1 570 153 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 2 4533 46 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 3 1685 56 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 4 4124 46 MECHANISMS OF DISEASE PROGRESSION AND RESISTANCE TO TYROSINE KINASE INHIBITOR THERAPY IN CHRONIC MYELOID LEUKEMIA: AN UPDATE. CHRONIC MYELOID LEUKEMIA (CML) IS CHARACTERIZED BY THE PRESENCE OF THE BCR-ABL1 FUSION GENE, WHICH ENCODES A CONSTITUTIVE ACTIVE TYROSINE KINASE CONSIDERED TO BE THE PATHOGENIC DRIVER CAPABLE OF INITIATING AND MAINTAINING THE DISEASE. DESPITE THE REMARKABLE EFFICACY OF TYROSINE KINASE INHIBITORS (TKIS) TARGETING BCR-ABL1, SOME PATIENTS MAY NOT RESPOND (PRIMARY RESISTANCE) OR MAY RELAPSE AFTER AN INITIAL RESPONSE (SECONDARY RESISTANCE). IN A SMALL PROPORTION OF CASES, DEVELOPMENT OF RESISTANCE IS ACCOMPANIED OR SHORTLY FOLLOWED BY PROGRESSION FROM CHRONIC TO BLASTIC PHASE (BP), CHARACTERIZED BY A DISMAL PROGNOSIS. EVOLUTION FROM CP INTO BP IS A MULTIFACTORIAL AND PROBABLY MULTISTEP PHENOMENON. INCREASE IN BCR-ABL1 TRANSCRIPT LEVELS IS THOUGHT TO PROMOTE THE ONSET OF SECONDARY CHROMOSOMAL OR GENETIC DEFECTS, INDUCE DIFFERENTIATION ARREST, PERTURB RNA TRANSCRIPTION, EDITING AND TRANSLATION THAT TOGETHER WITH EPIGENETIC AND METABOLIC CHANGES MAY ULTIMATELY LEAD TO THE EXPANSION OF HIGHLY PROLIFERATING, DIFFERENTIATION-ARRESTED MALIGNANT CELLS. A MULTITUDE OF STUDIES OVER THE PAST TWO DECADES HAVE INVESTIGATED THE MECHANISMS UNDERLYING THE CLOSELY INTERTWINED PHENOMENA OF DRUG RESISTANCE AND DISEASE PROGRESSION. HERE, WE PROVIDE AN UPDATE ON WHAT IS CURRENTLY KNOWN ON THE MECHANISMS UNDERLYING PROGRESSION AND PRESENT THE LATEST ACQUISITIONS ON BCR-ABL1-INDEPENDENT RESISTANCE AND LEUKEMIA STEM CELL PERSISTENCE. 2019 5 109 52 A REVIEW ON THE THERAPEUTIC ROLE OF TKIS IN CASE OF CML IN COMBINATION WITH EPIGENETIC DRUGS. CHRONIC MYELOID LEUKEMIA IS A MALIGNANCY OF BONE MARROW THAT AFFECTS WHITE BLOOD CELLS. THERE IS STRONG EVIDENCE THAT DISEASE PROGRESSION, TREATMENT RESPONSES, AND OVERALL CLINICAL OUTCOMES OF CML PATIENTS ARE INFLUENCED BY THE ACCUMULATION OF OTHER GENETIC AND EPIGENETIC ABNORMALITIES, RATHER THAN ONLY THE BCR/ABL1 ONCOPROTEIN. BOTH GENETIC AND EPIGENETIC FACTORS INFLUENCE THE EFFICACY OF CML TREATMENT STRATEGIES. TARGETED MEDICINES KNOWN AS TYROSINE-KINASE INHIBITORS HAVE DRAMATICALLY IMPROVED LONG-TERM SURVIVAL RATES IN CML PATIENTS DURING THE PREVIOUS 2 DECADES. WHEN COMPARED TO EARLIER CHEMOTHERAPY TREATMENTS, THESE DRUGS HAVE REVOLUTIONIZED CML TREATMENT AND ALLOWED MOST PEOPLE TO LIVE LONGER LIVES. ALTHOUGH EPIGENETIC INHIBITORS' ACTIVITY IS DISRUPTED IN MANY CANCERS, INCLUDING CML, BUT WHEN COMBINED WITH TKI, THEY MAY OFFER POTENTIAL THERAPEUTIC STRATEGIES FOR THE TREATMENT OF CML CELLS. THE EPIGENETICS OF TYROSINE KINASE INHIBITORS AND RESISTANCE TO THEM IS BEING STUDIED, WITH A PARTICULAR FOCUS ON IMATINIB, WHICH IS USED TO TREAT CML. IN ADDITION, THE USE OF EPIGENETIC DRUGS IN CONJUNCTION WITH TKIS HAS BEEN DISCUSSED. RESISTANCE TO TKIS IS STILL A PROBLEM IN CURING THE DISEASE, NECESSITATING THE DEVELOPMENT OF NEW THERAPIES. THIS STUDY FOCUSED ON EPIGENETIC PATHWAYS INVOLVED IN CML PATHOGENESIS AND TUMOR CELL RESISTANCE TO TKIS, BOTH OF WHICH CONTRIBUTE TO LEUKEMIC CLONE BREAKOUT AND PROLIFERATION. 2021 6 5212 43 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 7 1142 46 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 8 5718 38 SIRTUIN1 AND CHRONIC MYELOID LEUKEMIA: A COMPREHENSIVE GLANCE AT DRUG RESISTANCE. BACKGROUND: CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER, WHICH IS CAUSED BY BCR-ABL FUSION THAT HAS TYROSINE KINASE ACTIVITY. THE EMERGENCE OF THE FIRST GENERATION OF TYROSINE KINASE INHIBITORS INCREASED SURVIVAL IN PATIENTS. CML PATIENTS REMAIN IN SILENT PHASE FOR A LONG TIME BY USING DRUGS SUCH AS IMATINIB. RESISTANCE TO IMATINIB CAUSES RELAPSE OF DISEASE AFTER USING IT. DIFFERENT FACTORS SUCH AS MUTATIONS, EPIGENETIC FACTORS, AND CHANGES IN THE DRUG'S RECEPTOR CAN PLAY AN IMPORTANT ROLE IN DRUG RESISTANCE. SIRT1 IS AN NAD-DEPENDENT DEACETYLASE THAT HAS A ROLE IN REGULATION OF METABOLIC ACTIVITIES. IT HAS BEEN RECENTLY CONSIDERED AS A KEY REGULATOR OF DRUG RESISTANCE IN MALIGNANCIES SUCH AS CML. METHODS: THE RESOURCES OF THIS STUDY ARE FROM DIFFERENT SITES AND JOURNALS SUCH AS NCBI.NLM.NIH.GOV/PUBMED, SCOPUS.COM, AMERICAN JOURNAL OF HEMATOLOGY, INTERNATIONAL JOURNAL OF HEMATOLOGY, ETC. RESULTS: EXPRESSION OF SIRT1 IS INCREASED IN PATIENTS WITH IMATINIB RESISTANCE. THE MECHANISM OF THIS RESISTANCE IS NOT EXACTLY UNDERSTOOD. THE INHIBITION OF SIRT1 IN CML CAUSES INCREASED SENSITIVITY TO IMATINIB. CONCLUSIONS: RECOGNITION OF DRUG RESISTANCE FACTORS, REDUCTION OR NEUTRALIZATION OF THEM IS SO IMPORTANT IN PATIENTS' SURVIVAL. THIS STUDY INDICATES THE ROLE OF SIRT1 AS ONE OF THE MOST COMMON CAUSES OF DRUG RESISTANCE IN MANY CANCERS SUCH AS CML. 2021 9 599 37 BETA-CELL DIFFERENTIATION STATUS IN TYPE 2 DIABETES. TYPE 2 DIABETES (T2D) AFFECTS 415 MILLION PEOPLE WORLDWIDE AND IS CHARACTERIZED BY CHRONIC HYPERGLYCAEMIA AND INSULIN RESISTANCE, PROGRESSING TO INSUFFICIENT INSULIN PRODUCTION, AS A RESULT OF BETA-CELL FAILURE. OVER TIME, CHRONIC HYPERGLYCAEMIA CAN ULTIMATELY LEAD TO LOSS OF BETA-CELL FUNCTION, LEAVING PATIENTS INSULIN-DEPENDENT. UNTIL RECENTLY THE LOSS OF BETA-CELL MASS SEEN IN T2D WAS CONSIDERED TO BE THE RESULT OF INCREASED RATES OF APOPTOSIS; HOWEVER, IT HAS BEEN PROPOSED THAT APOPTOSIS ALONE CANNOT ACCOUNT FOR THE EXTENT OF BETA-CELL MASS LOSS SEEN IN THE DISEASE, AND THAT A LOSS OF FUNCTION MAY ALSO OCCUR AS A RESULT OF CHANGES IN BETA-CELL DIFFERENTIATION STATUS. IN THE PRESENT REVIEW, WE CONSIDER CURRENT KNOWLEDGE OF DETERMINANTS OF BETA-CELL FATE IN THE CONTEXT OF UNDERSTANDING ITS RELEVANCE TO DISEASE PROCESS IN T2D, AND ALSO THE IMPACT OF A DIABETOGENIC ENVIRONMENT (HYPERGLYCAEMIA, HYPOXIA, INFLAMMATION AND DYSLIPIDAEMIA) ON THE EXPRESSION OF GENES INVOLVED IN MAINTENANCE OF BETA-CELL IDENTITY. WE DESCRIBE CURRENT KNOWLEDGE OF THE IMPACT OF THE DIABETIC MICROENVIRONMENT ON GENE REGULATORY PROCESSES SUCH ALTERNATIVE SPLICING, THE EXPRESSION OF DISALLOWED GENES AND EPIGENETIC MODIFICATIONS. ELUCIDATING THE MOLECULAR MECHANISMS THAT UNDERPIN CHANGES TO BETA-CELL DIFFERENTIATION STATUS AND THE CONCOMITANT BETA-CELL FAILURE OFFERS POTENTIAL TREATMENT TARGETS FOR THE FUTURE MANAGEMENT OF PATIENTS WITH T2D. 2016 10 6609 44 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 11 953 41 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 12 955 40 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 13 6259 23 THE MOLECULAR MECHANISMS BY WHICH VITAMIN D PREVENTS INSULIN RESISTANCE AND ASSOCIATED DISORDERS. NUMEROUS STUDIES HAVE SHOWN THAT VITAMIN D DEFICIENCY IS VERY COMMON IN MODERN SOCIETIES AND IS PERCEIVED AS AN IMPORTANT RISK FACTOR IN THE DEVELOPMENT OF INSULIN RESISTANCE AND RELATED DISEASES SUCH AS OBESITY AND TYPE 2 DIABETES (T2DM). WHILE IT IS GENERALLY ACCEPTED THAT VITAMIN D IS A REGULATOR OF BONE HOMEOSTASIS, ITS ABILITY TO COUNTERACT INSULIN RESISTANCE IS SUBJECT TO DEBATE. THE GOAL OF THIS COMMUNICATION IS TO REVIEW THE MOLECULAR MECHANISM BY WHICH VITAMIN D REDUCES INSULIN RESISTANCE AND RELATED COMPLICATIONS. THE UNIVERSITY LIBRARY, PUBMED, AND GOOGLE SCHOLAR WERE SEARCHED TO FIND RELEVANT STUDIES TO BE SUMMARIZED IN THIS REVIEW ARTICLE. INSULIN RESISTANCE IS ACCOMPANIED BY CHRONIC HYPERGLYCAEMIA AND INFLAMMATION. RECENT STUDIES HAVE SHOWN THAT VITAMIN D EXHIBITS INDIRECT ANTIOXIDATIVE PROPERTIES AND PARTICIPATES IN THE MAINTENANCE OF NORMAL RESTING ROS LEVEL. APPEALINGLY, VITAMIN D REDUCES INFLAMMATION AND REGULATES CA(2+) LEVEL IN MANY CELL TYPES. THEREFORE, THE BENEFICIAL ACTIONS OF VITAMIN D INCLUDE DIMINISHED INSULIN RESISTANCE WHICH IS OBSERVED AS AN IMPROVEMENT OF GLUCOSE AND LIPID METABOLISM IN INSULIN-SENSITIVE TISSUES. 2020 14 2393 44 EPIGENETIC REPROGRAMMING AND EMERGING EPIGENETIC THERAPIES IN CML. CHRONIC MYELOID LEUKEMIA (CML) IS A HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY BCR-ABL1, AN ONCOGENIC FUSION GENE ARISING FROM THE PHILADELPHIA CHROMOSOME. THE DEVELOPMENT OF TYROSINE KINASE INHIBITORS (TKIS) TO OVERCOME THE CONSTITUTIVE TYROSINE KINASE ACTIVITY OF THE BCR-ABL PROTEIN HAS DRAMATICALLY IMPROVED DISEASE MANAGEMENT AND PATIENT OUTCOMES OVER THE PAST 20 YEARS. HOWEVER, THE MAJORITY OF PATIENTS ARE NOT CURED AND DEVELOPING NOVEL THERAPEUTIC STRATEGIES THAT TARGET EPIGENETIC PROCESSES ARE A PROMISING AVENUE TO IMPROVE CURE RATES. A NUMBER OF EPIGENETIC MECHANISMS ARE ALTERED OR REPROGRAMMED DURING THE DEVELOPMENT AND PROGRESSION OF CML, RESULTING IN ALTERATIONS IN HISTONE MODIFICATIONS, DNA METHYLATION AND DYSREGULATION OF THE TRANSCRIPTIONAL MACHINERY. IN THIS REVIEW THESE EPIGENETIC ALTERATIONS ARE EXAMINED AND THE POTENTIAL OF EPIGENETIC THERAPIES ARE DISCUSSED AS A MEANS OF ERADICATING RESIDUAL DISEASE AND OFFERING A POTENTIAL CURE FOR CML IN COMBINATION WITH CURRENT THERAPIES. 2019 15 5589 34 ROLE OF SIRT1 IN THE GROWTH AND REGULATION OF NORMAL HEMATOPOIETIC AND LEUKEMIA STEM CELLS. PURPOSE OF REVIEW: RECENT STUDIES HAVE ENHANCED OUR UNDERSTANDING OF THE ROLE OF THE SIRT1 DEACETYLASE IN REGULATION OF NORMAL HEMATOPOIETIC STEM CELLS (HSCS) AND LEUKEMIA STEM CELLS (LSCS), AND ITS IMPORTANCE IN REGULATING AUTOPHAGY AND EPIGENETIC REPROGRAMMING IN RESPONSE TO METABOLIC ALTERATIONS. RECENT FINDINGS: STUDIES EMPLOYING CONDITIONAL DELETION MOUSE MODELS INDICATE AN IMPORTANT ROLE OF SIRT1 IN MAINTENANCE OF ADULT HSCS UNDER CONDITIONS OF STRESS. SIRT1 IS SIGNIFICANTLY OVEREXPRESSED IN LSC POPULATIONS FROM ACUTE MYELOID LEUKEMIA (AML) PATIENTS WITH THE FLT3-ITD MUTATION, AND MAINTAINS THEIR SURVIVAL, GROWTH AND DRUG RESISTANCE, AS PREVIOUSLY DESCRIBED FOR CHRONIC MYELOGENOUS LEUKEMIA (CML). SIRT1 CAN ALSO ENHANCE LEUKEMIA EVOLUTION AND DRUG RESISTANCE BY PROMOTING GENETIC INSTABILITY. RECENT STUDIES INDICATE AN IMPORTANT ROLE OF SIRT1 IN REGULATING AUTOPHAGY IN RESPONSE TO OXIDATIVE STRESS AND NUTRIENT REQUIREMENTS, AND HAVE ELUCIDATED COMPLEX MECHANISMS BY WHICH SIRT1 REGULATES EPIGENETIC REPROGRAMMING OF STEM CELLS. SUMMARY: SIRT1 INHIBITION HOLDS PROMISE AS A NOVEL APPROACH FOR ABLATION OF LSCS IN CHRONIC PHASE CML OR FLT3-ITD-ASSOCIATED AML. ADDITIONAL STUDIES TO UNDERSTAND THE ROLE OF SIRT1 IN LINKING METABOLIC ALTERATIONS TO GENOMIC STABILITY, AUTOPHAGY AND EPIGENETIC REPROGRAMMING OF STEM CELLS ARE WARRANTED. 2015 16 6198 51 THE IMPLICATION OF CANCER PROGENITOR CELLS AND THE ROLE OF EPIGENETICS IN THE DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES FOR CHRONIC MYELOID LEUKEMIA. SIGNIFICANCE: CHRONIC MYELOID LEUKEMIA (CML) INVOLVES THE MALIGNANT TRANSFORMATION OF HEMATOPOIETIC STEM CELLS, DEFINED LARGELY BY THE PHILADELPHIA CHROMOSOME AND EXPRESSION OF THE BREAKPOINT CLUSTER REGION-ABELSON (BCR-ABL) ONCOPROTEIN. PHARMACOLOGICAL TYROSINE KINASE INHIBITORS (TKIS), INCLUDING IMATINIB MESYLATE, HAVE OVERCOME LIMITATIONS IN CONVENTIONAL TREATMENT FOR THE IMPROVED CLINICAL MANAGEMENT OF CML. RECENT ADVANCES: ACCUMULATED EVIDENCE HAS LED TO THE IDENTIFICATION OF A SUBPOPULATION OF QUIESCENT LEUKEMIA PROGENITOR CELLS WITH STEM-LIKE SELF RENEWAL PROPERTIES THAT MAY INITIATE LEUKEMOGENESIS, WHICH ARE ALSO SHOWN TO BE PRESENT IN RESIDUAL DISEASE DUE TO THEIR INSENSITIVITY TO TYROSINE KINASE INHIBITION. CRITICAL ISSUES: THE CHARACTERIZATION OF QUIESCENT LEUKEMIA PROGENITOR CELLS AS A UNIQUE CELL POPULATION IN CML PATHOGENESIS HAS BECOME CRITICAL WITH THE COMPLETE ELUCIDATION OF MECHANISMS INVOLVED IN THEIR SURVIVAL INDEPENDENT OF BCR-ABL THAT IS IMPORTANT IN THE DEVELOPMENT OF NOVEL ANTICANCER STRATEGIES. UNDERSTANDING OF THESE FUNCTIONAL PATHWAYS IN CML PROGENITOR CELLS WILL ALLOW FOR THEIR SELECTIVE THERAPEUTIC TARGETING. IN ADDITION, DISEASE PATHOGENESIS AND DRUG RESPONSIVENESS IS ALSO THOUGHT TO BE MODULATED BY EPIGENETIC REGULATORY MECHANISMS SUCH AS DNA METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION, WITH A CAPACITY TO CONTROL CML-ASSOCIATED GENE TRANSCRIPTION. FUTURE DIRECTIONS: A NUMBER OF COMPOUNDS IN COMBINATION WITH TKIS ARE UNDER PRECLINICAL AND CLINICAL INVESTIGATION TO ASSESS THEIR SYNERGISTIC POTENTIAL IN TARGETING LEUKEMIC PROGENITOR CELLS AND/OR THE EPIGENOME IN CML. DESPITE THE COLLECTIVE PROMISE, FURTHER RESEARCH IS REQUIRED IN ORDER TO REFINE UNDERSTANDING, AND, ULTIMATELY, ADVANCE ANTILEUKEMIC THERAPEUTIC STRATEGIES. 2015 17 2085 54 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 18 5549 27 ROLE OF EPIGENETICS IN CHRONIC MYELOID LEUKEMIA. THE EFFICACY OF THERAPEUTIC MODALITIES IN CHRONIC MYELOID LEUKEMIA (CML) DEPENDS ON BOTH GENETIC AND EPIGENETIC MECHANISMS. THIS REVIEW FOCUSES ON EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF CML AND IN RESISTANCE OF TUMOR CELLS TO TYROSINE KINASE INHIBITORS LEADING TO THE LEUKEMIC CLONE ESCAPE AND PROPAGATION. REGULATORY EVENTS AT THE LEVELS OF GENE REGULATION BY TRANSCRIPTION FACTORS AND MICRORNAS ARE DISCUSSED IN THE CONTEXT OF CML PATHOGENESIS AND THERAPEUTIC MODALITIES. 2013 19 6182 39 THE IMPACT OF ADIPOSE TISSUE-DERIVED MIRNAS IN METABOLIC SYNDROME, OBESITY, AND CANCER. OBESITY IS A MULTIFACTORIAL AND COMPLEX CONDITION THAT IS CHARACTERIZED BY ABNORMAL AND EXCESSIVE WHITE ADIPOSE TISSUE ACCUMULATION, WHICH CAN LEAD TO THE DEVELOPMENT OF METABOLIC DISEASES, SUCH AS TYPE 2 DIABETES MELLITUS, NONALCOHOLIC FATTY LIVER DISEASE, CARDIOVASCULAR DISEASES, AND SEVERAL TYPES OF CANCER. OBESITY IS CHARACTERIZED BY EXCESSIVE ADIPOSE TISSUE ACCUMULATION AND ASSOCIATED WITH ALTERATIONS IN IMMUNITY, DISPLAYING A CHRONIC LOW-GRADE INFLAMMATION PROFILE. ADIPOSE TISSUE IS A DYNAMIC AND COMPLEX ENDOCRINE ORGAN COMPOSED NOT ONLY BY ADIPOCYTES, BUT SEVERAL IMMUNOLOGICAL CELLS, WHICH CAN SECRETE HORMONES, CYTOKINES AND MANY OTHER FACTORS CAPABLE OF REGULATING METABOLIC HOMEOSTASIS AND SEVERAL CRITICAL BIOLOGICAL PATHWAYS. REMARKABLY, ADIPOSE TISSUE IS A MAJOR SOURCE OF CIRCULATING MICRORNAS (MIRNAS), RECENTLY DESCRIBED AS A NOVEL FORM OF ADIPOKINES. SEVERAL ADIPOSE TISSUE-DERIVED MIRNAS ARE DEEPLY ASSOCIATED WITH ADIPOCYTES DIFFERENTIATION AND HAVE BEEN IDENTIFIED WITH AN ESSENTIAL ROLE IN OBESITY-ASSOCIATED INFLAMMATION, INSULIN RESISTANCE, AND TUMOR MICROENVIRONMENT. DURING OBESITY, ADIPOSE TISSUE CAN COMPLETELY CHANGE THE PROFILE OF THE SECRETED MIRNAS, INFLUENCING CIRCULATING MIRNAS AND IMPACTING THE DEVELOPMENT OF DIFFERENT PATHOLOGICAL CONDITIONS, SUCH AS OBESITY, METABOLIC SYNDROME, AND CANCER. IN THIS REVIEW, WE DISCUSS HOW MIRNAS CAN ACT AS EPIGENETIC REGULATORS AFFECTING ADIPOGENESIS, ADIPOCYTE DIFFERENTIATION, LIPID METABOLISM, BROWNING OF THE WHITE ADIPOSE TISSUE, GLUCOSE HOMEOSTASIS, AND INSULIN RESISTANCE, IMPACTING DEEPLY OBESITY AND METABOLIC DISEASES. MOREOVER, WE CHARACTERIZE HOW MIRNAS CAN OFTEN ACT AS ONCOGENIC AND TUMOR SUPPRESSOR MOLECULES, SIGNIFICANTLY MODULATING CANCER ESTABLISHMENT AND PROGRESSION. FURTHERMORE, WE HIGHLIGHT IN THIS MANUSCRIPT HOW ADIPOSE TISSUE-DERIVED MIRNAS CAN FUNCTION AS IMPORTANT NEW THERAPEUTIC TARGETS. 2020 20 952 38 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