRIMARY LEUKEMIC CELLS IN THE MAJORITY OF PATIENTS WITH CHRONIC PHASE CML. IN THE BLAST PHASE OF CML, JQ1 WAS LESS EFFECTIVE. HOWEVER, THE BRD4 DEGRADER DBET6 WAS FOUND TO BLOCK PROLIFERATION AND/OR SURVIVAL OF PRIMARY CML CELLS IN ALL PATIENTS TESTED, INCLUDING BLAST PHASE CML AND CML CELLS EXHIBITING THE T315I VARIANT OF BCR::ABL1. MOREOVER, DBET6 WAS FOUND TO BLOCK MYC EXPRESSION AND TO SYNERGIZE WITH BCR::ABL1 TKI IN INHIBITING THE PROLIFERATION IN THE JQ1-RESISTANT CELL LINE K562. FURTHERMORE, BRD4 DEGRADATION WAS FOUND TO OVERCOME OSTEOBLAST-INDUCED TKI RESISTANCE OF CML LSC IN A CO-CULTURE SYSTEM AND TO BLOCK INTERFERON-GAMMA-INDUCED UPREGULATION OF THE CHECKPOINT ANTIGEN PD-L1 IN LSC. FINALLY, DBET6 WAS FOUND TO SUPPRESS THE IN VITRO SURVIVAL OF CML LSC AND THEIR ENGRAFTMENT IN NSG MICE. TOGETHER, TARGETING OF BRD4 AND MYC THROUGH BET DEGRADATION SENSITIZES CML CELLS AGAINST BCR::ABL1 TKI AND IS A POTENT APPROACH TO OVERCOME MULTIPLE FORMS OF DRUG RESISTANCE IN CML LSC. 2022