1 690 117 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 2 5940 36 TARGETING METHYLTRANSFERASE PRMT5 ELIMINATES LEUKEMIA STEM CELLS IN CHRONIC MYELOGENOUS LEUKEMIA. IMATINIB-INSENSITIVE LEUKEMIA STEM CELLS (LSCS) ARE BELIEVED TO BE RESPONSIBLE FOR RESISTANCE TO BCR-ABL TYROSINE KINASE INHIBITORS AND RELAPSE OF CHRONIC MYELOGENOUS LEUKEMIA (CML). IDENTIFYING THERAPEUTIC TARGETS TO ERADICATE CML LSCS MAY BE A STRATEGY TO CURE CML. IN THE PRESENT STUDY, WE DISCOVERED A POSITIVE FEEDBACK LOOP BETWEEN BCR-ABL AND PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5) IN CML CELLS. OVEREXPRESSION OF PRMT5 WAS OBSERVED IN HUMAN CML LSCS. SILENCING PRMT5 WITH SHRNA OR BLOCKING PRMT5 METHYLTRANSFERASE ACTIVITY WITH THE SMALL-MOLECULE INHIBITOR PJ-68 REDUCED SURVIVAL, SERIAL REPLATING CAPACITY, AND LONG-TERM CULTURE-INITIATING CELLS (LTC-ICS) IN LSCS FROM CML PATIENTS. FURTHER, PRMT5 KNOCKDOWN OR PJ-68 TREATMENT DRAMATICALLY PROLONGED SURVIVAL IN A MURINE MODEL OF RETROVIRAL BCR-ABL-DRIVEN CML AND IMPAIRED THE IN VIVO SELF-RENEWAL CAPACITY OF TRANSPLANTED CML LSCS. PJ-68 ALSO INHIBITED LONG-TERM ENGRAFTMENT OF HUMAN CML CD34+ CELLS IN IMMUNODEFICIENT MICE. MOREOVER, INHIBITION OF PRMT5 ABROGATED THE WNT/BETA-CATENIN PATHWAY IN CML CD34+ CELLS BY DEPLETING DISHEVELLED HOMOLOG 3 (DVL3). THIS STUDY SUGGESTS THAT EPIGENETIC METHYLATION MODIFICATION ON HISTONE PROTEIN ARGININE RESIDUES IS A REGULATORY MECHANISM TO CONTROL SELF-RENEWAL OF LSCS AND INDICATES THAT PRMT5 MAY REPRESENT A POTENTIAL THERAPEUTIC TARGET AGAINST LSCS. 2016 3 791 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 4 2402 38 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 5 955 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 6 5924 32 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 7 5212 30 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 8 2719 25 EXOME SEQUENCING REVEALS DNMT3A AND ASXL1 VARIANTS ASSOCIATE WITH PROGRESSION OF CHRONIC MYELOID LEUKEMIA AFTER TYROSINE KINASE INHIBITOR THERAPY. OBJECTIVE: THE DEVELOPMENT OF TYROSINE KINASE INHIBITORS (TKIS) HAS SIGNIFICANTLY IMPROVED THE TREATMENT OF CHRONIC MYELOID LEUKEMIA (CML). HOWEVER, APPROXIMATELY ONE THIRD OF PATIENTS ARE RESISTANT TO TKI AND/OR PROGRESS TO ADVANCED DISEASE STAGES. TKI THERAPY FAILURE HAS A WELL-KNOWN ASSOCIATION WITH ABL1 KINASE DOMAIN (KD) MUTATIONS, BUT ONLY AROUND HALF OF TKI NON-RESPONDERS HAVE DETECTABLE ABL1 KD MUTATIONS. METHOD: WE ATTEMPT TO IDENTIFY GENETIC MARKERS ASSOCIATED WITH TKI THERAPY FAILURE IN 13 PATIENTS (5 RESISTANT, 8 PROGRESSED) WITHOUT ABL1 KD MUTATIONS USING WHOLE-EXOME SEQUENCING. RESULTS: IN 6 PATIENTS, WE DETECTED MUTATIONS IN 6 GENES COMMONLY MUTATED IN OTHER MYELOID NEOPLASMS: ABL1, ASXL1, DNMT3A, IDH1, SETBP1, AND TP63. WE THEN USED TARGETED DEEP SEQUENCING TO VALIDATE OUR FINDING IN AN INDEPENDENT COHORT CONSISTING OF 100 CML PATIENTS WITH VARYING DRUG RESPONSES (74 RESPONSIVE, 18 RESISTANT, AND 8 PROGRESSED PATIENTS). MUTATIONS IN GENES ASSOCIATED WITH EPIGENETIC REGULATIONS SUCH AS DNMT3A AND ASXL1 SEEM TO PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF CML PROGRESSION AND TKI-RESISTANCE INDEPENDENT OF ABL1 KD MUTATIONS. CONCLUSION: THIS STUDY SUGGESTS THE INVOLVEMENT OF OTHER SOMATIC MUTATIONS IN THE DEVELOPMENT OF TKI RESISTANT PROGRESSION TO ADVANCED DISEASE STAGES IN CML, PARTICULARLY IN PATIENTS LACKING ABL1 KD MUTATIONS. 2017 9 4361 41 MIR-96 ACTS AS A TUMOR SUPPRESSOR VIA TARGETING THE BCR-ABL1 ONCOGENE IN CHRONIC MYELOID LEUKEMIA BLASTIC TRANSFORMATION. MICRORNA-MEDIATED POSTTRANSCRIPTIONAL REGULATION IS AN IMPORTANT EPIGENETIC REGULATORY MECHANISM OF GENE EXPRESSION, AND ITS DYSREGULATION IS INVOLVED IN THE DEVELOPMENT AND PROGRESSION OF A VARIETY OF MALIGNANCIES, INCLUDING CHRONIC MYELOID LEUKEMIA (CML). THE BCR-ABL1 FUSION GENE IS NOT ONLY THE INITIATING FACTOR OF CML, BUT IT IS ALSO AN IMPORTANT DRIVING FACTOR FOR BLASTIC TRANSFORMATION. TYROSINE KINASE INHIBITORS (TKIS) TARGETING BCR-ABL1 TYROSINE KINASE ACTIVITY, REPRESENTED BY IMATINIB, ARE CURRENTLY THE FIRST-LINE TREATMENT FOR CML. HOWEVER, DUE TO PRIMARY RESISTANCE OR SECONDARY RESISTANCE CAUSED BY MUTATIONS IN THE BCR-ABL1 KINASE DOMAIN, TKIS CANNOT COMPLETELY PREVENT THE PROGRESSION OF CML; THUS, THE STUDY OF BCR-ABL1 GENE EXPRESSION REGULATION IS OF GREAT SIGNIFICANCE. IN THIS STUDY, BIOINFORMATICS ANALYSIS AND OUR RESULTS SHOWED THAT MIR-96 COULD DIRECTLY BIND TO THE 3'UTR REGION OF BCR-ABL1 TO REGULATE FUSION PROTEIN EXPRESSION, THEREBY REGULATING ITS DOWNSTREAM SIGNALING PATHWAY ACTIVITY. WE ALSO FOUND THAT MIR-96 WAS DOWNREGULATED DURING THE PROGRESSION FROM THE CHRONIC PHASE (CML-CP) TO THE BLAST CRISIS (CML-BC). DOWNREGULATION OF MIR-96 COULD PROMOTE THE PROLIFERATION AND PARTICIPATE IN THE CELL DIFFERENTIATION OF CML-BC CELLS. ADDITIONALLY, WE FOUND THAT THE NOVEL HISTONE DEACETYLASE DRUG CHIDAMIDE AND THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE COULD RESTORE THE LOW EXPRESSION OF MIR-96 IN CML CELLS, AND THERE WERE TWO ABNORMAL HYPERMETHYLATED SITES IN THE PROMOTER REGION OF MIR-96 IN CML, SUGGESTING THAT ITS LOW EXPRESSION MIGHT BE AT LEAST PARTIALLY REGULATED BY EPIGENETIC MECHANISMS. IN ADDITION, RE-EXPRESSION OF MIR-96 COULD INCREASE THE SENSITIVITY OF CML-BC CELLS TO IMATINIB. THUS, MIR-96 FUNCTIONS AS A TUMOR SUPPRESSOR, AND RE-EXPRESSION OF THIS MICRORNA MIGHT HAVE THERAPEUTIC BENEFITS IN CML BLASTIC TRANSFORMATION. 2019 10 572 35 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 11 4741 39 NOVEL HDAC INHIBITOR MAKV-8 AND IMATINIB SYNERGISTICALLY KILL CHRONIC MYELOID LEUKEMIA CELLS VIA INHIBITION OF BCR-ABL/MYC-SIGNALING: EFFECT ON IMATINIB RESISTANCE AND STEM CELLS. BACKGROUND: CHRONIC MYELOID LEUKEMIA (CML) PATHOGENESIS IS MAINLY DRIVEN BY THE ONCOGENIC BREAKPOINT CLUSTER REGION-ABELSON MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1 (BCR-ABL) FUSION PROTEIN. SINCE BCR-ABL DISPLAYS ABNORMAL CONSTITUTIVE TYROSINE KINASE ACTIVITY, THERAPIES USING TYROSINE KINASE INHIBITORS (TKIS) SUCH AS IMATINIB REPRESENT A MAJOR BREAKTHROUGH FOR THE OUTCOME OF CML PATIENTS. NEVERTHELESS, THE DEVELOPMENT OF TKI RESISTANCE AND THE PERSISTENCE OF LEUKEMIA STEM CELLS (LSCS) REMAIN BARRIERS TO CURE THE DISEASE, JUSTIFYING THE DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES. SINCE THE ACTIVITY OF HISTONE DEACETYLASE (HDAC) IS DEREGULATED IN NUMEROUS CANCERS INCLUDING CML, PAN-HDAC INHIBITORS MAY REPRESENT PROMISING THERAPEUTIC REGIMENS FOR THE TREATMENT OF CML CELLS IN COMBINATION WITH TKI. RESULTS: WE ASSESSED THE ANTI-LEUKEMIC ACTIVITY OF A NOVEL HYDROXAMATE-BASED PAN-HDAC INHIBITOR MAKV-8, WHICH COMPLIED WITH THE LIPINSKI'S "RULE OF FIVE," IN VARIOUS CML CELLS ALONE OR IN COMBINATION WITH IMATINIB. WE VALIDATED THE IN VITRO HDAC-INHIBITORY POTENTIAL OF MAKV-8 AND DEMONSTRATED EFFICIENT BINDING TO THE LIGAND-BINDING POCKET OF HDAC ISOENZYMES. IN CELLULO, MAKV-8 SIGNIFICANTLY INDUCED TARGET PROTEIN ACETYLATION, DISPLAYED CYTOSTATIC AND CYTOTOXIC PROPERTIES, AND TRIGGERED CONCOMITANT ER STRESS/PROTECTIVE AUTOPHAGY LEADING TO CANONICAL CASPASE-DEPENDENT APOPTOSIS. CONSIDERING THE SPECIFIC UPREGULATION OF SELECTED HDACS IN LSCS FROM CML PATIENTS, WE INVESTIGATED THE DIFFERENTIAL TOXICITY OF A CO-TREATMENT WITH MAKV-8 AND IMATINIB IN CML VERSUS HEALTHY CELLS. WE ALSO SHOWED THAT BECLIN-1 KNOCKDOWN PREVENTED MAKV-8-IMATINIB COMBINATION-INDUCED APOPTOSIS. MOREOVER, MAKV-8 AND IMATINIB CO-TREATMENT SYNERGISTICALLY REDUCED BCR-ABL-RELATED SIGNALING PATHWAYS INVOLVED IN CML CELL GROWTH AND SURVIVAL. SINCE OUR RESULTS SHOWED THAT LSCS FROM CML PATIENTS OVEREXPRESSED C-MYC, IMPORTANTLY MAKV-8-IMATINIB CO-TREATMENT REDUCED C-MYC LEVELS AND THE LSC POPULATION. IN VIVO, TUMOR GROWTH OF XENOGRAFTED K-562 CELLS IN ZEBRAFISH WAS COMPLETELY ABROGATED UPON COMBINED TREATMENT WITH MAKV-8 AND IMATINIB. CONCLUSIONS: COLLECTIVELY, THE PRESENT FINDINGS SHOW THAT COMBINATIONS HDAC INHIBITOR-IMATINIB ARE LIKELY TO OVERCOME DRUG RESISTANCE IN CML PATHOLOGY. 2020 12 4533 43 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 13 3530 33 IMATINIB (ST1571) PROVIDES ONLY LIMITED SELECTIVITY FOR CML CELLS AND TREATMENT MIGHT BE COMPLICATED BY SILENT BCR-ABL GENES. VERY PROMISING RESULTS HAVE BEEN OBTAINED IN CLINICAL TRIALS ON CHRONIC-PHASE CHRONIC MYELOID LEUKEMIA (CP-CML) PATIENTS TREATED WITH IMATINIB MESYLATE (IM; GLEEVECR, STI571), A BCR-ABL TYROSINE KINASE INHIBITOR. HOWEVER, WE FOUND THAT IM CAUSED CONSIDERABLE INHIBITION OF NORMAL HEMATOPOIETIC PROGENITOR CELLS UPON TREATING CONTROL BONE MARROW (BM) CULTURES. IN VITRO IM TREATMENT GAVE A DECREASE IN THE YIELD AND SIZE OF COLONIES FROM BM OF UNTREATED CP-CML PATIENTS THAT WAS ONLY TWO TO THREE TIMES THAT FROM THE NORMAL SAMPLES. MOREOVER, ABOUT 30% OF MYELOID PROGENITORS (CFU-GM) FROM CML BM STILL FORMED COLONIES IN THE PRESENCE OF IM, MOST OF WHICH HAD BCR-ABL RNA. ABOUT HALF OF THESE TREATED COLONIES ALSO DISPLAYED METHYLATION OF THE INTERNAL ABL PA PROMOTER, A CML-SPECIFIC EPIGENETIC ALTERATION, WHICH WAS USED IN THIS STUDY AS A MARKER FOR BCR-ABL TRANSLOCATION-CONTAINING CELLS. HOWEVER, ~5-8% OF THE TREATED OR THE UNTREATED CML BM-DERIVED COLONIES HAD NO DETECTABLE BCR-ABL RNA BY TWO OR THREE ROUNDS OF RT-PCR DESPITE BEING POSITIVE FOR THE INTERNAL STANDARD RNA AND DISPLAYING HALLMARKS OF CML, EITHER T(9;22)(Q34;QL 1) OR ABL PA METHYLATION. OUR RESULTS INDICATE THAT IM IS ONLY PARTIALLY SPECIFIC FOR CML PROGENITOR CELLS COMPARED TO NORMAL HEMATOPOIETIC PROGENITOR CELLS AND SUGGEST THAT SOME CML CELLS MAY HAVE A SILENT BCR-ABL ONCOGENE THAT COULD INTERFERE WITH THERAPY. 2003 14 6609 30 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 15 954 16 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 5319 36 PTEN IS FUNDAMENTAL FOR ELIMINATION OF LEUKEMIA STEM CELLS MEDIATED BY GSK126 TARGETING EZH2 IN CHRONIC MYELOGENOUS LEUKEMIA. PURPOSE: LEUKEMIA STEM CELLS (LSCS) ARE AN IMPORTANT SOURCE OF TYROSINE KINASE INHIBITOR RESISTANCE AND DISEASE RELAPSE IN PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA (CML). TARGETING LSCS MAY BE AN ATTRACTIVE STRATEGY TO OVERRIDE THIS THORNY PROBLEM. GIVEN THAT EZH2 WAS OVEREXPRESSED IN PRIMARY CML CD34(+) CELLS, OUR PURPOSE IN THIS STUDY WAS TO EVALUATE THE EFFECTS OF TARGETING EZH2 ON CML LSCS AND CLARIFY ITS UNDERLYING MECHANISM.EXPERIMENTAL DESIGN: HUMAN PRIMARY CML CD34(+) CELLS AND RETROVIRALLY BCR-ABL-DRIVEN CML MOUSE MODELS WERE EMPLOYED TO EVALUATE THE EFFECTS OF SUPPRESSION OF EZH2 BY GSK126- OR EZH2-SPECIFIC SHRNA IN VITRO AND IN VIVO RECRUITMENT OF EZH2 AND H3K27ME3 ON THE PROMOTER OF TUMOR-SUPPRESSOR GENE PTEN IN CML CELLS WAS MEASURED BY CHROMATIN IMMUNOPRECIPITATION ASSAY.RESULTS: OUR RESULTS SHOWED THAT PHARMACOLOGIC INHIBITION OF EZH2 BY GSK126 NOT ONLY ELICITED APOPTOSIS AND RESTRICTED CELL GROWTH IN CML BULK LEUKEMIA CELLS, BUT ALSO DECREASED LSCS IN CML CD34(+) CELLS WHILE SPARING THOSE FROM NORMAL BONE MARROW CD34(+) CELLS. SUPPRESSION OF EZH2 BY GSK126 OR SPECIFIC SHRNA PROLONGED SURVIVAL OF CML MICE AND REDUCED THE NUMBER OF LSCS IN MICE. EZH2 KNOCKDOWN RESULTED IN ELEVATION OF PTEN AND LED TO IMPAIRED RECRUITMENT OF EZH2 AND H3K27ME3 ON THE PROMOTER OF PTEN GENE. THE EFFECT OF EZH2 KNOCKDOWN IN THE CML MICE WAS AT LEAST PARTIALLY REVERSED BY PTEN KNOCKDOWN.CONCLUSIONS: THESE FINDINGS IMPROVE THE UNDERSTANDING OF THE EPIGENETIC REGULATION OF STEMNESS IN CML LSCS AND WARRANT CLINICAL TRIAL OF GSK126 IN REFRACTORY PATIENTS WITH CML. CLIN CANCER RES; 24(1); 145-57. (C)2017 AACR. 2018 17 32 34 A CASE OF TYROSINE KINASE INHIBITOR-RESISTANT CHRONIC MYELOID LEUKEMIA, CHRONIC PHASE WITH ASXL1 MUTATION. HEMATOLOGICAL MALIGNANCIES, INCLUDING CHRONIC MYELOID LEUKEMIA (CML), EXHIBIT ASXL1 MUTATIONS; HOWEVER, THE FUNCTION AND MOLECULAR MECHANISM OF THESE MUTATIONS REMAIN UNCLEAR. ASXL1 WAS ORIGINALLY IDENTIFIED AS TUMOR SUPPRESSOR GENE, IN WHICH LOSS OF FUNCTION CAUSES MYELODYSPLASTIC SYNDROME (MDS). ASXL1 MUTATIONS ARE COMMON AND ASSOCIATED WITH DISEASE PROGRESSION IN MYELOID MALIGNANCIES INCLUDING MDS, ACUTE MYELOID LEUKEMIA, AND SIMILARLY IN CML. IN MDS, ASXL1 MUTATIONS HAVE BEEN ASSOCIATED WITH POOR PROGNOSIS; HOWEVER, THE IMPACT OF ASXL1 MUTATIONS IN CML HAS NOT BEEN WELL DESCRIBED. A 31-YEAR-OLD MALE WAS DIAGNOSED AS CML-CHRONIC PHASE (CP). LABORATORY FINDINGS SHOWED A WHITE BLOOD CELL COUNT OF 187,200/MICROL, WITH ASYMPTOMATIC SPLENOMEGALY. BLAST COUNT WAS 5.0% IN PERIPHERAL BLOOD AND 7.3% IN BONE MARROW. THERE WAS NO ADDITIONAL CHROMOSOMAL ABNORMALITY EXCEPT FOR T(9;22)(Q34;Q11.2) BY CHROMOSOMAL ANALYSIS. AT ONSET, THE SOKAL SCORE WAS 1.4, INDICATING HIGH RISK. THE PATIENT RECEIVED TYROSINE KINASE INHIBITOR (TKI) THERAPY, COMPRISING NILOTINIB APPROXIMATELY 600 MG/DAY, BOSUTINIB APPROXIMATELY 600 MG/DAY, PONATINIB APPROXIMATELY 45 MG/DAY, AND DASATINIB APPROXIMATELY 100 MG/DAY. NEVERTHELESS, AFTER 1.5 YEARS OF CONTINUOUS TKI THERAPY, THE BEST OUTCOME WAS A HEMATOLOGICAL RESPONSE. ALTHOUGH ADDITIONAL CHROMOSOMAL ABERRATIONS AND ABL1 KINASE MUTATIONS WERE ANALYZED REPEATEDLY BEFORE AND DURING TKI THERAPY, KNOWN GENETIC ABNORMALITIES WERE NOT DETECTED. THEREAFTER, THE PATIENT UNDERWENT BONE MARROW TRANSPLANTATION FROM AN HLA 7/8 MATCHED UNRELATED DONOR (HLA-CW 1 LOCUS MISMATCH, GRAFT-VERSUS-HOST DIRECTION). THE PATIENT ACHIEVED NEUTROPHIL ENGRAFTMENT, 18 DAYS AFTER TRANSPLANTATION, LEADING TO COMPLETE REMISSION WITH AN UNDETECTABLE LEVEL OF BCR-ABL1 MRNA. THE PATIENT, HOWEVER, DIED FROM GRAFT-VERSUS-HOST DISEASE AND THROMBOTIC MICROANGIOPATHY AFTER 121 DAYS. GENE SEQUENCE ANALYSIS OF HIS CML CELL BEFORE STEM CELL TRANSPLANTATION REVEALED ASXL1 MUTATIONS. PHYSIOLOGICALLY, ASXL1 CONTRIBUTES TO EPIGENETIC REGULATION. IN THE CML-CP PATIENT IN THIS CASE REPORT, ASXL1 MUTATION CONFERRED RESISTANCE TO TKI THROUGH OBSCURE RESISTANCE MECHANISMS. EVEN THOUGH A MOLECULAR MECHANISM FOR TKI RESISTANCE IN ASXL1 MUTATION IN CML HAS REMAINED OBSCURE, EPIGENETIC MODULATION IS A PLAUSIBLE MODE OF CML DISEASE PROGRESSION. THE CLINICAL IMPACT INCLUDING PROGNOSIS OF ASXL1 FOR CML IS UNDERSCORED. AND THE TREATMENT STRATEGY OF CML WITH ASXL1 MUTATION HAS NOT BEEN ESTABLISHED. A DISCUSSION OF THIS CASE WAS EXPECTED TO FACILITATE TREATMENT OPTIONS. 2020 18 571 28 BCR-ABL INDUCES AUTOCRINE IGF-1 SIGNALING. BCR-ABL ONCOGENE IS RESPONSIBLE FOR THE INITIAL PHASE OF CHRONIC MYELOGENOUS LEUKEMIA (CML), WHICH IS EFFECTIVELY TREATED BY THE BCR-ABL INHIBITOR IMATINIB. OVER TIME PATIENTS BECOME RESISTANT TO TREATMENT AND PROGRESS TO BLAST CRISIS, AN EVENT THAT IS DRIVEN BY ADDITIONAL GENETIC AND EPIGENETIC ABERRATIONS. RECENTLY, WE SHOWED THAT RIZ1 EXPRESSION DECREASES IN BLAST CRISIS AND THAT RE-EXPRESSION OF RIZ1 INHIBITS IGF-1 EXPRESSION. IGF-1 SIGNALING IS REQUIRED IN MANY STAGES OF HEMATOPOIESIS AND INAPPROPRIATE ACTIVATION OF AUTOCRINE IGF-1 SIGNALING MAY FACILITATE TRANSFORMATION TO BLAST CRISIS. WE OBSERVED THAT IN 8 OUT OF 11 MATCHED CML PATIENT BIOPSIES THE IGF-1 EXPRESSION IS ELEVATED IN BLAST CRISIS. WE EXAMINED MECHANISMS USED BY CML BLAST CRISIS CELL LINES TO ACTIVATE IGF-1 EXPRESSION. WE FOUND THAT BCR-ABL ACTIVATES AUTOCRINE IGF-1 SIGNALING USING HCK AND STAT5B. INHIBITION OF THESE SIGNALING COMPONENTS USING SMALL MOLECULE DRUGS OR SHRNA DECREASES PROLIFERATION AND ENHANCES APOPTOSIS. TOGETHER, OUR STUDY SUGGESTS THAT ABERRANT IGF-1 SIGNALING IS AN IMPORTANT EVENT IN BLAST CRISIS TRANSFORMATION AND IT PROVIDES A MECHANISM TO EXPLAIN THE ACTIVITY OF IGF-1R AND HCK INHIBITORS IN BLOCKING CML BLAST CRISIS PHENOTYPES. 2008 19 953 34 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 20 1685 34 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