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 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 3 959 28 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 4 4565 26 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 5 4748 25 NOVEL MUTATIONS AND THEIR FUNCTIONAL AND CLINICAL RELEVANCE IN MYELOPROLIFERATIVE NEOPLASMS: JAK2, MPL, TET2, ASXL1, CBL, IDH AND IKZF1. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ORIGINATE FROM GENETICALLY TRANSFORMED HEMATOPOIETIC STEM CELLS THAT RETAIN THE CAPACITY FOR MULTILINEAGE DIFFERENTIATION AND EFFECTIVE MYELOPOIESIS. BEGINNING IN EARLY 2005, A NUMBER OF NOVEL MUTATIONS INVOLVING JANUS KINASE 2 (JAK2), MYELOPROLIFERATIVE LEUKEMIA VIRUS (MPL), TET ONCOGENE FAMILY MEMBER 2 (TET2), ADDITIONAL SEX COMBS-LIKE 1 (ASXL1), CASITAS B-LINEAGE LYMPHOMA PROTO-ONCOGENE (CBL), ISOCITRATE DEHYDROGENASE (IDH) AND IKAROS FAMILY ZINC FINGER 1 (IKZF1) HAVE BEEN DESCRIBED IN BCR-ABL1-NEGATIVE MPNS. HOWEVER, NONE OF THESE MUTATIONS WERE MPN SPECIFIC, DISPLAYED MUTUAL EXCLUSIVITY OR COULD BE TRACED BACK TO A COMMON ANCESTRAL CLONE. JAK2 AND MPL MUTATIONS APPEAR TO EXERT A PHENOTYPE-MODIFYING EFFECT AND ARE DISTINCTLY ASSOCIATED WITH POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA AND PRIMARY MYELOFIBROSIS; THE CORRESPONDING MUTATIONAL FREQUENCIES ARE APPROXIMATELY 99, 55 AND 65% FOR JAK2 AND 0, 3 AND 10% FOR MPL MUTATIONS. THE INCIDENCE OF TET2, ASXL1, CBL, IDH OR IKZF1 MUTATIONS IN THESE DISORDERS RANGES FROM 0 TO 17%; THESE LATTER MUTATIONS ARE MORE COMMON IN CHRONIC (TET2, ASXL1, CBL) OR JUVENILE (CBL) MYELOMONOCYTIC LEUKEMIAS, MASTOCYTOSIS (TET2), MYELODYSPLASTIC SYNDROMES (TET2, ASXL1) AND SECONDARY ACUTE MYELOID LEUKEMIA, INCLUDING BLAST-PHASE MPN (IDH, ASXL1, IKZF1). THE FUNCTIONAL CONSEQUENCES OF MPN-ASSOCIATED MUTATIONS INCLUDE UNREGULATED JAK-STAT (JANUS KINASE/SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION) SIGNALING, EPIGENETIC MODULATION OF TRANSCRIPTION AND ABNORMAL ACCUMULATION OF ONCOPROTEINS. HOWEVER, IT IS NOT CLEAR AS TO WHETHER AND HOW THESE ABNORMALITIES CONTRIBUTE TO DISEASE INITIATION, CLONAL EVOLUTION OR BLASTIC TRANSFORMATION. 2010 6 5911 29 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 7 1266 29 CYTOGENETIC AND MOLECULAR ABNORMALITIES IN CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER ASSOCIATED WITH PERIPHERAL BLOOD MONOCYTOSIS AND AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKEMIA. CMML HAS OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. CLONAL CYTOGENETIC CHANGES ARE SEEN IN ~30%, WHEREAS GENE MUTATIONS ARE SEEN IN >90% OF PATIENTS. COMMON CYTOGENETIC ABNORMALITIES INCLUDE; TRISOMY 8, -Y, -7/DEL(7Q), TRISOMY 21 AND DEL(20Q), WITH THE MAYO-FRENCH RISK STRATIFICATION EFFECTIVELY RISK STRATIFYING PATIENTS BASED ON CYTOGENETIC ABNORMALITIES. GENE MUTATIONS FREQUENTLY INVOLVE EPIGENETIC REGULATORS (TET2 ~60%), MODULATORS OF CHROMATIN (ASXL1 ~40%), SPLICEOSOME COMPONENTS (SRSF2 ~50%), TRANSCRIPTION FACTORS (RUNX1 ~15%) AND SIGNAL PATHWAYS (RAS ~30%, CBL ~15%). OF THESE, THUS FAR, ONLY NONSENSE AND FRAMESHIFT ASXL1 MUTATIONS HAVE BEEN SHOWN TO NEGATIVELY IMPACT OVERALL SURVIVAL. THIS HAS RESULTED IN THE DEVELOPMENT OF CONTEMPORARY, MOLECULARLY INTEGRATED (INCLUSIVE OF ASXL1 MUTATIONS) CMML PROGNOSTIC MODELS, INCLUDING MOLECULAR MAYO MODEL AND THE GROUPE FRANCAIS DES MYELODYSPLASIES MODEL. BETTER UNDERSTANDING OF THE PREVALENT GENETIC AND EPIGENETIC DYSREGULATION HAS RESULTED IN EMERGING TARGETED TREATMENT OPTIONS FOR SOME PATIENTS. THE DEVELOPMENT OF AN INTEGRATED (CYTOGENETIC AND MOLECULAR) PROGNOSTIC MODEL ALONG WITH CMML-SPECIFIC RESPONSE ASSESSMENT CRITERIA ARE MUCH NEEDED FUTURE GOALS. 2016 8 6856 22 [NOT AVAILABLE]. BIOLOGICAL ASPECTS OF JAK/STAT SIGNALING IN BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: MYELOPROLIFERATIVE DISORDERS MORE RECENTLY NAMED MYELOPROLIFERATIVE NEOPLASMS (MPN) DISPLAY SEVERAL CLINICAL ENTITIES: CHRONIC MYELOID LEUKEMIA (CML), THE CLASSICAL MPN INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET), PRIMARY MYELOFIBROSIS (PMF) AND ATYPICAL AND UNCLASSIFIABLE NMP. THE TERM MPN IS MOSTLY USED FOR CLASSICAL BCR-ABL-NEGATIVE (MYELOPROLIFERATIVE DISORDER) (ET, PV, PMF). THESE ARE CLONAL DISEASES RESULTING FROM THE TRANSFORMATION OF AN HEMATOPOIETIC STEM CELL AND LEADING TO AN ABNORMAL PRODUCTION OF MYELOID CELLS. THE GENETIC DEFECTS RESPONSIBLE FOR THE MYELOPROLIFERATIVE ABNORMALITIES ARE CALLED << DRIVER >> MUTATIONS AND ALL RESULT IN DEREGULATION OF THE CYTOKINE RECEPTOR / JAK2 / STAT AXIS. AMONG THEM, JAK2, THE THROMBOPOIETIN RECEPTOR (MPL) AND CALRETICULIN (CALR) MUTATIONS ARE FOUND IN AROUND 90% OF THE CASES. THESE DRIVER MPN MUTATIONS CAN BE ASSOCIATED WITH OTHER DRIVER MUTATIONS ALSO FOUND IN OTHER HEMATOLOGICAL MALIGNANCIES, ESPECIALLY IN PMFS. THESE ARE CHRONIC DISEASES WITH MAJOR RISKS BEING THROMBOSIS, HEMORRHAGE AND CYTOPENIAS FOR PMF AND THE LONG-TERM PROGRESSION TO MYELOFIBROSIS AND THE TRANSFORMATION TO LEUKEMIA. MOST RECENT THERAPEUTIC HAVE FOCUSED ON TARGETING THE JAK2 SIGNALING PATHWAY DIRECTLY BY INHIBITORS OF JAK2 OR INDIRECTLY. INTERFERON A ALLOWS IN SOME CASES HEMATOLOGIC AND MOLECULAR REMISSION PATIENTS. 2016 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 5953 20 TARGETS IN MPNS AND POTENTIAL THERAPEUTICS. PHILADELPHIA-NEGATIVE CLASSICAL MYELOPROLIFERATIVE NEOPLASMS (MPNS), INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF), ARE CLONAL HEMOPATHIES THAT EMERGE IN THE HEMATOPOIETIC STEM CELL (HSC) COMPARTMENT. MPN DRIVER MUTATIONS ARE RESTRICTED TO SPECIFIC EXONS (14 AND 12) OF JANUS KINASE 2 (JAK2), THROMBOPOIETIN RECEPTOR (MPL/TPOR) AND CALRETICULIN (CALR) GENES, ARE INVOLVED DIRECTLY IN CLONAL MYELOPROLIFERATION AND GENERATE THE MPN PHENOTYPE. AS A RESULT, AN INCREASED NUMBER OF FULLY FUNCTIONAL ERYTHROCYTES, PLATELETS AND LEUKOCYTES IS OBSERVED IN THE PERIPHERAL BLOOD. NEVERTHELESS, THE COMPLEXITY AND HETEROGENEITY OF MPN CLINICAL PHENOTYPES CANNOT BE SOLELY EXPLAINED BY THE TYPE OF DRIVER MUTATION. OTHER FACTORS, SUCH AS ADDITIONAL SOMATIC MUTATIONS AFFECTING EPIGENETIC REGULATORS OR SPLICEOSOMES COMPONENTS, MUTANT ALLELE BURDENS AND MODIFIERS OF SIGNALING BY DRIVER MUTANTS, CLONAL ARCHITECTURE AND THE ORDER OF MUTATION ACQUISITION, SIGNALING EVENTS THAT OCCUR DOWNSTREAM OF A DRIVER MUTATION, THE PRESENCE OF SPECIFIC GERM-LINE VARIANTS, THE INTERACTION OF THE NEOPLASTIC CLONE WITH BONE MARROW MICROENVIRONMENT AND CHRONIC INFLAMMATION, ALL CAN MODULATE THE DISEASE PHENOTYPE, INFLUENCE THE MPN CLINICAL COURSE AND THEREFORE, MIGHT BE USEFUL THERAPEUTIC TARGETS. 2022 11 4555 25 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 1070 25 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 13 4680 28 NEW MUTATIONS AND PATHOGENESIS OF MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL DISORDERS CHARACTERIZED BY EXCESSIVE PRODUCTION OF MATURE BLOOD CELLS. IN THE MAJORITY OF CLASSIC MPN--POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA, AND PRIMITIVE MYELOFIBROSIS--DRIVER ONCOGENIC MUTATIONS AFFECTING JANUS KINASE 2 (JAK2) OR MPL LEAD TO CONSTITUTIVE ACTIVATION OF CYTOKINE-REGULATED INTRACELLULAR SIGNALING PATHWAYS. LNK, C-CBL, OR SOCSS (ALL NEGATIVE REGULATORS OF SIGNALING PATHWAYS), ALTHOUGH INFREQUENTLY TARGETED, MAY EITHER DRIVE THE DISEASE OR SYNERGIZE WITH JAK2 AND MPL MUTATIONS. IZF1 DELETIONS OR TP53 MUTATIONS ARE MAINLY FOUND AT TRANSFORMATION PHASES AND ARE PRESENT AT GREATER FREQUENCY THAN IN DE NOVO ACUTE MYELOID LEUKEMIAS. LOSS-OF-FUNCTION MUTATIONS IN 3 GENES INVOLVED IN EPIGENETIC REGULATION, TET2, ASXL1, AND EZH2, MAY BE EARLY EVENTS PRECEDING JAK2V617F BUT MAY ALSO OCCUR LATE DURING DISEASE PROGRESSION. THEY ARE MORE FREQUENTLY OBSERVED IN PMF THAN PV AND ET AND ARE ALSO PRESENT IN OTHER TYPES OF MALIGNANT MYELOID DISEASES. A LIKELY HYPOTHESIS IS THAT THEY FACILITATE CLONAL SELECTION, ALLOWING THE DOMINANCE OF THE JAK2V617F SUBCLONE DURING THE CHRONIC PHASE AND, TOGETHER WITH COOPERATING MUTATIONS, PROMOTE BLAST CRISIS. THEIR PRECISE ROLES IN HEMATOPOIESIS AND IN THE PATHOGENESIS OF MPN, AS WELL AS THEIR PROGNOSTIC IMPACT AND POTENTIAL AS A THERAPEUTIC TARGET, ARE CURRENTLY UNDER INVESTIGATION. 2011 14 962 29 CHRONIC MYELOMONOCYTIC LEUKEMIA: FOCUS ON CLINICAL PRACTICE. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER WITH FEATURES THAT OVERLAP THOSE OF MYELODYSPLASTIC SYNDROMES (MDSS) AND MYELOPROLIFERATIVE NEOPLASMS (MPNS). CHRONIC MYELOMONOCYTIC LEUKEMIA OFTEN RESULTS IN PERIPHERAL BLOOD MONOCYTOSIS AND HAS AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKEMIA. CLONAL CYTOGENETIC CHANGES ARE SEEN IN APPROXIMATELY 30% OF PATIENTS, AND MOLECULAR ABNORMALITIES ARE SEEN IN MORE THAN 90%. GENE MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT, WITH NONSENSE AND FRAMESHIFT ASXL1 MUTATIONS BEING THE ONLY MUTATIONS IDENTIFIED THUS FAR TO HAVE AN INDEPENDENT NEGATIVE PROGNOSTIC EFFECT ON OVERALL SURVIVAL. CONTEMPORARY MOLECULARLY INTEGRATED PROGNOSTIC MODELS (INCLUSIVE OF ASXL1 MUTATIONS) INCLUDE THE MOLECULAR MAYO MODEL AND THE GROUPE FRANCAIS DES MYELODYSPLASIES MODEL. GIVEN THE LACK OF FORMAL TREATMENT AND RESPONSE CRITERIA, MANAGEMENT OF CMML IS OFTEN EXTRAPOLATED FROM MDS AND MPN, WITH ALLOGENEIC STEM CELL TRANSPLANT BEING THE ONLY CURATIVE OPTION. HYDROXYUREA AND OTHER CYTOREDUCTIVE AGENTS HAVE BEEN USED TO CONTROL MPN-LIKE FEATURES, WHILE EPIGENETIC MODIFIERS SUCH AS HYPOMETHYLATING AGENTS HAVE BEEN USED FOR MDS-LIKE FEATURES. GIVEN THE RELATIVELY POOR RESPONSE TO THESE AGENTS AND THE INHERENT RISKS ASSOCIATED WITH HEMATOPOIETIC STEM CELL TRANSPLANT, NEWER DRUGS EXPLOITING MOLECULAR AND EPIGENETIC ABNORMALITIES IN CMML ARE BEING DEVELOPED. THE CREATION OF CMML-SPECIFIC RESPONSE CRITERIA IS A MUCH NEEDED STEP IN ORDER TO IMPROVE CLINICAL OUTCOMES. 2016 15 1184 17 COOPERATIVE EPIGENETIC REMODELING BY TET2 LOSS AND NRAS MUTATION DRIVES MYELOID TRANSFORMATION AND MEK INHIBITOR SENSITIVITY. MUTATIONS IN EPIGENETIC MODIFIERS AND SIGNALING FACTORS OFTEN CO-OCCUR IN MYELOID MALIGNANCIES, INCLUDING TET2 AND NRAS MUTATIONS. CONCURRENT TET2 LOSS AND NRAS(G12D) EXPRESSION IN HEMATOPOIETIC CELLS INDUCED MYELOID TRANSFORMATION, WITH A FULLY PENETRANT, LETHAL CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), WHICH WAS SERIALLY TRANSPLANTABLE. TET2 LOSS AND NRAS MUTATION COOPERATIVELY LED TO DECREASE IN NEGATIVE REGULATORS OF MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) ACTIVATION, INCLUDING SPRY2, THEREBY CAUSING SYNERGISTIC ACTIVATION OF MAPK SIGNALING BY EPIGENETIC SILENCING. TET2/NRAS DOUBLE-MUTANT LEUKEMIA SHOWED PREFERENTIAL SENSITIVITY TO MAPK KINASE (MEK) INHIBITION IN BOTH MOUSE MODEL AND PATIENT SAMPLES. THESE DATA PROVIDE INSIGHTS INTO HOW EPIGENETIC AND SIGNALING MUTATIONS COOPERATE IN MYELOID TRANSFORMATION AND PROVIDE A RATIONALE FOR MECHANISM-BASED THERAPY IN CMML PATIENTS WITH THESE HIGH-RISK GENETIC LESIONS. 2018 16 961 27 CHRONIC MYELOMONOCYTIC LEUKEMIA: A GENETIC AND CLINICAL UPDATE. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER, CHARACTERIZED BY PERIPHERAL BLOOD MONOCYTOSIS AND OVERLAPPING FEATURES BETWEEN MYELODYSPLASTIC SYNDROMES (MDS) AND MYELOPROLIFERATIVE NEOPLASMS (MPNS). CLONAL CYTOGENETIC CHANGES ARE SEEN IN UP TO 30 % PATIENTS, WHILE APPROXIMATELY 90 % HAVE DETECTABLE MOLECULAR ABNORMALITIES. MOST PATIENTS ARE DIAGNOSED IN THE SEVENTH DECADE OF LIFE. GENE MUTATIONS IN TEN-ELEVEN TRANSLOCATION (TET) ONCOGENE FAMILY MEMBER 2 (TET2) (60 %), SRSF2 (50 %), ASXL1 (40 %), AND RAS (20-30 %) ARE FREQUENT, WITH ONLY FRAME SHIFT AND NONSENSE ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. WITH THE LACK OF FORMAL GUIDELINES, MANAGEMENT AND RESPONSE CRITERIA ARE OFTEN EXTRAPOLATED FROM MDS AND MPN. CONTEMPORARY MOLECULARLY INTEGRATED CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) MODEL AND THE MOLECULAR MAYO MODEL, BOTH INCORPORATING ASXL1 MUTATIONAL STATUS. HYPOMETHYLATING AGENTS AND ALLOGENEIC STEM CELL TRANSPLANT REMAIN THE TWO MOST COMMONLY USED TREATMENT STRATEGIES, WITH SUBOPTIMAL RESULTS. CLINICAL TRIALS EXPLOITING EPIGENETIC AND SIGNAL PATHWAY ABNORMALITIES, FREQUENT IN CMML, OFFER HOPE AND PROMISE. 2015 17 1043 24 CLINICAL CHARACTERISTICS AND WHOLE EXOME/TRANSCRIPTOME SEQUENCING OF COEXISTING CHRONIC MYELOID LEUKEMIA AND MYELOFIBROSIS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL HEMATOPOIETIC STEM CELL (HSC) DISORDERS THAT CAN BE CLASSIFIED ON THE BASIS OF GENETIC, CLINICAL, PHENOTYPIC FEATURES. GENETIC LESIONS SUCH AS JAK2 MUTATIONS AND BCR-ABL TRANSLOCATION ARE OFTEN MUTUALLY EXCLUSIVE IN MPN PATIENTS AND LEAD TO ESSENTIAL THROMBOCYTHEMIA, POLYCYTHEMIA VERA, OR MYELOFIBROSIS OR CHRONIC MYELOID LEUKEMIA, RESPECTIVELY. NEVERTHELESS, COEXISTENCE OF THESE GENETIC ABERRATIONS IN THE SAME PATIENT HAS BEEN REPORTED. WHETHER THESE ABERRATIONS OCCUR IN THE SAME STEM CELL OR A DIFFERENT CELL IS UNCLEAR, BUT AN UNSTABLE GENOME IN THE HSCS SEEMS TO BE THE COMMON ANTECEDENT. IN AN EFFORT TO CHARACTERIZE THE UNDERLYING GENETIC EVENTS THAT MIGHT CONTRIBUTE TO THE APPEARANCE OF MORE THAN ONE MPN IN A PATIENT, WE STUDIED NEOPLASTIC CELLS FROM PATIENTS WITH DUAL MPNS BY NEXT-GENERATION SEQUENCING. WE OBSERVED THAT MOST PATIENTS WITH TWO MPNS HARBORED MUTATIONS IN GENES KNOWN TO CONTRIBUTE TO CLONAL HEMATOPOIESIS THROUGH ALTERED EPIGENETIC REGULATION SUCH AS TET2, ASXL1/2, SRSF2, AND IDH2 AT VARYING FREQUENCIES (1%-47%). IN ADDITION, WE FOUND THAT SOME PATIENTS ALSO HARBORED ONCOGENIC MUTATIONS IN N/KRAS, TP53, BRAF, EZH2, AND GNAS AT LOW FREQUENCIES, WHICH PROBABLY REPRESENT CLONAL EVOLUTION. THESE FINDINGS SUPPORT THE HYPOTHESIS THAT HEMATOPOIETIC CELLS FROM MPN PATIENTS HARBOR MULTIPLE GENETIC ABERRATIONS, SOME OF WHICH CAN CONTRIBUTE TO CLONAL DOMINANCE. ACQUIRING MUTATIONS IN JAK2/CALR/MPL OR THE BCR-ABL TRANSLOCATION PROBABLY DRIVE THE ONCOGENIC PHENOTYPE TOWARDS A SPECIFIC MPN. FURTHER, WE PROPOSE THAT THE ACQUISITION OF BCR-ABL IN THESE PATIENTS IS FREQUENTLY A SECONDARY EVENT RESULTING FROM AN UNSTABLE GENOME. 2017 18 5664 17 SF3B1 MUTATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA. SF3B1 IS A CRITICAL COMPONENT OF THE SPLICING MACHINERY, WHICH CATALYZES THE REMOVAL OF INTRONS FROM PRECURSOR MESSENGER RNA (MRNA). NEXT-GENERATION SEQUENCING STUDIES HAVE IDENTIFIED MUTATIONS IN SF3B1 IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AT HIGH FREQUENCY. IN CLL, SF3B1 MUTATION IS ASSOCIATED WITH MORE AGGRESSIVE DISEASE AND SHORTER SURVIVAL, AND RECENT STUDIES SUGGEST THAT IT CAN BE INCORPORATED INTO PROGNOSTIC SCHEMA TO IMPROVE THE PREDICTION OF DISEASE PROGRESSION. MUTATIONS IN SF3B1 ARE PREDOMINANTLY SUBCLONAL GENETIC EVENTS IN CLL, AND HENCE ARE LIKELY LATER EVENTS IN THE PROGRESSION OF CLL. EVIDENCE OF ALTERED PRE-MRNA SPLICING HAS BEEN DETECTED IN CLL CASES WITH SF3B1 MUTATIONS. ALTHOUGH THE CAUSATIVE LINK BETWEEN SF3B1 MUTATION AND CLL PATHOGENESIS REMAINS UNCLEAR, SEVERAL LINES OF EVIDENCE SUGGEST SF3B1 MUTATION MIGHT BE LINKED TO GENOMIC STABILITY AND EPIGENETIC MODIFICATION. 2013 19 2956 24 GENETIC AND EPIGENETIC FACTORS INTERACTING WITH CLONAL HEMATOPOIESIS RESULTING IN CHRONIC MYELOMONOCYTIC LEUKEMIA. PURPOSE OF REVIEW: SINCE 2016, THE WHO HAS RECOGNIZED THE SIGNIFICANT PHENOTYPIC HETEROGENEITY OF CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AS A MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM (MDS/MPN) OVERLAP DISEASE. ALTHOUGH SHARING MANY SOMATIC MUTATIONS WITH MDS AND MPN, THE PURPOSE OF THIS REVIEW IS TO PUT RECENT BIOLOGICAL FINDINGS OF CMML IN THE CONTEXT OF EVOLUTIONARY THEORY, HIGHLIGHTING IT AS A DISTINCT EVOLUTIONARY TRAJECTORY OCCURRING IN THE CONTEXT OF CLONAL HEMATOPOIESIS. RECENT FINDINGS: CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP), WITH A MUTATIONAL SPECTRUM AND PREVALENCE CORRELATED WITH AGE, HAS BEEN DEFINED. ENRICHED IN DNMT3A, TET2, AND ASXL1 MUTATIONS, CLONAL EVOLUTION CAN PROGRESS INTO VARIOUS EVOLUTIONARY TRAJECTORIES INCLUDING CMML. IMPACT OF FOUNDER MUTATIONS (PRIMARILY TET2) ON INCREASED HEMATOPOIETIC STEM CELL FITNESS HAS BEEN WELL CHARACTERIZED. EPISTATIC INTERACTIONS BETWEEN MUTATIONS AND EPIGENETIC EVENTS HAVE BEEN EXPLORED, BOTH IN CMML AND ITS PEDIATRIC COUNTERPART JUVENILE MYELOMONOCYTIC LEUKEMIA, INCLUDING CMML TRANSFORMATION TO ACUTE MYELOID LEUKEMIA. TOGETHER, THESE FINDINGS HAVE CONTRIBUTED SIGNIFICANTLY TOWARD CMML EVOLUTIONARY DYNAMICS. SUMMARY: DESPITE RELATIVELY FEW 'DRIVER' MUTATIONS IN CMML, EVOLUTIONARY DEVELOPMENT OF CHRONIC LEUKEMIA REMAINS INCOMPLETELY UNDERSTOOD. RECENT STUDIES HAVE SHED LIGHT ON THE IMPORTANCE OF STUDYING EPIGENETIC CONSEQUENCES OF MUTATIONS AND EPISTASIS BETWEEN KEY MUTATIONS TO BETTER UNDERSTAND CLONAL ARCHITECTURE AND EVOLUTIONARY DYNAMICS. 2020 20 3871 22 JUVENILE MYELOMONOCYTIC LEUKEMIA - A BONA FIDE RASOPATHY SYNDROME. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROME WITH SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS, AGGRESSIVE FEATURES, AND POOR OUTCOMES. IN >90% OF CASES JMML IS DRIVEN BY GERMLINE OR SOMATIC MUTATIONS INVOLVING THE CANONICAL RAS PATHWAY (PTPN11, NRAS, CBL, KRAS AND NF1), WITH SOMATIC MUTATIONS/ALTERATIONS IN RAS PATHWAY GENES (SECOND HIT), SETBP1, ASXL1 AND JAK3 RESULTING IN DISEASE PROGRESSION. WHILE SPONTANEOUS REGRESSION HAS BEEN SEEN IN GERMLINE PTPN11 AND CBL MUTANT JMML, IN MOST PATIENTS, ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY CURATIVE MODALITY. JMML SHARES SEVERAL PHENOTYPIC FEATURES WITH ITS ADULT COUNTERPART PROLIFERATIVE, CHRONIC MYELOMONOCYTIC LEUKEMIA (PCMML). PCMML LARGELY OCCURS DUE TO RAS PATHWAY MUTATIONS THAT OCCUR IN THE CONTEXT OF AGE RELATED CLONAL HEMATOPOIESIS (TET2, SRSF2, ASXL1), WHILE JMML IS A BONA FIDE RASOPATHY, WITH ADDITIONAL SOMATIC MUTATIONS, INCLUDING IN EPIGENETIC REGULATORS GENES RESULTING IN DISEASE PROGRESSION. 2020