1 954 64 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 2 1465 28 DISSECTING THE ROLE OF ABERRANT DNA METHYLATION IN HUMAN LEUKAEMIA. CHRONIC MYELOID LEUKAEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY THE GENETIC TRANSLOCATION T(9;22)(Q34;Q11.2) ENCODING FOR THE BCR-ABL FUSION ONCOGENE. HOWEVER, MANY MOLECULAR MECHANISMS OF THE DISEASE PROGRESSION STILL REMAIN POORLY UNDERSTOOD. A GROWING BODY OF EVIDENCE SUGGESTS THAT THE EPIGENETIC ABNORMALITIES ARE INVOLVED IN TYROSINE KINASE RESISTANCE IN CML, LEADING TO LEUKAEMIC CLONE ESCAPE AND DISEASE PROPAGATION. HERE WE SHOW THAT, BY APPLYING CELLULAR REPROGRAMMING TO PRIMARY CML CELLS, ABERRANT DNA METHYLATION CONTRIBUTES TO THE DISEASE EVOLUTION. IMPORTANTLY, USING A BCR-ABL INDUCIBLE MURINE MODEL, WE DEMONSTRATE THAT A SINGLE ONCOGENIC LESION TRIGGERS DNA METHYLATION CHANGES, WHICH IN TURN ACT AS A PRECIPITATING EVENT IN LEUKAEMIA PROGRESSION. 2015 3 5549 16 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 4 2393 27 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 5 1082 26 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 6 4552 27 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 7 6618 29 UNDERSTANDING AND MONITORING CHRONIC MYELOID LEUKEMIA BLAST CRISIS: HOW TO BETTER MANAGE PATIENTS. CHRONIC MYELOID LEUKEMIA (CML) IS TRIGGERED PRIMARILY BY THE T(9;22) (Q34.13; Q11.23) TRANSLOCATION. THIS RECIPROCAL CHROMOSOMAL TRANSLOCATION LEADS TO THE FORMATION OF THE BCR-ABL FUSION GENE. PATIENTS IN THE CHRONIC PHASE (CP) EXPERIENCE A GOOD CURATIVE EFFECT WITH TYROSINE KINASE INHIBITORS. HOWEVER, CASES ARE TREATMENT REFRACTORY, WITH A DISMAL PROGNOSIS, WHEN THE DISEASE HAS PROGRESSED TO THE ACCELERATED PHASE (AP) OR BLAST PHASE (BP). UNTIL NOW, FEW REPORTS HAVE PROVIDED A COMPREHENSIVE DESCRIPTION OF THE MECHANISMS INVOLVED AT DIFFERENT MOLECULAR LEVELS. INDEED, THE UNDERLYING PATHOGENESIS OF CML EVOLUTION COMPRISES GENETIC ABERRATIONS, CHROMOSOMAL TRANSLOCATIONS (EXCEPT FOR THE PHILADELPHIA CHROMOSOME), TELOMERE BIOLOGY, AND EPIGENETIC ANOMALIES. HEREIN, WE PROVIDE KNOWLEDGE OF THE BIOLOGY RESPONSIBLE FOR BLAST TRANSFORMATION OF CML AT SEVERAL LEVELS, SUCH AS GENETICS, TELOMERE BIOLOGY, AND EPIGENETIC ANOMALIES. BECAUSE OF THE LIMITED TREATMENT OPTIONS AVAILABLE AND POOR OUTCOMES, ONLY THE THERAPEUTIC RESPONSE IS MONITORED REGULARLY, WHICH INVOLVES BCR-ABL TRANSCRIPT LEVEL ASSESSMENT AND IMMUNOLOGIC SURVEILLANCE, WITH THE OPTIMAL TREATMENT STRATEGY FOR PATIENTS IN CP ADAPTED TO EVALUATE DISEASE RECURRENCE OR PROGRESSION. OVERALL, SELECTING OPTIMAL TREATMENT ENDPOINTS TO PREDICT SURVIVAL AND SUCCESSFUL TFR IMPROVES THE QUALITY OF LIFE OF PATIENTS. THUS, IDENTIFYING RISK FACTORS AND DEVELOPING RISK-ADAPTED THERAPEUTIC OPTIONS MAY CONTRIBUTE TO A BETTER OUTCOME FOR ADVANCED-PHASE PATIENTS. 2021 8 109 25 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 9 6198 30 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 10 3234 23 HEMATOPOIETIC AND CHRONIC MYELOID LEUKEMIA STEM CELLS: MULTI-STABILITY VERSUS LINEAGE RESTRICTION. THERE IS COMPELLING EVIDENCE TO SUPPORT THE VIEW THAT THE CELL-OF-ORIGIN FOR CHRONIC MYELOID LEUKEMIA IS A HEMATOPOIETIC STEM CELL. UNLIKE NORMAL HEMATOPOIETIC STEM CELLS, THE PROGENY OF THE LEUKEMIA STEM CELLS ARE PREDOMINANTLY NEUTROPHILS DURING THE DISEASE CHRONIC PHASE AND THERE IS A MILD ANEMIA. THE HALLMARK ONCOGENE FOR CHRONIC MYELOID LEUKEMIA IS THE BCR-ABLP210 FUSION GENE. VARIOUS STUDIES HAVE EXCLUDED A ROLE FOR BCR-ABLP210 EXPRESSION IN MAINTAINING THE POPULATION OF LEUKEMIA STEM CELLS. STUDIES OF BCR-ABLP210 EXPRESSION IN EMBRYONAL STEM CELLS THAT WERE DIFFERENTIATED INTO HEMATOPOIETIC STEM CELLS AND OF THE EXPRESSION IN TRANSGENIC MICE HAVE REVEALED THAT BCR-ABLP210 IS ABLE TO VEER HEMATOPOIETIC STEM AND PROGENITOR CELLS TOWARDS A MYELOID FATE. FOR THE TRANSGENIC MICE, GLOBAL CHANGES TO THE EPIGENETIC LANDSCAPE WERE OBSERVED. IN CHRONIC MYELOID LEUKEMIA, THE ABILITY OF THE LEUKEMIA STEM CELLS TO CHOOSE FROM THE MANY FATES THAT ARE AVAILABLE TO NORMAL HEMATOPOIETIC STEM CELLS APPEARS TO BE DEREGULATED BY BCR-ABLP210 AND CHANGES TO THE EPIGENOME ARE ALSO IMPORTANT. EVEN SO, WE STILL DO NOT HAVE A PRECISE PICTURE AS TO WHY NEUTROPHILS ARE ABUNDANTLY PRODUCED IN CHRONIC MYELOID LEUKEMIA. 2022 11 955 19 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 12 1507 26 DNA METHYLATION AND INTRA-CLONAL HETEROGENEITY: THE CHRONIC MYELOID LEUKEMIA MODEL. CHRONIC MYELOID LEUKEMIA (CML) IS A MODEL TO INVESTIGATE THE IMPACT OF TUMOR INTRA-CLONAL HETEROGENEITY IN PERSONALIZED MEDICINE. INDEED, TYROSINE KINASE INHIBITORS (TKIS) TARGET THE BCR-ABL FUSION PROTEIN, WHICH IS CONSIDERED THE MAJOR CML DRIVER. TKI USE HAS HIGHLIGHTED THE EXISTENCE OF INTRA-CLONAL HETEROGENEITY, AS INDICATED BY THE PERSISTENCE OF A MINORITY SUBCLONE FOR SEVERAL YEARS DESPITE THE PRESENCE OF THE TARGET FUSION PROTEIN IN ALL CELLS. EPIGENETIC MODIFICATIONS COULD PARTLY EXPLAIN THIS HETEROGENEITY. THIS REVIEW SUMMARIZES THE RESULTS OF DNA METHYLATION STUDIES IN CML. NEXT-GENERATION SEQUENCING TECHNOLOGIES ALLOWED FOR MOVING FROM SINGLE-GENE TO GENOME-WIDE ANALYSES SHOWING THAT METHYLATION ABNORMALITIES ARE MUCH MORE WIDESPREAD IN CML CELLS. THESE DATA SHOWED THAT GLOBAL HYPOMETHYLATION IS ASSOCIATED WITH HYPERMETHYLATION OF SPECIFIC SITES ALREADY AT DIAGNOSIS IN THE EARLY PHASE OF CML. THE BCR-ABL-INDEPENDENCE OF SOME METHYLATION PROFILE ALTERATIONS AND THE RECENT DEMONSTRATION OF THE INITIAL INTRA-CLONAL DNA METHYLATION HETEROGENEITY SUGGESTS THAT SOME DNA METHYLATION ALTERATIONS MAY BE BIOMARKERS OF TKI SENSITIVITY/RESISTANCE AND OF DISEASE PROGRESSION RISK. THESE RESULTS ALSO OPEN PERSPECTIVES FOR UNDERSTANDING THE EPIGENETIC/GENETIC BACKGROUND OF CML PREDISPOSITION AND FOR DEVELOPING NEW THERAPEUTIC STRATEGIES. 2021 13 952 23 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 14 4124 26 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 15 572 28 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 16 358 25 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML. 2013 17 3565 24 IMPACT OF GENETIC POLYMORPHISMS AND BIOMARKERS ON THE EFFECTIVENESS AND TOXICITY OF TREATMENT OF CHRONIC MYELOID LEUKEMIA AND ACUTE MYELOID LEUKEMIA. MOST MALIGNANT HEMATOLOGICAL DISEASES ARE GENERALLY A CONSEQUENCE OF ACQUIRED MUTATIONS OR REARRANGEMENTS IN CELL REPLICATION PROCESSES. ACUTE MYELOID LEUKEMIA (AML) IS A CLINICALLY AND MOLECULARLY HETEROGENEOUS DISEASE THAT RESULTS FROM ACQUIRED GENETIC AND EPIGENETIC ALTERATIONS IN HEMATOPOIETIC PROGENITOR CELLS. DESPITE THE ADVANCES MADE IN UNDERSTANDING THE PATHOGENESIS OF THIS DISEASE, THE OVERALL SURVIVAL OF PATIENTS REMAINS VERY LOW DUE TO THE HIGH RELAPSE RATE. PHARMACOGENETICS AND MASSIVE SEQUENCING STUDIES HAVE ALLOWED THE IDENTIFICATION OF NEW RECURRENT MUTATIONS WITH SIGNIFICANT PROGNOSTIC IMPACT IN AML; FURTHERMORE, IT SEEMS LIKELY THAT WHOLE GENOME SEQUENCING WILL SOON BECOME A STANDARD DIAGNOSTIC TEST, WHICH WILL ALLOW THE MOLECULAR DIAGNOSIS OF PATIENTS. THEREFORE, IT IS NECESSARY TO DEVELOP MOLECULAR TARGETS THAT OPEN NEW THERAPEUTIC PERSPECTIVES AND ALLOW INDIVIDUALIZED TREATMENT OF PATIENTS WITH THIS AGGRESSIVE DISEASE. CHRONIC MYELOID LEUKEMIA (CML) IS THE FIRST NEOPLASTIC DISEASE FOR WHICH A CHARACTERISTIC GENETIC ALTERATION WAS DESCRIBED. IT HAS, BY DEFINITION, A GENETIC MARKER, THE BCR::ABL1 REARRANGEMENT, AS A CONSEQUENCE OF THE T9;22(Q34;Q11) TRANSLOCATION. ITS STUDY IS ESSENTIAL FOR THE DIAGNOSIS OF THIS ENTITY AND ALSO FOR MONITORING THE RESPONSE TO TREATMENT. DRUGS KNOWN AS TYROSINE KINASE INHIBITORS (TKIS) THAT TARGET THE BCR::ABL1 PROTEIN (ORAL TARGETED THERAPY) ARE THE CONVENTIONAL TREATMENT OF CML, REPRESENTING A CHANGE OF PARADIGM IN THE MANAGEMENT OF ONCOHEMATOLOGICAL PATIENTS. 2022 18 6609 21 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 19 1685 21 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 20 5212 20 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