1 4557 59 MUTATIONS IN ASXL1 ARE ASSOCIATED WITH POOR PROGNOSIS ACROSS THE SPECTRUM OF MALIGNANT MYELOID DISEASES. THE ASXL1 GENE IS ONE OF THE MOST FREQUENTLY MUTATED GENES IN MALIGNANT MYELOID DISEASES. THE ASXL1 PROTEIN BELONGS TO PROTEIN COMPLEXES INVOLVED IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. ASXL1 MUTATIONS ARE FOUND IN MYELOPROLIFERATIVE NEOPLASMS (MPN), MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ACUTE MYELOID LEUKEMIA (AML). THEY ARE GENERALLY ASSOCIATED WITH SIGNS OF AGGRESSIVENESS AND POOR CLINICAL OUTCOME. BECAUSE OF THIS, A SYSTEMATIC DETERMINATION OF ASXL1 MUTATIONAL STATUS IN MYELOID MALIGNANCIES SHOULD HELP IN PROGNOSIS ASSESSMENT. 2012 2 6574 23 TREATMENT OF CHRONIC MYELOMONOCYTIC LEUKEMIA WITH 5-AZACYTIDINE: CASE REPORTS. EPIGENETIC THERAPY WITH HYPOMETHYLATING AGENT (5-AZACYTIDINE; AZA) IS COMMON IN THE MANAGEMENT OF SPECIFIC SUBTYPES OF MYELODYSPLASTIC SYNDROME (MDS), BUT THERE ARE ONLY FEW STUDIES IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) PATIENTS. IN THIS PAPER OUR EXPERIENCE WITH 3 CMML PATIENTS TREATED WITH AZA IS DESCRIBED. IN ONE PATIENT TRANSFUSION INDEPENDENCY WAS OBSERVED AFTER 4 TREATMENT CYCLES; IN ONE CASE A PARTIAL RESPONSE WAS RECORDED, BUT A PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML) AFTER 13 AZA CYCLES HAS APPEARED. IN ONE PATIENT, AZA IN REDUCED DOSAGE WAS ADMINISTERED AS A BRIDGING TREATMENT BEFORE ALLOGENEIC STEM CELL TRANSPLANTATION (ASCT), BUT IN THE CONTROL BONE MARROW ASPIRATE (BEFORE ASCT) A PROGRESSION TO AML WAS RECORDED. FUTURE STUDIES ARE MANDATORY FOR EVALUATION OF NEW MOLECULAR AND CLINICAL FEATURES WHICH COULD PREDICT THE EFFICIENCY OF HYPOMETHYLATING AGENTS IN CMML THERAPY WITH RESPECT TO OVERALL SURVIVAL, EVENT-FREE SURVIVAL, QUALITY-ADJUSTED LIFE YEAR, AND PHARMACOECONOMY. 2012 3 535 24 ASXL1 MUTATION CORRECTION BY CRISPR/CAS9 RESTORES GENE FUNCTION IN LEUKEMIA CELLS AND INCREASES SURVIVAL IN MOUSE XENOGRAFTS. RECURRENT SOMATIC MUTATIONS OF THE EPIGENETIC MODIFIER AND TUMOR SUPPRESSOR ASXL1 ARE COMMON IN MYELOID MALIGNANCIES, INCLUDING CHRONIC MYELOID LEUKEMIA (CML), AND ARE ASSOCIATED WITH POOR CLINICAL OUTCOME. CRISPR/CAS9 HAS RECENTLY EMERGED AS A POWERFUL AND VERSATILE GENOME EDITING TOOL FOR GENOME ENGINEERING IN VARIOUS SPECIES. WE HAVE USED THE CRISPR/CAS9 SYSTEM TO CORRECT THE ASXL1 HOMOZYGOUS NONSENSE MUTATION PRESENT IN THE CML CELL LINE KBM5, WHICH LACKS ASXL1 PROTEIN EXPRESSION. CRISPR/CAS9-MEDIATED ASXL1 HOMOZYGOUS CORRECTION RESULTED IN PROTEIN RE-EXPRESSION WITH RESTORED NORMAL FUNCTION, INCLUDING DOWN-REGULATION OF POLYCOMB REPRESSIVE COMPLEX 2 TARGET GENES. SIGNIFICANTLY REDUCED CELL GROWTH AND INCREASED MYELOID DIFFERENTIATION WERE OBSERVED IN ASXL1 MUTATION-CORRECTED CELLS, PROVIDING NEW INSIGHTS INTO THE ROLE OF ASXL1 IN HUMAN MYELOID CELL DIFFERENTIATION. MICE XENOGRAFTED WITH MUTATION-CORRECTED KBM5 CELLS SHOWED SIGNIFICANTLY LONGER SURVIVAL THAN UNCORRECTED XENOGRAFTS. THESE RESULTS SHOW THAT THE SOLE CORRECTION OF A DRIVER MUTATION IN LEUKEMIA CELLS INCREASES SURVIVAL IN VIVO IN MICE. THIS STUDY PROVIDES PROOF-OF-CONCEPT FOR DRIVER GENE MUTATION CORRECTION VIA CRISPR/CAS9 TECHNOLOGY IN HUMAN LEUKEMIA CELLS AND PRESENTS A STRATEGY TO ILLUMINATE THE IMPACT OF ONCOGENIC MUTATIONS ON CELLULAR FUNCTION AND SURVIVAL. 2015 4 5606 23 RPPA-BASED PROTEOMICS RECOGNIZES DISTINCT EPIGENETIC SIGNATURES IN CHRONIC LYMPHOCYTIC LEUKEMIA WITH CLINICAL CONSEQUENCES. THE CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ARMAMENTARIUM HAS EVOLVED SIGNIFICANTLY, WITH NOVEL THERAPIES THAT INHIBIT BRUTON TYROSINE KINASE, PI3K DELTA AND/OR THE BCL2 PROTEIN IMPROVING OUTCOMES. STILL, THE CLINICAL COURSE OF CLL PATIENTS IS HIGHLY VARIABLE AND MOST PREVIOUSLY RECOGNIZED PROGNOSTIC FEATURES LACK THE CAPACITY TO PREDICT RESPONSE TO MODERN TREATMENTS INDICATING THE NEED FOR NEW PROGNOSTIC MARKERS. IN THIS STUDY, WE IDENTIFIED FOUR EPIGENETICALLY DISTINCT PROTEOMIC SIGNATURES OF A LARGE COHORT OF CLL AND RELATED DISEASES DERIVED SAMPLES (N = 871) USING REVERSE PHASE PROTEIN ARRAY TECHNOLOGY. THESE SIGNATURES ARE ASSOCIATED WITH CLINICAL FEATURES INCLUDING AGE, CYTOGENETIC ABNORMALITIES [TRISOMY 12, DEL(13Q) AND DEL(17P)], IMMUNOGLOBULIN HEAVY-CHAIN LOCUS (IGHV) MUTATIONAL LOAD, ZAP-70 STATUS, BINET AND RAI STAGING AS WELL AS WITH THE OUTCOME MEASURES OF TIME TO TREATMENT AND OVERALL SURVIVAL. PROTEIN SIGNATURE MEMBERSHIP WAS IDENTIFIED AS PREDICTIVE MARKER FOR OVERALL SURVIVAL REGARDLESS OF OTHER CLINICAL FEATURES. AMONG THE ANALYZED EPIGENETIC PROTEINS, EZH2, HDAC6, AND LOSS OF H3K27ME3 LEVELS WERE THE MOST INDEPENDENTLY ASSOCIATED WITH POOR SURVIVAL. THESE FINDINGS DEMONSTRATE THAT PROTEOMIC BASED EPIGENETIC BIOMARKERS CAN BE USED TO BETTER CLASSIFY CLL PATIENTS AND PROVIDE THERAPEUTIC GUIDANCE. 2022 5 2277 36 EPIGENETIC REGULATION BY ASXL1 IN MYELOID MALIGNANCIES. MYELOID MALIGNANCIES ARE CLONAL HEMATOPOIETIC DISORDERS THAT ARE COMPRISED OF A SPECTRUM OF GENETICALLY HETEROGENEOUS DISORDERS, INCLUDING MYELODYSPLASTIC SYNDROMES (MDS), MYELOPROLIFERATIVE NEOPLASMS (MPN), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), AND ACUTE MYELOID LEUKEMIA (AML). MYELOID MALIGNANCIES ARE CHARACTERIZED BY EXCESSIVE PROLIFERATION, ABNORMAL SELF-RENEWAL, AND/OR DIFFERENTIATION DEFECTS OF HEMATOPOIETIC STEM CELLS (HSCS) AND MYELOID PROGENITOR CELLS HEMATOPOIETIC STEM/PROGENITOR CELLS (HSPCS). MYELOID MALIGNANCIES CAN BE CAUSED BY GENETIC AND EPIGENETIC ALTERATIONS THAT PROVOKE KEY CELLULAR FUNCTIONS, SUCH AS SELF-RENEWAL, PROLIFERATION, BIASED LINEAGE COMMITMENT, AND DIFFERENTIATION. ADVANCES IN NEXT-GENERATION SEQUENCING LED TO THE IDENTIFICATION OF MULTIPLE MUTATIONS IN MYELOID NEOPLASMS, AND MANY NEW GENE MUTATIONS WERE IDENTIFIED AS KEY FACTORS IN DRIVING THE PATHOGENESIS OF MYELOID MALIGNANCIES. THE POLYCOMB PROTEIN ASXL1 WAS IDENTIFIED TO BE FREQUENTLY MUTATED IN ALL FORMS OF MYELOID MALIGNANCIES, WITH MUTATIONAL FREQUENCIES OF 20%, 43%, 10%, AND 20% IN MDS, CMML, MPN, AND AML, RESPECTIVELY. SIGNIFICANTLY, ASXL1 MUTATIONS ARE ASSOCIATED WITH A POOR PROGNOSIS IN ALL FORMS OF MYELOID MALIGNANCIES. THE FACT THAT ASXL1 MUTATIONS ARE ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH CMML, MDS, AND AML, POINTS TO THE POSSIBILITY THAT ASXL1 MUTATION IS A KEY FACTOR IN THE DEVELOPMENT OF MYELOID MALIGNANCIES. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN UNDERSTANDING MYELOID MALIGNANCIES WITH A SPECIFIC FOCUS ON ASXL1 MUTATIONS. 2023 6 952 14 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 7 557 18 B-CELL ANTIGEN RECEPTOR SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA: THERAPEUTIC TARGETS AND TRANSLATIONAL OPPORTUNITIES. B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY CLONALLY EXPANDED AND MOLECULARLY HETEROGENEOUS POPULATIONS OF B LYMPHOCYTES WITH IMPAIRED APOPTOTIC MECHANISMS. THIS OCCURS AS A RESULT OF MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES, INCLUDING CHROMOSOMAL ABERRATIONS AND ENHANCER REGION HYPOMETHYLATION, OFTEN IMPINGING ON INTRACELLULAR SIGNALING PATHWAYS THAT ARE ESSENTIAL TO NORMAL B-CELL ACTIVATION, PROLIFERATION, AND SURVIVAL. THE B-CELL ANTIGEN RECEPTOR (BCR) SIGNALING IS ONE SUCH PATHWAY USURPED BY MALIGNANT B CELLS, AS EXEMPLIFIED BY THE EARLY PHASE CLINICAL SUCCESS ACHIEVED BY SMALL-MOLECULE AGENTS TARGETING KEY PLAYERS INVOLVED IN THE PATHWAY. SUCH NEW TARGETED AGENTS, INCLUDING THOSE THAT INHIBIT THE FUNCTION OF SPLEEN TYROSINE KINASE (SYK), BRUTON'S TYROSINE KINASE (BTK), PHOSPHATIDYLINOSITOL 3-KINASES (PI3K), AND B-CELL LYMPHOMA 2 (BCL-2), ALONG WITH THE CURRENT STANDARD THERAPY COMPRISING CHEMO-IMMUNOTHERAPIES WITH OR WITHOUT B-CELL DEPLETING BIOLOGIC AGENT RITUXIMAB (ANTI-CD20 MONOCLONAL ANTIBODY), SHOULD EXPAND THE ARMAMENTARIUM FOR CLL THERAPY. WE REVIEW THE THERAPEUTIC AGENTS CURRENTLY IN CLINICAL DEVELOPMENT WHICH TARGET DIFFERENT EFFECTORS OF THE MALIGNANT BCR SIGNALING, AND DISCUSS THEIR OVERLAPPING AND DISCRIMINATING TRANSLATIONAL OPPORTUNITIES IN THE CONTEXT OF CLL TREATMENT. 2013 8 32 28 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 9 957 22 CHRONIC MYELOMONOCYTIC LEUKAEMIA: A CONCISE CLINICAL AND PATHOPHYSIOLOGICAL REVIEW. CHRONIC MYELOMONOCYTIC LEUKAEMIA (CMML) IS A CLONAL HAEMATOPOIETIC STEM CELL DISORDER WITH MYELODYSPLASTIC AND MYELOPROLIFERATIVE OVERLAP FEATURES, AND AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKAEMIA. APPROXIMATELY 30% OF PATIENTS PRESENT WITH CLONAL CYTOGENETIC ABNORMALITIES, WHILE ALMOST 90% HAVE MOLECULAR ABERRATIONS INVOLVING EPIGENETIC REGULATION, THE SPLICEOSOME COMPONENT MACHINERY, TUMOUR SUPPRESSOR GENES AND TRANSCRIPTION FACTORS/REGULATORS. NUMEROUS PROGNOSTIC MODELS EXIST FOR CMML, WITH MORE RECENT MODELS INCORPORATING PROGNOSTIC MUTATIONS, SUCH AS THOSE INVOLVING ASXL1. OTHER VARIABLES THAT SEEM TO CONSISTENTLY AFFECT OUTCOMES INCLUDE THE DEGREE OF LEUCOCYTOSIS/MONOCYTOSIS, ANAEMIA AND THROMBOCYTOPENIA. ALLOGENEIC STEM CELL TRANSPLANT REMAINS THE ONLY CURATIVE OPTION FOR CMML, WHILE HYPOMETHYLATING AGENTS CAN BE USED FOR TRANSPLANT-INELIGIBLE PATIENTS OR THOSE WITHOUT SUITABLE STEM CELL SOURCES. TARGETING BIOLOGICAL PATHWAYS ACTIVATED IN CMML OFFERS POTENTIAL HOPE FOR MORE EFFECTIVE AND LESS TOXIC THERAPIES. 2014 10 2087 24 EPIGENETIC DYSREGULATION OF ID4 PREDICTS DISEASE PROGRESSION AND TREATMENT OUTCOME IN MYELOID MALIGNANCIES. PROMOTER HYPERMETHYLATION-MEDIATED INACTIVATION OF ID4 PLAYS A CRUCIAL ROLE IN THE DEVELOPMENT OF SOLID TUMOURS. THIS STUDY AIMED TO INVESTIGATE ID4 METHYLATION AND ITS CLINICAL RELEVANCE IN MYELOID MALIGNANCIES. ID4 HYPERMETHYLATION WAS ASSOCIATED WITH HIGHER IPSS SCORES, BUT WAS NOT AN INDEPENDENT PROGNOSTIC BIOMARKER AFFECTING OVERALL SURVIVAL (OS) IN MYELODYSPLASTIC SYNDROME (MDS). HOWEVER, ID4 HYPERMETHYLATION CORRELATED WITH SHORTER OS AND LEUKAEMIA-FREE SURVIVAL (LFS) TIME AND ACTED AS AN INDEPENDENT RISK FACTOR AFFECTING OS IN ACUTE MYELOID LEUKAEMIA (AML). MOREOVER, ID4 METHYLATION WAS SIGNIFICANTLY DECREASED IN THE FOLLOW-UP PAIRED AML PATIENTS WHO ACHIEVED COMPLETE REMISSION (CR) AFTER INDUCTION THERAPY. IMPORTANTLY, ID4 METHYLATION WAS INCREASED DURING MDS PROGRESSION TO AML AND CHRONIC PHASE (CP) PROGRESSION TO BLAST CRISIS (BC) IN CHRONIC MYELOID LEUKAEMIA (CML). EPIGENETIC STUDIES SHOWED THAT ID4 METHYLATION MIGHT BE ONE OF THE MECHANISMS SILENCING ID4 EXPRESSION IN MYELOID LEUKAEMIA. FUNCTIONAL STUDIES IN VITRO SHOWED THAT RESTORATION OF ID4 EXPRESSION COULD INHIBIT CELL PROLIFERATION AND PROMOTE APOPTOSIS IN BOTH K562 AND HL60 CELLS. THESE FINDINGS INDICATE THAT ID4 ACTS AS A TUMOUR SUPPRESSOR IN MYELOID MALIGNANCIES, AND ID4 METHYLATION IS A POTENTIAL BIOMARKER IN PREDICTING DISEASE PROGRESSION AND TREATMENT OUTCOME. 2017 11 2719 22 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 12 955 14 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 13 149 22 ABERRANT HYDROXYMETHYLATION IN PROMOTER CPG REGIONS OF GENES RELATED TO THE CELL CYCLE AND APOPTOSIS CHARACTERIZES ADVANCED CHRONIC MYELOID LEUKEMIA DISEASE, POOR IMATINIB RESPONDENTS AND POOR SURVIVAL. BACKGROUND: THERE IS STRONG EVIDENCE THAT DISEASE PROGRESSION, DRUG RESPONSE AND OVERALL CLINICAL OUTCOMES OF CML DISEASE ARE NOT ONLY DECIDED BY BCR/ABL1 ONCOPROTEIN BUT DEPEND ON ACCUMULATION OF ADDITIONAL GENETIC AND EPIGENETIC ABERRATIONS. DNA HYDROXYMETHYLATION IS IMPLICATED IN THE DEVELOPMENT OF VARIETY OF DISEASES. DNA HYDROXYMETHYLATION IN GENE PROMOTERS PLAYS IMPORTANT ROLES IN DISEASE PROGRESSION, DRUG RESPONSE AND CLINICAL OUTCOME OF VARIOUS DISEASES. THEREFORE IN THIS STUDY, WE AIMED TO EXPLORE THE ROLE OF ABERRANT HYDROXYMETHYLATION IN PROMOTER REGIONS OF DIFFERENT TUMOR SUPPRESSOR GENES IN RELATION TO CML DISEASE PROGRESSION, RESPONSE TO IMATINIB THERAPY AND CLINICAL OUTCOME. METHODS: WE RECRUITED 150 CML PATIENTS AT DIFFERENT CLINICAL STAGES OF THE DISEASE. PATIENTS WERE FOLLOWED UP FOR 48 MONTHS AND HAEMATOLOGICAL/MOLECULAR RESPONSES WERE ANALYSED. HAEMATOLOGICAL RESPONSE WAS ANALYSED BY PERIPHERAL BLOOD SMEAR. BCR/ABL1 SPECIFIC TAQMAN PROBE BASED QRT-PCR WAS USED FOR ASSESSING THE MOLECULAR RESPONSE OF CML PATIENTS ON IMATINIB THERAPY. PROMOTER HYDROXYMETHYLATION OF THE GENES WAS CHARACTERIZED USING MS-PCR. RESULTS: WE OBSERVED THAT PROMOTER HYDROXYMETHYLATION OF DAPK1, RIZ1, P16INK4A, RASSF1A AND P14ARF(ARF) GENES CHARACTERIZE ADVANCED CML DISEASE AND POOR IMATINIB RESPONDENTS. ALTHOUGH, CYTOKINE SIGNALLING (SOCS1) GENE WAS HYPERMETHYLATED IN ADVANCED STAGES OF CML AND ACCUMULATED IN PATIENTS WITH POOR IMATINIB RESPONSE, BUT THE DIFFERENCES WERE NOT STATISTICALLY SIGNIFICANT. MOREOVER, WE FOUND HYPERMETHYLATION OF P14(ARF), RASSF1 AND P16(INK4A) GENES AND CYTOKINE SIGNALLING GENE (SOCS1) SIGNIFICANTLY ASSOCIATED WITH POOR OVERALL SURVIVAL OF CML PATIENTS ON IMATINIB THERAPY. THE RESULTS OF THIS STUDY ARE IN AGREEMENT OF THE ROLE OF ABERRANT DNA METHYLATION OF DIFFERENT TUMOR SUPPRESSOR GENES AS POTENTIAL BIOMARKERS OF CML DISEASE PROGRESSION, POOR IMATINIB RESPONSE AND OVERALL CLINICAL OUTCOME. CONCLUSION: IN THIS STUDY, WE REPORT THAT PROMOTER HYDROXYMETHYLATION OF DAPK1, RIZ1, P16INK4A, RASSF1A AND P14ARF(ARF) GENES IS A CHARACTERISTIC FEATURE OF CML DISEASE PROGRESSIONS, DEFINES POOR IMATINIB RESPONDENTS AND POOR OVERALL SURVIVAL OF CML PATIENTS TO IMATINIB THERAPY. 2022 14 5245 22 PROGNOSTIC RELEVANCE OF INTEGRATED GENETIC PROFILING IN ADULT T-CELL LEUKEMIA/LYMPHOMA. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATL) IS A HETEROGENEOUS GROUP OF PERIPHERAL T-CELL MALIGNANCIES CHARACTERIZED BY HUMAN T-CELL LEUKEMIA VIRUS TYPE-1 INFECTION, WHOSE GENETIC PROFILE HAS RECENTLY BEEN FULLY INVESTIGATED. HOWEVER, IT IS STILL POORLY UNDERSTOOD HOW THESE ALTERATIONS AFFECT CLINICAL FEATURES AND PROGNOSIS. WE INVESTIGATED THE EFFECTS OF GENETIC ALTERATIONS COMMONLY FOUND IN ATL ON DISEASE PHENOTYPES AND CLINICAL OUTCOMES, BASED ON GENOTYPING DATA OBTAINED FROM 414 AND 463 ATL PATIENTS USING TARGETED-CAPTURE SEQUENCING AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAY KARYOTYPING, RESPECTIVELY. AGGRESSIVE (ACUTE/LYMPHOMA) SUBTYPES WERE ASSOCIATED WITH AN INCREASED BURDEN OF GENETIC AND EPIGENETIC ALTERATIONS, HIGHER FREQUENCIES OF TP53 AND IRF4 MUTATIONS, AND MANY COPY NUMBER ALTERATIONS (CNAS), INCLUDING PD-L1 AMPLIFICATIONS AND CDKN2A DELETIONS, COMPARED WITH INDOLENT (CHRONIC/SMOLDERING) SUBTYPES. BY CONTRAST, STAT3 MUTATIONS WERE MORE CHARACTERISTIC OF INDOLENT ATL. HIGHER NUMBERS OF SOMATIC MUTATIONS AND CNAS SIGNIFICANTLY CORRELATED WITH WORSE SURVIVAL. IN A MULTIVARIATE ANALYSIS INCORPORATING BOTH CLINICAL FACTORS AND GENETIC ALTERATIONS, THE JAPAN CLINICAL ONCOLOGY GROUP PROGNOSTIC INDEX HIGH-RISK, OLDER AGE, PRKCB MUTATIONS, AND PD-L1 AMPLIFICATIONS WERE INDEPENDENT POOR PROGNOSTIC FACTORS IN AGGRESSIVE ATL. IN INDOLENT ATL, IRF4 MUTATIONS, PD-L1 AMPLIFICATIONS, AND CDKN2A DELETIONS WERE SIGNIFICANTLY ASSOCIATED WITH SHORTER SURVIVAL, ALTHOUGH THE CHRONIC SUBTYPE WITH UNFAVORABLE CLINICAL FACTORS WAS ONLY MARGINALLY SIGNIFICANT. THUS, SOMATIC ALTERATIONS CHARACTERIZING AGGRESSIVE DISEASES PREDICT WORSE PROGNOSIS IN INDOLENT ATL, AMONG WHICH PD-L1 AMPLIFICATIONS ARE A STRONG GENETIC PREDICTOR IN BOTH AGGRESSIVE AND INDOLENT ATL. ATL SUBTYPES ARE FURTHER CLASSIFIED INTO MOLECULARLY DISTINCT SUBSETS WITH DIFFERENT PROGNOSIS. GENETIC PROFILING MIGHT CONTRIBUTE TO IMPROVED PROGNOSTICATION AND MANAGEMENT OF ATL PATIENTS. 2018 15 6437 20 THERAPEUTIC ADVANCES IN LEUKEMIA AND MYELODYSPLASTIC SYNDROME OVER THE PAST 40 YEARS. MAJOR THERAPEUTIC PROGRESS HAS BEEN ACCOMPLISHED IN LEUKEMIA AND MYELODYSPLASTIC SYNDROME (MDS) OVER THE PAST 40 YEARS, WHICH MAY NOT BE FULLY APPRECIATED BY THE LARGER MEDICAL COMMUNITY. THE OBJECTIVE OF THIS REVIEW WAS TO BRIEFLY HIGHLIGHT THE TREATMENT BREAKTHROUGHS IN LEUKEMIA AND MDS. THERAPEUTIC PROGRESS HAPPENED THROUGH BETTER UNDERSTANDING OF DISEASE PATHOPHYSIOLOGIES AND RATIONAL DEVELOPMENT OF TARGETED AGENTS, LIKE IMATINIB MESYLATE IN CHRONIC MYELOID LEUKEMIA (CML), AND THROUGH ASTUTE, EMPIRICAL DISCOVERIES IN THE CLINIC, LIKE ALL-TRANS RETINOIC ACID AND ARSENIC TRIOXIDE IN ACUTE PROMYELOCYTIC LEUKEMIA (APL) AND CHLORODEOXYADENOSINE IN HAIRY CELL LEUKEMIA (HCL). TODAY, THE 5- TO 10-YEAR SURVIVAL RATES IN PATIENTS WITH APL AND HCL EXCEED 80%. IN PATIENTS WITH CML, IMATINIB THERAPY HAS BEEN ASSOCIATED WITH ESTIMATED 5- TO 7-YEAR SURVIVAL RATES FROM 85% TO 90%. IN PATIENTS WITH ADULT ACUTE LYMPHOCYTIC LEUKEMIA, MODERN INTENSIVE REGIMENS HAVE IMPROVED THE 5-YEAR SURVIVAL RATES FROM 20% UP TO 40%. IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA, CHEMOIMMUNOTHERAPY RECENTLY PRODUCED HIGH RATES OF QUALITY RESPONSES AND IMPROVED LONG-TERM OUTCOME. IN YOUNGER PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML), THE 5-YEAR SURVIVAL RATES RANGE FROM 40% TO 50%, ALTHOUGH ELDERLY AML REMAINS A THERAPEUTIC CHALLENGE. IN PATIENTS WITH MDS, IT WAS RECENTLY DEMONSTRATED THAT EPIGENETIC THERAPY WITH HYPOMETHYLATING AGENTS IMPROVED SURVIVAL. MUCH THERAPEUTIC PROGRESS HAS BEEN WITNESSED IN LEUKEMIA AND MDS, AND MUCH MORE IS EXPECTED TO OCCUR SOON. 2008 16 5762 16 SOMATIC VARIANTS IN EPIGENETIC MODIFIERS CAN PREDICT FAILURE OF RESPONSE TO IMATINIB BUT NOT TO SECOND-GENERATION TYROSINE KINASE INHIBITORS. THERE ARE NO VALIDATED MOLECULAR BIOMARKERS TO IDENTIFY NEWLY-DIAGNOSED INDIVIDUALS WITH CHRONIC-PHASE CHRONIC MYELOID LEUKEMIA LIKELY TO RESPOND POORLY TO IMATINIB AND WHO MIGHT BENEFIT FROM FIRST-LINE TREATMENT WITH A MORE POTENT SECOND-GENERATION TYROSINE KINASE INHIBITOR. OUR INABILITY TO PREDICT THESE 'HIGH-RISK' INDIVIDUALS REFLECTS THE POORLY UNDERSTOOD HETEROGENEITY OF THE DISEASE. TO INVESTIGATE THE POTENTIAL OF GENETIC VARIANTS IN EPIGENETIC MODIFIERS AS BIOMARKERS AT DIAGNOSIS, WE USED ION TORRENT NEXT-GENERATION SEQUENCING OF 71 CANDIDATE GENES FOR PREDICTING RESPONSE TO TYROSINE KINASE INHIBITORS AND PROBABILITY OF DISEASE PROGRESSION. A TOTAL OF 124 SUBJECTS WITH NEWLY-DIAGNOSED CHRONIC-PHASE CHRONIC MYELOID LEUKEMIA BEGAN WITH IMATINIB (N=62) OR SECOND-GENERATION TYROSINE KINASE INHIBITORS (N=62) AND WERE CLASSIFIED AS RESPONDERS OR NON-RESPONDERS BASED ON THE BCRABL1 TRANSCRIPT LEVELS WITHIN THE FIRST YEAR AND THE EUROPEAN LEUKEMIANET CRITERIA FOR FAILURE. SOMATIC VARIANTS AFFECTING 21 GENES (E.G. ASXL1, IKZF1, DNMT3A, CREBBP) WERE DETECTED IN 30% OF SUBJECTS, MOST OF WHOM WERE NON-RESPONDERS (41% NON-RESPONDERS, 18% RESPONDERS TO IMATINIB, 38% NON-RESPONDERS, 25% RESPONDERS TO SECOND-GENERATION TYROSINE KINASE INHIBITORS). THE PRESENCE OF VARIANTS PREDICTED THE RATE OF ACHIEVING A MAJOR MOLECULAR RESPONSE, EVENT-FREE SURVIVAL, PROGRESSION-FREE SURVIVAL AND CHRONIC MYELOID LEUKEMIA-RELATED SURVIVAL IN THE IMATINIB BUT NOT THE SECOND-GENERATION TYROSINE KINASE INHIBITORS COHORT. RARE GERMLINE VARIANTS HAD NO PROGNOSTIC SIGNIFICANCE IRRESPECTIVE OF TREATMENT WHILE SOME PRE-LEUKEMIA VARIANTS SUGGEST A MULTI-STEP DEVELOPMENT OF CHRONIC MYELOID LEUKEMIA. OUR DATA SUGGEST THAT IDENTIFICATION OF SOMATIC VARIANTS AT DIAGNOSIS FACILITATES STRATIFICATION INTO IMATINIB RESPONDERS/NON-RESPONDERS, THEREBY ALLOWING EARLIER USE OF SECOND-GENERATION TYROSINE KINASE INHIBITORS, WHICH, IN TURN, MAY OVERCOME THE NEGATIVE IMPACT OF SUCH VARIANTS ON DISEASE PROGRESSION. 2019 17 5212 15 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 18 4436 14 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 19 791 14 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 20 1082 15 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