1 4530 111 MULTILAYER INTRACLONAL HETEROGENEITY IN CHRONIC MYELOMONOCYTIC LEUKEMIA. THE FUNCTIONAL DIVERSITY OF CELLS THAT COMPOSE MYELOID MALIGNANCIES, I.E., THE RESPECTIVE ROLES OF GENETIC AND EPIGENETIC HETEROGENEITY IN THIS DIVERSITY, REMAINS POORLY UNDERSTOOD. THIS QUESTION IS ADDRESSED IN CHRONIC MYELOMONOCYTIC LEUKEMIA, A MYELOID NEOPLASM IN WHICH CLINICAL DIVERSITY CONTRASTS WITH LIMITED GENETIC HETEROGENEITY. TO GENERATE INDUCED PLURIPOTENT STEM CELL CLONES, WE REPROGRAMMED CD34(+) CELLS COLLECTED FROM A PATIENT WITH A CHRONIC MYELOMONOCYTIC LEUKEMIA IN WHICH WHOLE EXOME SEQUENCING OF PERIPHERAL BLOOD MONOCYTE DNA HAD IDENTIFIED 12 GENE MUTATIONS, INCLUDING A MUTATION IN KDM6A AND TWO HETEROZYGOUS MUTATIONS IN TET2 IN THE FOUNDING CLONE AND A SECONDARY KRAS(G12D) MUTATION. CD34(+) CELLS FROM AN AGE-MATCHED HEALTHY DONOR WERE ALSO REPROGRAMMED. WE CAPTURED A PART OF THE GENETIC HETEROGENEITY OBSERVED IN THE PATIENT, I.E. WE ANALYZED FIVE CLONES WITH TWO GENETIC BACKGROUNDS, WITHOUT AND WITH THE KRAS(G12D) MUTATION. HEMATOPOIETIC DIFFERENTIATION OF THESE CLONES RECAPITULATED THE MAIN FEATURES OF THE PATIENT'S DISEASE, INCLUDING OVERPRODUCTION OF GRANULOMONOCYTES AND DYSMEGAKARYOPOIESIS. THESE ANALYSES ALSO DISCLOSED SIGNIFICANT DISCREPANCIES IN THE BEHAVIOR OF HEMATOPOIETIC CELLS DERIVED FROM INDUCED PLURIPOTENT STEM CELL CLONES WITH SIMILAR GENETIC BACKGROUND, CORRELATING WITH LIMITED EPIGENETIC CHANGES. THESE ANALYSES SUGGEST THAT, BEYOND THE CODING MUTATIONS, SEVERAL LEVELS OF INTRACLONAL HETEROGENEITY MAY PARTICIPATE IN THE YET UNEXPLAINED CLINICAL HETEROGENEITY OF THE DISEASE. 2020 2 4436 24 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 3 4551 39 MUTATIONAL HIERARCHIES IN MYELODYSPLASTIC SYNDROMES DYNAMICALLY ADAPT AND EVOLVE UPON THERAPY RESPONSE AND FAILURE. CLONAL EVOLUTION IS BELIEVED TO BE A MAIN DRIVER FOR PROGRESSION OF VARIOUS TYPES OF CANCER AND IMPLICATED IN FACILITATING RESISTANCE TO DRUGS. HOWEVER, THE HIERARCHICAL ORGANIZATION OF MALIGNANT CLONES IN THE HEMATOPOIESIS OF MYELODYSPLASTIC SYNDROMES (MDS) AND ITS IMPACT ON RESPONSE TO DRUG THERAPY REMAIN POORLY UNDERSTOOD. USING HIGH-THROUGHPUT SEQUENCING OF PATIENT AND XENOGRAFTED CELLS, WE EVALUATED THE INTRATUMORAL HETEROGENEITY (N= 54) AND RECONSTRUCTED MUTATIONAL TRAJECTORIES (N = 39) IN PATIENTS SUFFERING FROM MDS (N = 52) AND CHRONIC MYELOMONOCYTIC LEUKEMIA-1 (N = 2). WE IDENTIFIED LINEAR AND ALSO BRANCHING EVOLUTION PATHS AND CONFIRMED ON A PATIENT-SPECIFIC LEVEL THAT SOMATIC MUTATIONS IN EPIGENETIC REGULATORS AND RNA SPLICING GENES FREQUENTLY CONSTITUTE ISOLATED DISEASE-INITIATING EVENTS. USING HIGH-THROUGHPUT EXOME- AND/OR DEEP-SEQUENCING, WE ANALYZED 103 CHRONOLOGICALLY ACQUIRED SAMPLES FROM 22 PATIENTS COVERING A CUMULATIVE OBSERVATION TIME OF 75 YEARS MDS DISEASE PROGRESSION. OUR DATA REVEALED HIGHLY DYNAMIC SHAPING OF COMPLEX OLIGOCLONAL ARCHITECTURES, SPECIFICALLY UPON TREATMENT WITH LENALIDOMIDE AND OTHER DRUGS. DESPITE INITIAL CLINICAL RESPONSE TO TREATMENT, PATIENTS' MARROW PERSISTENTLY REMAINED CLONAL WITH RAPID OUTGROWTH OF FOUNDER-, SUB-, OR EVEN FULLY INDEPENDENT CLONES, INDICATING AN INCREASED DYNAMIC RATE OF CLONAL TURNOVER. THE EMERGENCE AND DISAPPEARANCE OF SPECIFIC CLONES FREQUENTLY CORRELATED WITH CHANGES OF CLINICAL PARAMETERS, HIGHLIGHTING THEIR DISTINCT AND FAR-REACHING FUNCTIONAL PROPERTIES. INTRIGUINGLY, INCREASINGLY COMPLEX MUTATIONAL TRAJECTORIES ARE FREQUENTLY ACCOMPANIED BY CLINICAL PROGRESSION DURING THE COURSE OF DISEASE. THESE DATA SUBSTANTIATE A NEED FOR REGULAR BROAD MOLECULAR MONITORING TO GUIDE CLINICAL TREATMENT DECISIONS IN MDS. 2016 4 2277 34 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 5 536 27 ASXL1 MUTATIONS PREDICT INFERIOR MOLECULAR RESPONSE TO NILOTINIB TREATMENT IN CHRONIC MYELOID LEUKEMIA. GENE MUTATIONS INDEPENDENT OF BCR::ABL1 HAVE BEEN IDENTIFIED IN NEWLY DIAGNOSED PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) IN CHRONIC PHASE, WHEREBY MUTATIONS IN EPIGENETIC MODIFIER GENES WERE MOST COMMON. THESE FINDINGS PROMPTED THE SYSTEMATIC ANALYSIS OF PREVALENCE, DYNAMICS, AND PROGNOSTIC SIGNIFICANCE OF SUCH MUTATIONS, IN A CLINICALLY WELL-CHARACTERIZED PATIENT POPULATION OF 222 CML PATIENTS FROM THE TIGER STUDY (CML-V) BY TARGETED NEXT-GENERATION SEQUENCING COVERING 54 MYELOID LEUKEMIA-ASSOCIATED GENES. IN TOTAL, 53/222 CML PATIENTS (24%) CARRIED 60 MUTATIONS AT DIAGNOSIS WITH ASXL1 BEING MOST COMMONLY AFFECTED (N = 20). TO STUDY MUTATION DYNAMICS, LONGITUDINAL DEEP SEQUENCING ANALYSIS OF SERIAL SAMPLES WAS PERFORMED IN 100 PATIENTS AFTER 12, 24, AND 36 MONTHS OF THERAPY. TYPICAL PATTERNS OF CLONAL EVOLUTION INCLUDED ERADICATION, PERSISTENCE, AND EMERGENCE OF MUTATED CLONES. PATIENTS CARRYING AN ASXL1 MUTATION AT DIAGNOSIS SHOWED A LESS FAVORABLE MOLECULAR RESPONSE TO NILOTINIB TREATMENT, AS A MAJOR MOLECULAR RESPONSE (MMR) WAS ACHIEVED LESS FREQUENTLY AT MONTH 12, 18, AND 24 COMPARED TO ALL OTHER PATIENTS. PATIENTS WITH ASXL1 MUTATIONS WERE ALSO YOUNGER AND MORE FREQUENTLY FOUND IN THE HIGH RISK CATEGORY, SUGGESTING A CENTRAL ROLE OF CLONAL EVOLUTION ASSOCIATED WITH ASXL1 MUTATIONS IN CML PATHOGENESIS. 2022 6 4557 20 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 7 5911 25 TARGETED NEXT-GENERATION SEQUENCING IN MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA AIDS DIAGNOSIS IN CHALLENGING CASES AND IDENTIFIES FREQUENT SPLICEOSOME MUTATIONS IN TRANSFORMED ACUTE MYELOID LEUKEMIA. OBJECTIVES: OPTIMAL INTEGRATION OF NEXT-GENERATION SEQUENCING (NGS) INTO CLINICAL PRACTICE IN HEMATOLOGIC MALIGNANCIES REMAINS UNCLEAR. WE EVALUATE THE UTILITY OF NGS IN MYELOID MALIGNANCIES. METHODS: A 42-GENE PANEL WAS USED TO SEQUENCE 109 CASES OF MYELODYSPLASTIC SYNDROME (MDS, N = 38), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML, N = 14), MYELOPROLIFERATIVE NEOPLASM (MPN, N = 24), AND MDS AND/OR MPN TRANSFORMED TO ACUTE MYELOID LEUKEMIA (AML, N = 33). RESULTS: AT LEAST ONE PATHOGENIC MUTATION WAS IDENTIFIED IN 74% OF CASES OF MDS, 100% OF CMMLS, AND 96% OF MPNS. IN CONTRAST, ONLY 47% OF CASES OF MDS (18/38) AND 7% (1/14) OF CMMLS EXHIBITED ABNORMAL CYTOGENETICS. IN DIAGNOSTICALLY DIFFICULT CASES OF MDS OR CMML WITH NORMAL CYTOGENETICS, NGS IDENTIFIED A PATHOGENIC MUTATION AND WAS CRITICAL IN ESTABLISHING THE CORRECT DIAGNOSIS. SPLICEOSOMAL GENES AND EPIGENETIC MODIFIERS WERE FREQUENTLY MUTATED. SPLICEOSOME MUTATIONS WERE ALSO FREQUENTLY DETECTED IN AML ARISING FROM MDS, CMML, OR MPN (39%) COMPARED WITH THE REPORTED RATE IN DE NOVO AML (7%-14%). CONCLUSIONS: IN DIFFICULT CASES OF MDS OR MPN, NGS FACILITATES DIAGNOSIS BY DETECTION OF GENE MUTATIONS TO CONFIRM CLONALITY, AND AMLS EVOLVING FROM MDS OR MPN CARRY FREQUENT MUTATIONS IN SPLICEOSOMAL GENES. 2016 8 959 31 CHRONIC MYELOMONOCYTIC LEUKEMIA AND ATYPICAL CHRONIC MYELOID LEUKEMIA: NOVEL PATHOGENETIC LESIONS. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) ARE DISTINCT, YET RELATED, ENTITIES OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) CHARACTERIZED BY MORPHOLOGIC DYSPLASIA WITH ACCUMULATION OF MONOCYTES OR NEUTROPHILS, RESPECTIVELY. OUR UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CMML AND ACML HAS ADVANCED, MAINLY DUE TO THE APPLICATION OF NOVEL TECHNOLOGIES SUCH AS ARRAY-BASED KARYOTYPING AND NEXT-GENERATION SEQUENCING. IN ADDITION TO PREVIOUSLY KNOWN RECURRENT ABERRATIONS, SOMATIC UNIPARENTAL DISOMY AFFECTING CHROMOSOMES 3, 4, 7, AND 11 FREQUENTLY OCCURS IN CMML. NOVEL SOMATIC MUTATIONS OF GENES, INCLUDING THOSE ASSOCIATED WITH PROLIFERATION SIGNALING (CBL, RAS, RUNX1, JAK2 (V617F)) AND WITH MODIFICATION OF EPIGENETIC STATUS (TET2, ASXL1, UTX, EZH2) HAVE BEEN FOUND. VARIOUS COMBINATIONS OF MUTATIONS SUGGEST A MULTISTEP PATHOGENESIS AND MAY ACCOUNT FOR CLINICAL HETEROGENEITY. MOST RECENTLY, SEVERAL SPLICEOSOME-ASSOCIATED-GENE MUTATIONS WERE REPORTED AND SRSF2 MUTATIONS ARE FREQUENTLY DETECTED IN CMML. THE PROGNOSTIC AND DIAGNOSTIC SIGNIFICANCE OF THESE MOLECULAR LESIONS, IN PARTICULAR THEIR VALUE AS BIOMARKERS OF RESPONSE OR RESISTANCE TO SPECIFIC THERAPIES, WHILE UNCERTAIN NOW IS LIKELY TO BE CLARIFIED AS LARGE SYSTEMATIC STUDIES COME TO COMPLETION. 2012 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 5790 29 SRSF2-P95 HOTSPOT MUTATION IS HIGHLY ASSOCIATED WITH ADVANCED FORMS OF MASTOCYTOSIS AND MUTATIONS IN EPIGENETIC REGULATOR GENES. MASTOCYTOSIS IS A RARE AND CHRONIC DISEASE WITH PHENOTYPES RANGING FROM INDOLENT TO SEVERE. PROGNOSIS FOR THIS DISEASE IS VARIABLE AND VERY FEW BIOMARKERS TO PREDICT DISEASE EVOLUTION OR OUTCOME ARE CURRENTLY KNOWN. WE HAVE PERFORMED COMPREHENSIVE SCREENING IN OUR LARGE COHORT OF MASTOCYTOSIS PATIENTS FOR MUTATIONS PREVIOUSLY FOUND IN OTHER MYELOID DISEASES AND THAT COULD SERVE AS PROGNOSTIC INDICATORS. KIT, SRSF2-P95 AND TET2 MUTATIONS WERE BY FAR THE MOST FREQUENT, DETECTED IN 81%, 24% AND 21% OF PATIENTS, RESPECTIVELY. WHERE TET2 AND SRSF2-P95 MUTATION BOTH CORRELATED WITH ADVANCED DISEASE PHENOTYPES, SRSF2-P95 HOTSPOT MUTATION WAS FOUND ALMOST EXCLUSIVELY IN PATIENTS DIAGNOSED WITH ASSOCIATED CLONAL HEMATOLOGIC NON-MAST CELL DISEASE. STATISTICALLY, TET2 AND SRSF2-P95 MUTATIONS WERE HIGHLY ASSOCIATED, SUGGESTING A MECHANISTIC LINK BETWEEN THESE TWO FACTORS. FINALLY, ANALYSIS OF BOTH CLONAL AND SORTED CELL POPULATIONS FROM PATIENTS CONFIRMS THE PRESENCE OF THESE MUTATIONS IN THE MAST CELL COMPONENT OF THE DISEASE, SUGGESTS AN ONTOLOGICAL MUTATION HIERARCHY AND PROVIDES EVIDENCE FOR THE EXPANSION OF MULTIPLE CLONES. THIS HIGHLIGHTS THE PROGNOSTIC POTENTIAL OF SUCH APPROACHES, IF APPLIED SYSTEMATICALLY, FOR DELINEATING THE ROLES OF SPECIFIC MUTATIONS IN PREDISPOSING AND/OR DRIVING DISTINCT DISEASE PHENOTYPES. 2014 11 4555 30 MUTATIONAL SPECTRUM ANALYSIS OF CHRONIC MYELOMONOCYTIC LEUKEMIA INCLUDES GENES ASSOCIATED WITH EPIGENETIC REGULATION: UTX, EZH2, AND DNMT3A. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), A MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM, IS CHARACTERIZED BY MONOCYTIC PROLIFERATION, DYSPLASIA, AND PROGRESSION TO ACUTE MYELOID LEUKEMIA. CMML HAS BEEN ASSOCIATED WITH SOMATIC MUTATIONS IN DIVERSE RECENTLY IDENTIFIED GENES. WE ANALYZED 72 WELL-CHARACTERIZED PATIENTS WITH CMML (N = 52) AND CMML-DERIVED ACUTE MYELOID LEUKEMIA (N = 20) FOR RECURRENT CHROMOSOMAL ABNORMALITIES WITH THE USE OF ROUTINE CYTOGENETICS AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAYS ALONG WITH COMPREHENSIVE MUTATIONAL SCREENING. CYTOGENETIC ABERRATIONS WERE PRESENT IN 46% OF CASES, WHEREAS SINGLE NUCLEOTIDE POLYMORPHISM ARRAY INCREASED THE DIAGNOSTIC YIELD TO 60%. AT LEAST 1 MUTATION WAS FOUND IN 86% OF ALL CASES; NOVEL UTX, DNMT3A, AND EZH2 MUTATIONS WERE FOUND IN 8%, 10%, AND 5.5% OF PATIENTS, RESPECTIVELY. TET2 MUTATIONS WERE PRESENT IN 49%, ASXL1 IN 43%, CBL IN 14%, IDH1/2 IN 4%, KRAS IN 7%, NRAS IN 4%, AND JAK2 V617F IN 1% OF PATIENTS. VARIOUS MUTANT GENOTYPE COMBINATIONS WERE OBSERVED, INDICATING MOLECULAR HETEROGENEITY IN CMML. OUR RESULTS SUGGEST THAT MOLECULAR DEFECTS AFFECTING DISTINCT PATHWAYS CAN LEAD TO SIMILAR CLINICAL PHENOTYPES. 2011 12 1039 33 CLINICAL AND BIOLOGICAL IMPLICATIONS OF DRIVER MUTATIONS IN MYELODYSPLASTIC SYNDROMES. MYELODYSPLASTIC SYNDROMES (MDS) ARE A HETEROGENEOUS GROUP OF CHRONIC HEMATOLOGICAL MALIGNANCIES CHARACTERIZED BY DYSPLASIA, INEFFECTIVE HEMATOPOIESIS AND A VARIABLE RISK OF PROGRESSION TO ACUTE MYELOID LEUKEMIA. SEQUENCING OF MDS GENOMES HAS IDENTIFIED MUTATIONS IN GENES IMPLICATED IN RNA SPLICING, DNA MODIFICATION, CHROMATIN REGULATION, AND CELL SIGNALING. WE SEQUENCED 111 GENES ACROSS 738 PATIENTS WITH MDS OR CLOSELY RELATED NEOPLASMS (INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA AND MDS-MYELOPROLIFERATIVE NEOPLASMS) TO EXPLORE THE ROLE OF ACQUIRED MUTATIONS IN MDS BIOLOGY AND CLINICAL PHENOTYPE. SEVENTY-EIGHT PERCENT OF PATIENTS HAD 1 OR MORE ONCOGENIC MUTATIONS. WE IDENTIFY COMPLEX PATTERNS OF PAIRWISE ASSOCIATION BETWEEN GENES, INDICATIVE OF EPISTATIC INTERACTIONS INVOLVING COMPONENTS OF THE SPLICEOSOME MACHINERY AND EPIGENETIC MODIFIERS. COUPLED WITH INFERENCES ON SUBCLONAL MUTATIONS, THESE DATA SUGGEST A HYPOTHESIS OF GENETIC "PREDESTINATION," IN WHICH EARLY DRIVER MUTATIONS, TYPICALLY AFFECTING GENES INVOLVED IN RNA SPLICING, DICTATE FUTURE TRAJECTORIES OF DISEASE EVOLUTION WITH DISTINCT CLINICAL PHENOTYPES. DRIVER MUTATIONS HAD EQUIVALENT PROGNOSTIC SIGNIFICANCE, WHETHER CLONAL OR SUBCLONAL, AND LEUKEMIA-FREE SURVIVAL DETERIORATED STEADILY AS NUMBERS OF DRIVER MUTATIONS INCREASED. THUS, ANALYSIS OF ONCOGENIC MUTATIONS IN LARGE, WELL-CHARACTERIZED COHORTS OF PATIENTS ILLUSTRATES THE INTERCONNECTIONS BETWEEN THE CANCER GENOME AND DISEASE BIOLOGY, WITH CONSIDERABLE POTENTIAL FOR CLINICAL APPLICATION. 2013 13 1070 34 CLONAL ARCHITECTURE OF CHRONIC MYELOMONOCYTIC LEUKEMIAS. GENOMIC STUDIES IN CHRONIC MYELOID MALIGNANCIES, INCLUDING MYELOPROLIFERATIVE NEOPLASMS (MPN), MYELODYSPLASTIC SYNDROMES (MDS), AND MPN/MDS, HAVE IDENTIFIED COMMON MUTATIONS IN GENES ENCODING SIGNALING, EPIGENETIC, TRANSCRIPTION, AND SPLICING FACTORS. IN THE PRESENT STUDY, WE INTERROGATED THE CLONAL ARCHITECTURE BY MUTATION-SPECIFIC DISCRIMINATION ANALYSIS OF SINGLE-CELL-DERIVED COLONIES IN 28 PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIAS (CMML), THE MOST FREQUENT MPN/MDS. THIS ANALYSIS REVEALS A LINEAR ACQUISITION OF THE STUDIED MUTATIONS WITH LIMITED BRANCHING THROUGH LOSS OF HETEROZYGOSITY. SERIAL ANALYSIS OF UNTREATED AND TREATED SAMPLES DEMONSTRATES A DYNAMIC ARCHITECTURE ON WHICH MOST CURRENT THERAPEUTIC APPROACHES HAVE LIMITED EFFECTS. THE MAIN DISEASE CHARACTERISTICS ARE EARLY CLONAL DOMINANCE, ARISING AT THE CD34(+)/CD38(-) STAGE OF HEMATOPOIESIS, AND GRANULOMONOCYTIC DIFFERENTIATION SKEWING OF MULTIPOTENT AND COMMON MYELOID PROGENITORS. COMPARISON OF CLONAL EXPANSIONS OF TET2 MUTATIONS IN MDS, MPN, AND CMML, TOGETHER WITH FUNCTIONAL INVALIDATION OF TET2 IN SORTED PROGENITORS, SUGGESTS A CAUSATIVE LINK BETWEEN EARLY CLONAL DOMINANCE AND SKEWED GRANULOMONOCYTIC DIFFERENTIATION. ALTOGETHER, EARLY CLONAL DOMINANCE MAY DISTINGUISH CMML FROM OTHER CHRONIC MYELOID NEOPLASMS WITH SIMILAR GENE MUTATIONS. 2013 14 5245 36 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 15 384 39 AN EVOLUTIONARY PERSPECTIVE ON CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) SHARES WITH OTHER MYELOID DISEASES A NUMBER OF SOMATIC GENE MUTATIONS. THESE MUTATIONS CAN NOW BE INTEGRATED WITHIN THE FRAMEWORK OF EVOLUTION THEORY TO ADDRESS THE MECHANISMS OF THE DISEASE. SEVERAL EVIDENCES INDICATE THAT THE DISEASE EMERGES IN ADULT HEMATOPOIETIC STEM CELLS (HSC) THROUGH THE AGE-DEPENDENT ACCUMULATION OF DNA DAMAGE, LEADING STOCHASTICALLY TO A DRIVER MUTATION THAT CONFERS A COMPETITIVE ADVANTAGE TO THE CELL. A MUTATION IN TET2 GENE COULD BE ONE OF THESE DRIVER MUTATIONS PROVOKING THE EMERGENCE OF CLONALITY. AFTER A LONG LATENCY, SECONDARY LESIONS, SUCH AS MUTATIONS IN THE SRSF2 GENE, CONTRIBUTE TO PROGRESSION TO FULL-BLOWN MALIGNANCY, WITH ABNORMAL DIFFERENTIATION. ADDITIONAL MUTATIONS ACCUMULATE AND BRANCHING ARISING MOSTLY THROUGH MITOTIC RECOMBINATION GENERATES CLONAL HETEROGENEITY. MODIFICATIONS IN THE MICROENVIRONMENT PROBABLY AFFECT THIS CLONAL DYNAMICS, WHEREAS EPIGENETIC ALTERATIONS, SUCH AS HYPERMETHYLATION OF THE TIF1GAMMA GENE PROMOTER, MAY GENERATE PHENOTYPIC DIVERSIFICATION OF OTHERWISE CLONAL POPULATIONS. THE PRESERVED ALTHOUGH DEREGULATED MYELOID DIFFERENTIATION THAT CHARACTERIZES CMML, WITH GRANULOMONOCYTE EXPANSION AND VARIOUS CYTOPENIAS, MAY DEPEND ON EARLY CLONAL DOMINANCE IN THE HEMATOPIETIC CELL HIERARCHY. PROGRESSION TO ACUTE MYELOID LEUKEMIA OBSERVED IN 25-30% OF THE PATIENTS MAY ARISE FROM THE MASSIVE EXPANSION OF A CLONE WITH NOVEL GENETIC LESIONS, PROVIDING A HIGH FITNESS TO PREVIOUSLY MINOR SUBCLONES WHEN IN CHRONIC PHASE OF THE DISEASE. THIS REVIEW DISCUSSES THE VARIOUS MODELS OF DISEASE EMERGENCE AND PROGRESSION AND HOW THIS RECENT KNOWLEDGE COULD DRIVE RATIONAL THERAPEUTIC STRATEGIES. 2013 16 4565 24 MYELOID MALIGNANCIES: MUTATIONS, MODELS AND MANAGEMENT. MYELOID MALIGNANT DISEASES COMPRISE CHRONIC (INCLUDING MYELODYSPLASTIC SYNDROMES, MYELOPROLIFERATIVE NEOPLASMS AND CHRONIC MYELOMONOCYTIC LEUKEMIA) AND ACUTE (ACUTE MYELOID LEUKEMIA) STAGES. THEY ARE CLONAL DISEASES ARISING IN HEMATOPOIETIC STEM OR PROGENITOR CELLS. MUTATIONS RESPONSIBLE FOR THESE DISEASES OCCUR IN SEVERAL GENES WHOSE ENCODED PROTEINS BELONG PRINCIPALLY TO FIVE CLASSES: SIGNALING PATHWAYS PROTEINS (E.G. CBL, FLT3, JAK2, RAS), TRANSCRIPTION FACTORS (E.G. CEBPA, ETV6, RUNX1), EPIGENETIC REGULATORS (E.G. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), TUMOR SUPPRESSORS (E.G. TP53), AND COMPONENTS OF THE SPLICEOSOME (E.G. SF3B1, SRSF2). LARGE-SCALE SEQUENCING EFFORTS WILL SOON LEAD TO THE ESTABLISHMENT OF A COMPREHENSIVE REPERTOIRE OF THESE MUTATIONS, ALLOWING FOR A BETTER DEFINITION AND CLASSIFICATION OF MYELOID MALIGNANCIES, THE IDENTIFICATION OF NEW PROGNOSTIC MARKERS AND THERAPEUTIC TARGETS, AND THE DEVELOPMENT OF NOVEL THERAPIES. GIVEN THE IMPORTANCE OF EPIGENETIC DEREGULATION IN MYELOID DISEASES, THE USE OF DRUGS TARGETING EPIGENETIC REGULATORS APPEARS AS A MOST PROMISING THERAPEUTIC APPROACH. 2012 17 937 22 CHRONIC LYMPHOCYTIC LEUKAEMIA GENOMICS AND THE PRECISION MEDICINE ERA. MASSIVE GENOMIC ANALYSES HAVE UNDERSCORED THE DIVERSITY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) BETWEEN PATIENTS. GENETIC HETEROGENEITY OF TUMOUR CLONES WITHIN A PATIENT MAY FUEL TUMOUR EVOLUTION. SEVERAL RECURRENTLY DEREGULATED INTRA-CELLULAR PATHWAYS ARE CANDIDATES FOR TARGETED THERAPIES THAT ARE VERY PROMISING AND ARE DRAMATICALLY CHANGING CLINICAL PATIENTS' PERSPECTIVES. IN THIS REVIEW WE PRESENT AN OVERVIEW OF THE GENETIC AND EPIGENETIC FEATURES OF CLL AND THEIR CLINICAL AND BIOLOGICAL IMPLICATIONS. 2017 18 4485 36 MOLECULAR SIMILARITY BETWEEN MYELODYSPLASTIC FORM OF CHRONIC MYELOMONOCYTIC LEUKEMIA AND REFRACTORY ANEMIA WITH RING SIDEROBLASTS. CHRONIC MYELOMONOCYTIC LEUKEMIA IS SIMILAR TO BUT A SEPARATE ENTITY FROM BOTH MYELOPROLIFERATIVE NEOPLASMS AND MYELODYSPLASTIC SYNDROMES, AND SHOWS EITHER MYELOPROLIFERATIVE OR MYELODYSPLASTIC FEATURES. WE ASK WHETHER THIS DISTINCTION MAY HAVE A MOLECULAR BASIS. WE ESTABLISHED THE GENE EXPRESSION PROFILES OF 39 SAMPLES OF CHRONIC MYELOMONOCYTIC LEUKEMIA (INCLUDING 12 CD34-POSITIVE) AND 32 CD34-POSITIVE SAMPLES OF MYELODYSPLASTIC SYNDROMES BY USING AFFYMETRIX MICROARRAYS, AND STUDIED THE STATUS OF 18 GENES BY SANGER SEQUENCING AND ARRAY-COMPARATIVE GENOMIC HYBRIDIZATION IN 53 SAMPLES. ANALYSIS OF 12 MRNAS FROM CHRONIC MYELOMONOCYTIC LEUKEMIA ESTABLISHED A GENE EXPRESSION SIGNATURE OF 122 PROBE SETS DIFFERENTIALLY EXPRESSED BETWEEN PROLIFERATIVE AND DYSPLASTIC CASES OF CHRONIC MYELOMONOCYTIC LEUKEMIA. AS COMPARED TO PROLIFERATIVE CASES, DYSPLASTIC CASES OVER-EXPRESSED GENES INVOLVED IN RED BLOOD CELL BIOLOGY. WHEN APPLIED TO 32 MYELODYSPLASTIC SYNDROMES, THIS GENE EXPRESSION SIGNATURE WAS ABLE TO DISCRIMINATE REFRACTORY ANEMIAS WITH RING SIDEROBLASTS FROM REFRACTORY ANEMIAS WITH EXCESS OF BLASTS. BY COMPARING MRNAS FROM THESE TWO FORMS OF MYELODYSPLASTIC SYNDROMES WE DERIVED A SECOND GENE EXPRESSION SIGNATURE. THIS SIGNATURE SEPARATED THE MYELODYSPLASTIC AND MYELOPROLIFERATIVE FORMS OF CHRONIC MYELOMONOCYTIC LEUKEMIAS. THESE RESULTS WERE VALIDATED USING TWO INDEPENDENT GENE EXPRESSION DATA SETS. WE FOUND THAT MYELODYSPLASTIC CHRONIC MYELOMONOCYTIC LEUKEMIAS ARE CHARACTERIZED BY MUTATIONS IN TRANSCRIPTION/EPIGENETIC REGULATORS (ASXL1, RUNX1, TET2) AND SPLICING GENES (SRSF2) AND THE ABSENCE OF MUTATIONS IN SIGNALING GENES. MYELODYSPLASTIC CHRONIC MYELOMONOCYTIC LEUKEMIAS AND REFRACTORY ANEMIAS WITH RING SIDEROBLASTS SHARE A COMMON EXPRESSION PROGRAM SUGGESTING THEY ARE PART OF A CONTINUUM, WHICH IS NOT TOTALLY EXPLAINED BY THEIR SIMILAR BUT NOT, HOWEVER, IDENTICAL MUTATION SPECTRUM. 2013 19 2106 35 EPIGENETIC EVOLUTION AND LINEAGE HISTORIES OF CHRONIC LYMPHOCYTIC LEUKAEMIA. GENETIC AND EPIGENETIC INTRA-TUMORAL HETEROGENEITY COOPERATE TO SHAPE THE EVOLUTIONARY COURSE OF CANCER(1). CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS A HIGHLY INFORMATIVE MODEL FOR CANCER EVOLUTION AS IT UNDERGOES SUBSTANTIAL GENETIC DIVERSIFICATION AND EVOLUTION AFTER THERAPY(2,3). THE CLL EPIGENOME IS ALSO AN IMPORTANT DISEASE-DEFINING FEATURE(4,5), AND GROWING POPULATIONS OF CELLS IN CLL DIVERSIFY BY STOCHASTIC CHANGES IN DNA METHYLATION KNOWN AS EPIMUTATIONS(6). HOWEVER, PREVIOUS STUDIES USING BULK SEQUENCING METHODS TO ANALYSE THE PATTERNS OF DNA METHYLATION WERE UNABLE TO DETERMINE WHETHER EPIMUTATIONS AFFECT CLL POPULATIONS HOMOGENEOUSLY. HERE, TO MEASURE THE EPIMUTATION RATE AT SINGLE-CELL RESOLUTION, WE APPLIED MULTIPLEXED SINGLE-CELL REDUCED-REPRESENTATION BISULFITE SEQUENCING TO B CELLS FROM HEALTHY DONORS AND PATIENTS WITH CLL. WE OBSERVED THAT THE COMMON CLONAL ORIGIN OF CLL RESULTS IN A CONSISTENTLY INCREASED EPIMUTATION RATE, WITH LOW VARIABILITY IN THE CELL-TO-CELL EPIMUTATION RATE. BY CONTRAST, VARIABLE EPIMUTATION RATES ACROSS HEALTHY B CELLS REFLECT DIVERSE EVOLUTIONARY AGES ACROSS THE TRAJECTORY OF B CELL DIFFERENTIATION, CONSISTENT WITH EPIMUTATIONS SERVING AS A MOLECULAR CLOCK. HERITABLE EPIMUTATION INFORMATION ALLOWED US TO RECONSTRUCT LINEAGES AT HIGH-RESOLUTION WITH SINGLE-CELL DATA, AND TO APPLY THIS DIRECTLY TO PATIENT SAMPLES. THE CLL LINEAGE TREE SHAPE REVEALED EARLIER BRANCHING AND LONGER BRANCH LENGTHS THAN IN NORMAL B CELLS, REFLECTING RAPID DRIFT AFTER THE INITIAL MALIGNANT TRANSFORMATION AND A GREATER PROLIFERATIVE HISTORY. INTEGRATION OF SINGLE-CELL BISULFITE SEQUENCING ANALYSIS WITH SINGLE-CELL TRANSCRIPTOMES AND GENOTYPING CONFIRMED THAT GENETIC SUBCLONES MAPPED TO DISTINCT CLADES, AS INFERRED SOLELY ON THE BASIS OF EPIMUTATION INFORMATION. FINALLY, TO EXAMINE POTENTIAL LINEAGE BIASES DURING THERAPY, WE PROFILED SERIAL SAMPLES DURING IBRUTINIB-ASSOCIATED LYMPHOCYTOSIS, AND IDENTIFIED CLADES OF CELLS THAT WERE PREFERENTIALLY EXPELLED FROM THE LYMPH NODE AFTER TREATMENT, MARKED BY DISTINCT TRANSCRIPTIONAL PROFILES. THE SINGLE-CELL INTEGRATION OF GENETIC, EPIGENETIC AND TRANSCRIPTIONAL INFORMATION THUS CHARTS THE LINEAGE HISTORY OF CLL AND ITS EVOLUTION WITH THERAPY. 2019 20 5405 31 REGULATED EXPRESSION OF P210 BCR-ABL DURING EMBRYONIC STEM CELL DIFFERENTIATION STIMULATES MULTIPOTENTIAL PROGENITOR EXPANSION AND MYELOID CELL FATE. P210 BCR-ABL IS AN ACTIVATED TYROSINE KINASE ONCOGENE ENCODED BY THE PHILADELPHIA CHROMOSOME ASSOCIATED WITH HUMAN CHRONIC MYELOGENOUS LEUKEMIA (CML). THE DISEASE REPRESENTS A CLONAL DISORDER ARISING IN THE PLURIPOTENT HEMATOPOIETIC STEM CELL. DURING THE CHRONIC PHASE, PATIENTS PRESENT WITH A DRAMATIC EXPANSION OF MYELOID CELLS AND A MILD ANEMIA. RETROVIRAL GENE TRANSFER AND TRANSGENIC EXPRESSION IN RODENTS HAVE DEMONSTRATED THE ABILITY OF BCR-ABL TO INDUCE VARIOUS TYPES OF LEUKEMIA. HOWEVER, STUDY OF HUMAN CML OR RODENT MODELS HAS NOT DETERMINED THE DIRECT AND IMMEDIATE EFFECTS OF BCR-ABL ON HEMATOPOIETIC CELLS FROM THOSE REQUIRING SECONDARY GENETIC OR EPIGENETIC CHANGES SELECTED DURING THE PATHOGENIC PROCESS. WE UTILIZED TETRACYCLINE-REGULATED EXPRESSION OF BCR-ABL FROM A PROMOTER ENGINEERED FOR ROBUST EXPRESSION IN PRIMITIVE STEM CELLS THROUGH MULTILINEAGE BLOOD CELL DEVELOPMENT IN COMBINATION WITH THE IN VITRO DIFFERENTIATION OF EMBRYONAL STEM CELLS INTO HEMATOPOIETIC ELEMENTS. OUR RESULTS DEMONSTRATE THAT BCR-ABL EXPRESSION ALONE IS SUFFICIENT TO INCREASE THE NUMBER OF MULTIPOTENT AND MYELOID LINEAGE COMMITTED PROGENITORS IN A DOSE-DEPENDENT MANNER WHILE SUPPRESSING THE DEVELOPMENT OF COMMITTED ERYTHROID PROGENITORS. THESE EFFECTS ARE REVERSIBLE UPON EXTINGUISHING BCR-ABL EXPRESSION. THESE FINDINGS ARE CONSISTENT WITH BCR-ABL BEING THE SOLE GENETIC CHANGE NEEDED FOR THE ESTABLISHMENT OF THE CHRONIC PHASE OF CML AND PROVIDE A POWERFUL SYSTEM FOR THE ANALYSIS OF ANY GENETIC CHANGE THAT ALTERS CELL GROWTH AND LINEAGE CHOICES OF THE HEMATOPOIETIC STEM CELL. 2000