1 4553 154 MUTATIONAL LANDSCAPE OF CHRONIC MYELOMONOCYTIC LEUKEMIA IN CHINESE PATIENTS. BACKGROUND: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A RARE AND HETEROGENEOUS HEMATOLOGICAL MALIGNANCY. IT HAS BEEN SHOWN THAT THE MOLECULAR ABNORMALITIES SUCH AS ASXL1, TET2, SETBP1, AND SRSF2 MUTATIONS ARE COMMON IN CAUCASIAN POPULATION. METHODS: WE RETROSPECTIVELY ANALYZED 178 CHINESE CMML PATIENTS. THE TARGETED NEXT GENERATION SEQUENCING (NGS) WAS USED TO EVALUATE 114 GENE VARIATIONS, AND THE PROGNOSTIC FACTORS FOR OS WERE DETERMINED BY COX REGRESSION ANALYSIS. RESULTS: THE CMML PATIENTS SHOWED A UNIQUE MUTATIONAL SPECTRUM, INCLUDING TET2 (36.5%), NRAS (31.5%), ASXL1 (28.7%), SRSF2 (24.7%), AND RUNX1 (21.9%). OF THE 102 PATIENTS WITH CLONAL ANALYSIS, THE ANCESTRAL EVENTS PREFERENTIALLY OCCURRED IN TET2 (18.5%), SPLICING FACTORS (16.5%), RAS (14.0%), AND ASXL1 (7.8%), AND THE SUBCLONAL GENES WERE MAINLY ASXL1, TET2, AND RAS. IN ADDITION, THE SECONDARY ACUTE MYELOID LEUKEMIA (SAML) TRANSFORMED FROM CMML OFTEN HAD MUTATIONS IN DNMT3A, ETV6, FLT3, AND NPM1, WHILE THE PRIMARY AML (PAML) DEMONSTRATED MORE MUTATIONS IN CEBPA, DNMT3A, FLT3, IDH1/2, NPM1, AND WT1. IT WAS OF NOTE THAT A SERIES OF CLONES WERE EMERGED DURING THE PROGRESSION FROM CMML TO AML, INCLUDING DNMT3A, FLT3, AND NPM1. BY UNIVARIATE ANALYSIS, ASXL1 MUTATION, INTERMEDIATE- AND HIGH-RISK CYTOGENETIC ABNORMALITY, CMML-SPECIFIC PROGNOSTIC SCORING SYSTEM (CPSS) STRATIFICATIONS (INTERMEDIATE-2 AND HIGH GROUP), AND TREATMENT OPTIONS (BEST SUPPORTIVE CARE) PREDICTED FOR WORSE OS. MULTIVARIATE ANALYSIS REVEALED A SIMILAR OUTCOME. CONCLUSIONS: THE COMMON MUTATIONS IN CHINESE CMML PATIENTS INCLUDED EPIGENETIC MODIFIERS (TET2 AND ASXL1), SIGNALING TRANSDUCTION PATHWAY COMPONENTS (NRAS), AND SPLICING FACTOR (SRSF2). THE CMML PATIENTS WITH DNMT3A, ETV6, FLT3, AND NPM1 MUTATIONS TENDED TO PROGRESS TO SAML. ASXL1 MUTATION AND THERAPEUTIC MODALITIES WERE INDEPENDENT PROGNOSTIC FACTORS FOR CMML. 2022 2 3871 33 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 3 5246 51 PROGNOSTIC SCORE INCLUDING GENE MUTATIONS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. PURPOSE: SEVERAL PROGNOSTIC SCORING SYSTEMS HAVE BEEN PROPOSED FOR CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), A DISEASE IN WHICH SOME GENE MUTATIONS-INCLUDING ASXL1-HAVE BEEN ASSOCIATED WITH POOR PROGNOSIS IN UNIVARIABLE ANALYSES. WE DEVELOPED AND VALIDATED A PROGNOSTIC SCORE FOR OVERALL SURVIVAL (OS) BASED ON MUTATIONAL STATUS AND STANDARD CLINICAL VARIABLES. PATIENTS AND METHODS: WE GENOTYPED ASXL1 AND UP TO 18 OTHER GENES INCLUDING EPIGENETIC (TET2, EZH2, IDH1, IDH2, DNMT3A), SPLICING (SF3B1, SRSF2, ZRSF2, U2AF1), TRANSCRIPTION (RUNX1, NPM1, TP53), AND SIGNALING (NRAS, KRAS, CBL, JAK2, FLT3) REGULATORS IN 312 PATIENTS WITH CMML. GENOTYPES AND CLINICAL VARIABLES WERE INCLUDED IN A MULTIVARIABLE COX MODEL OF OS VALIDATED BY BOOTSTRAPPING. A SCORING SYSTEM WAS DEVELOPED USING REGRESSION COEFFICIENTS FROM THIS MODEL. RESULTS: ASXL1 MUTATIONS (P < .0001) AND, TO A LESSER EXTENT, SRSF2 (P = .03), CBL (P = .003), AND IDH2 (P = .03) MUTATIONS PREDICTED INFERIOR OS IN UNIVARIABLE ANALYSIS. THE RETAINED INDEPENDENT PROGNOSTIC FACTORS INCLUDED ASXL1 MUTATIONS, AGE OLDER THAN 65 YEARS, WBC COUNT GREATER THAN 15 X10(9)/L, PLATELET COUNT LESS THAN 100 X10(9)/L, AND ANEMIA (HEMOGLOBIN < 10 G/DL IN FEMALE PATIENTS, < 11G/DL IN MALE PATIENTS). THE RESULTING FIVE-PARAMETER PROGNOSTIC SCORE DELINEATED THREE GROUPS OF PATIENTS WITH MEDIAN OS NOT REACHED, 38.5 MONTHS, AND 14.4 MONTHS, RESPECTIVELY (P < .0001), AND WAS VALIDATED IN AN INDEPENDENT COHORT OF 165 PATIENTS (P < .0001). CONCLUSION: A NEW PROGNOSTIC SCORE INCLUDING ASXL1 STATUS, AGE, HEMOGLOBIN, WBC, AND PLATELET COUNTS DEFINES THREE GROUPS OF CMML PATIENTS WITH DISTINCT OUTCOMES. BASED ON CONCORDANCE ANALYSIS, THIS SCORE APPEARS MORE DISCRIMINATIVE THAN THOSE BASED SOLELY ON CLINICAL PARAMETERS. 2013 4 5980 46 TET2 MUTATIONS WERE PREDICTIVE OF INFERIOR PROGNOSIS IN THE PRESENCE OF ASXL1 MUTATIONS IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. BACKGROUND: SOMATIC MUTATIONS INVOLVING EPIGENETIC REGULATORS, HISTONE MODIFICATION AND CHROMATIN REGULATION, SPLICING COMPONENTS, TRANSCRIPTION FACTORS AND SIGNALING REGULATOR GENES ARE COMMON IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) PATIENTS. IT HAS BEEN CONSENSUS THAT ASXL1 MUTATIONS HAVE ADVERSELY IMPACT ON OVERALL SURVIVAL (OS), WHILE THE EFFECT OF TET2 MUTATIONS REMAINS CONTROVERSIAL AND UNDEFINED. METHODS: ASXL1 AND TET2 MUTATIONS WERE ANALYZED IN 141 PATIENTS WITH CMML USING SANGER SEQUENCING, WITH THE AIM TO IDENTIFY THE INTERPLAY OF ASXL1 AND TET2 MUTATIONS IN THE PROGNOSIS OF CMML. RESULTS: SIXTY-FIVE (46.1%) OF THE CMML PATIENTS HARBORED ASXL1 MUTATIONS (FRAMESHIFT AND NONSENSE), AND 46 (32.6%) HAD TET2 MUTATIONS (FRAME SHIFT, NONSENSE AND MISSENSE). IN A SEPARATE MULTIVARIABLE ANALYSIS THAT INCLUDED THE MAYO PROGNOSTIC MODEL AS A SINGLE VARIABLE ALONG WITH ASXL1WT/TET2WT, THE RESPECTIVE HAZARD RATIOS OF ASXL1MUT/TET2MUT, ASXL1MUT/TET2WT AND ASXL1WT/TET2MUT WERE 4.7 (95% CI, 2.2-10.3; P<0.001), 2.2 (95% CI, 1.1-4.2; P=0.025) AND 1.3 (95% CI, 0.6-2.5; P=0.521). CONCLUSIONS: OUR STUDY SHOWED THAT ASXL1 MUTATIONS PREDICT INFERIOR OS, AND ADDITIONAL TET2 MUTATIONS WERE ASSOCIATED WITH POOR SURVIVAL IN THE PRESENCE OF ASXL1 MUTATIONS OF CMML PATIENTS. 2016 5 5244 37 PROGNOSTIC INTERACTION BETWEEN ASXL1 AND TET2 MUTATIONS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. MUTATIONS INVOLVING EPIGENETIC REGULATORS (TET2~60% AND ASXL1~40%) AND SPLICING COMPONENTS (SRSF2~50%) ARE FREQUENT IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). ON A 27-GENE TARGETED CAPTURE PANEL PERFORMED ON 175 CMML PATIENTS (66% MALES, MEDIAN AGE 70 YEARS), COMMON MUTATIONS INCLUDED: TET2 46%, ASXL1 47%, SRSF2 45% AND SETBP1 19%. A TOTAL OF 172 (98%) PATIENTS HAD AT LEAST ONE MUTATION, 21 (12%) HAD 2, 24 (14%) HAD 3 AND 30 (17%) HAD >3 MUTATIONS. IN A UNIVARIATE ANALYSIS, THE PRESENCE OF ASXL1 MUTATIONS (P=0.02) AND THE ABSENCE OF TET2 MUTATIONS (P=0.03), ADVERSELY IMPACTED SURVIVAL; WHILE THE NUMBER OF CONCURRENT MUTATIONS HAD NO IMPACT (P=0.3). IN A MULTIVARIABLE ANALYSIS THAT INCLUDED HEMOGLOBIN, PLATELET COUNT, ABSOLUTE MONOCYTE COUNT AND CIRCULATING IMMATURE MYELOID CELLS (MAYO MODEL), THE PRESENCE OF ASXL1 MUTATIONS (P=0.01) AND ABSENCE OF TET2 MUTATIONS (P=0.003) RETAINED PROGNOSTIC SIGNIFICANCE. PATIENTS WERE STRATIFIED INTO FOUR CATEGORIES: ASXL1WT/TET2WT (N=56), ASXL1MUT/TET2WT (N=31), ASXL1MUT/TET2MUT (N=50) AND ASXL1WT/TET2MUT (N=38). SURVIVAL DATA DEMONSTRATED A SIGNIFICANT DIFFERENCE IN FAVOR OF ASXL1WT/TET2MUT (38 MONTHS; P=0.016), COMPARED WITH THOSE WITH ASXL1WT/TET2WT (19 MONTHS), ASXL1MUT/TET2WT (21 MONTHS) AND ASXL1MUT/TET2MUT (16 MONTHS) (P=0.3). WE CONFIRM THE NEGATIVE PROGNOSTIC IMPACT IMPARTED BY ASXL1 MUTATIONS AND SUGGEST A FAVORABLE IMPACT FROM TET2 MUTATIONS IN THE ABSENCE OF ASXL1 MUTATIONS. 2016 6 4562 39 MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROMES: A FOCUSED REVIEW. MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) OVERLAP SYNDROMES ARE UNIQUE MYELOID NEOPLASMS, WITH OVERLAPPING FEATURES OF MDS AND MPN. THEY CONSIST OF FOUR ADULT ONSET ENTITIES INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), MDS/MPN-RING SIDEROBLASTS-THROMBOCYTOSIS (MDS/MPN-RS-T), BCR-ABL1 NEGATIVE ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) AND MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U); WITH JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) BEING THE ONLY PEDIATRIC ONSET ENTITY. AMONG THESE OVERLAP NEOPLASMS, CMML IS THE MOST FREQUENT AND IS HALLMARKED BY THE PRESENCE OF SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS WITH RECURRENT MUTATIONS INVOLVING TET2 (60%), SRSF2 (50%) AND ASXL1 (40%); WITH RAS PATHWAY MUTATIONS AND JAK2V617F BEING RELATIVELY ENRICHED IN PROLIFERATIVE CMML SUBTYPES (WBC >/=13 X 109/L). CMML USUALLY PRESENTS IN THE 7TH DECADE OF LIFE, WITH A MALE PREPONDERANCE AND IS ASSOCIATED WITH A MEDIAN OVERALL SURVIVAL OF <36 MONTHS. ADVERSE PROGNOSTICATORS IN CMML INCLUDE INCREASING AGE, HIGH WBC, PRESENCE OF CIRCULATING IMMATURE MYELOID CELLS, ANEMIA, THROMBOCYTOPENIA AND TRUNCATING ASXL1 MUTATIONS. WHILE ALLOGENEIC STEM CELL TRANSPLANTATION REMAINS THE ONLY CURATIVE OPTION, GIVEN THE LATE ONSET OF THIS NEOPLASM AND HIGH FREQUENCY OF COMORBIDITIES, MOST PATIENTS REMAIN INELIGIBLE. HYPOMETHYLATING AGENTS SUCH AS AZACITIDINE, DECITABINE AND ORAL DECITABINE/CEDAZURIDINE HAVE BEEN US FDA APPROVED FOR THE MANAGEMENT OF CMML, WITH OVERALL RESPONSE RATES OF 40-50% AND COMPLETE REMISSION RATES OF <20%. WHILE THESE AGENTS EPIGENETICALLY RESTORE HEMATOPOIESIS IN A SUBSET OF RESPONDING PATIENTS, THEY DO NOT IMPACT MUTATIONAL ALLELE BURDENS AND EVENTUAL DISEASE PROGRESSION TO AML REMAINS INEVITABLE. NEWER TREATMENT MODALITIES EXPLOITING EPIGENETIC, SIGNALING AND SPLICING ABNORMALITIES COMMONLY SEEN IN CMML ARE MUCH NEEDED. 2020 7 1311 47 DEFINITIONS, BIOLOGY, AND CURRENT THERAPEUTIC LANDSCAPE OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS. MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE HEMATOLOGICAL DISORDERS CHARACTERIZED BY BOTH PROLIFERATIVE AND DYSPLASTIC FEATURES. ACCORDING TO THE 2022 INTERNATIONAL CONSENSUS CLASSIFICATION (ICC), MDS/MPN CONSISTS OF CLONAL MONOCYTOSIS OF UNDETERMINED SIGNIFICANCE (CMUS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML), MDS/MPN WITH SF3B1 MUTATION (MDS/MPN-T-SF3B1), MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS NOT OTHERWISE SPECIFIED (MDS/MPN-RS-T-NOS), AND MDS/MPN-NOS. THESE DISORDERS EXHIBIT A DIVERSE RANGE OF GENETIC ALTERATIONS INVOLVING VARIOUS TRANSCRIPTION FACTORS (E.G., RUNX1), SIGNALING MOLECULES (E.G., NRAS, JAK2), SPLICING FACTORS (E.G., SF3B, SRSF2), AND EPIGENETIC REGULATORS (E.G., TET2, ASXL1, DNMT3A), AS WELL AS SPECIFIC CYTOGENETIC ABNORMALITIES (E.G., 8 TRISOMIES, 7 DELETIONS/MONOSOMIES). CLINICAL STUDIES EXPLORING THERAPEUTIC OPTIONS FOR HIGHER-RISK MDS/MPN OVERLAP SYNDROMES MOSTLY INVOLVE HYPOMETHYLATING AGENTS, BUT OTHER TREATMENTS SUCH AS LENALIDOMIDE AND TARGETED AGENTS SUCH AS JAK INHIBITORS AND INHIBITORS TARGETING PARP, HISTONE DEACETYLASES, AND THE RAS PATHWAY ARE UNDER INVESTIGATION. WHILE THESE TREATMENT MODALITIES CAN PROVIDE PARTIAL DISEASE CONTROL, ALLOGENEIC BONE MARROW TRANSPLANTATION (ALLO-BMT) IS THE ONLY POTENTIALLY CURATIVE OPTION FOR PATIENTS. IMPORTANT PROGNOSTIC FACTORS CORRELATING WITH OUTCOMES AFTER ALLO-BMT INCLUDE COMORBIDITIES, SPLENOMEGALY, KARYOTYPE ALTERATIONS, AND THE BONE MARROW BLASTS PERCENTAGE AT THE TIME OF TRANSPLANTATION. FUTURE RESEARCH IS IMPERATIVE TO OPTIMIZING THERAPEUTIC STRATEGIES AND ENHANCING PATIENT OUTCOMES IN MDS/MPN NEOPLASMS. IN THIS REVIEW, WE SUMMARIZE MDS/MPN DIAGNOSTIC CRITERIA, BIOLOGY, AND CURRENT AND FUTURE TREATMENT OPTIONS, INCLUDING BONE MARROW TRANSPLANTATION. 2023 8 5911 37 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 9 569 37 BCOR AND BCORL1 MUTATIONS IN MYELODYSPLASTIC SYNDROMES AND RELATED DISORDERS. PATIENTS WITH LOW-RISK MYELODYSPLASTIC SYNDROMES (MDS) THAT RAPIDLY PROGRESS TO ACUTE MYELOID LEUKEMIA (AML) REMAIN A CHALLENGE IN DISEASE MANAGEMENT. USING WHOLE-EXOME SEQUENCING OF AN MDS PATIENT, WE IDENTIFIED A SOMATIC MUTATION IN THE BCOR GENE ALSO MUTATED IN AML. SEQUENCING OF BCOR AND RELATED BCORL1 GENES IN A COHORT OF 354 MDS PATIENTS IDENTIFIED 4.2% AND 0.8% OF MUTATIONS RESPECTIVELY. BCOR MUTATIONS WERE ASSOCIATED WITH RUNX1 (P = .002) AND DNMT3A MUTATIONS (P = .015). BCOR IS ALSO MUTATED IN CHRONIC MYELOMONOCYTIC LEUKEMIA PATIENTS (7.4%) AND BCORL1 IN AML PATIENTS WITH MYELODYSPLASIA-RELATED CHANGES (9.1%). USING DEEP SEQUENCING, WE SHOW THAT BCOR MUTATIONS ARISE AFTER MUTATIONS AFFECTING GENES INVOLVED IN SPLICING MACHINERY OR EPIGENETIC REGULATION. IN UNIVARIATE ANALYSIS, BCOR MUTATIONS WERE ASSOCIATED WITH POOR PROGNOSIS IN MDS (OVERALL SURVIVAL [OS]: P = .013; CUMULATIVE INCIDENCE OF AML TRANSFORMATION: P = .005). MULTIVARIATE ANALYSIS INCLUDING AGE, INTERNATIONAL PROGNOSTIC SCORING SYSTEM, TRANSFUSION DEPENDENCY, AND MUTATIONAL STATUS CONFIRMED A SIGNIFICANT INFERIOR OS TO PATIENTS WITH A BCOR MUTATION (HAZARD RATIO, 3.3; 95% CONFIDENCE INTERVAL, 1.4-8.1; P = .008). THESE DATA SUGGEST THAT BCOR MUTATIONS DEFINE THE CLINICAL COURSE RATHER THAN DISEASE INITIATION. DESPITE INFREQUENT MUTATIONS, BCOR ANALYSES SHOULD BE CONSIDERED IN RISK STRATIFICATION. 2013 10 1184 29 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 11 4555 42 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 12 472 41 ARRAY COMPARATIVE GENOMIC HYBRIDIZATION AND SEQUENCING OF 23 GENES IN 80 PATIENTS WITH MYELOFIBROSIS AT CHRONIC OR ACUTE PHASE. MYELOFIBROSIS IS A MYELOPROLIFERATIVE NEOPLASM THAT OCCURS DE NOVO (PRIMARY MYELOFIBROSIS) OR RESULTS FROM THE PROGRESSION OF POLYCYTHEMIA VERA OR ESSENTIAL THROMBOCYTEMIA (HEREAFTER DESIGNATED AS SECONDARY MYELOFIBROSIS OR POST-POLYCYTHEMIA VERA/ ESSENTIAL THROMBOCYTHEMIA MYELOFIBROSIS). TO PROGRESS IN THE UNDERSTANDING OF MYELOFIBROSIS AND TO FIND MOLECULAR PROGNOSTIC MARKERS WE STUDIED 104 SAMPLES OF PRIMARY AND SECONDARY MYELOFIBROSIS AT CHRONIC (N=68) AND ACUTE PHASES (N=12) FROM 80 PATIENTS, BY USING ARRAY-COMPARATIVE GENOMIC HYBRIDIZATION AND SEQUENCING OF 23 GENES (ASXL1, BMI1, CBL, DNMT3A, EZH2, IDH1/2, JAK2, K/NRAS, LNK, MPL, NF1, PPP1R16B, PTPN11, RCOR1, SF3B1, SOCS2, SRSF2, SUZ12, TET2, TP53, TRPS1). WE FOUND COPY NUMBER ABERRATIONS IN 54% OF SAMPLES, OFTEN INVOLVING GENES WITH A KNOWN OR POTENTIAL ROLE IN LEUKEMOGENESIS. WE SHOW THAT CASES CARRYING A DEL(20Q), DEL(17) OR DEL(12P) EVOLVE IN ACUTE MYELOID LEUKEMIA (P=0.03). WE FOUND THAT 88% OF THE CASES WERE MUTATED, MAINLY IN SIGNALING PATHWAY (JAK2 69%, NF1 6%) AND EPIGENETIC GENES (ASXL1 26%, TET2 14%, EZH2 8%). OVERALL SURVIVAL WAS POOR IN PATIENTS WITH MORE THAN ONE MUTATION (P=0.001) AND IN PATIENTS WITH JAK2/ASXL1 MUTATIONS (P=0.02). OUR STUDY HIGHLIGHTS THE HETEROGENEITY OF MYELOFIBROSIS, AND POINTS TO SEVERAL INTERESTING COPY NUMBER ABERRATIONS AND GENES WITH DIAGNOSTIC AND PROGNOSTIC IMPACT. 2014 13 1100 34 COMBINATION OF MYELOPROLIFERATIVE NEOPLASM DRIVER GENE ACTIVATION WITH MUTATIONS OF SPLICE FACTOR OR EPIGENETIC MODIFIER GENES INCREASES RISK OF RAPID BLASTIC PROGRESSION. OBJECTIVES: MYELOPROLIFERATIVE NEOPLASMS (MPN) COMPRISING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF) FOLLOW A BI-PHASIC COURSE OF DISEASE WITH FIBROTIC AND/OR BLASTIC PROGRESSION. AT PRESENTATION IN THE CHRONIC PHASE, CURRENTLY THERE ARE ONLY INSUFFICIENT TOOLS TO PREDICT THE RISK OF PROGRESSION IN INDIVIDUAL CASES. METHODS: IN THIS STUDY, CHRONIC PHASE MPN (16 PMF, 11 PV, AND 11 MPN UNCLASSIFIED) WITH BLASTIC TRANSFORMATION DURING COURSE OF DISEASE (N = 38, MEDIAN FOLLOW-UP 5.3 YEARS) WERE ANALYZED BY HIGH-THROUGHPUT SEQUENCING. MPN CASES WITH A COMPARABLE FOLLOW-UP PERIOD AND WITHOUT EVIDENCE OF BLAST INCREASE SERVED AS CONTROL (N = 63, MEDIAN FOLLOW-UP 5.8 YEARS). RESULTS: FREQUENT ARCH/CHIP-ASSOCIATED MUTATIONS (TET2, ASXL1, DNMT3A) FOUND AT PRESENTATION WERE NOT SIGNIFICANTLY ASSOCIATED WITH BLASTIC TRANSFORMATION. BY CONTRAST, MUTATIONS OF SRSF2, U2AF1, AND IDH1/2 AT FIRST PRESENTATION WERE FREQUENTLY OBSERVED IN THE PROGRESSION COHORT (13/38, 34.2%) AND WERE COMPLETELY MISSING IN THE CONTROL GROUP WITHOUT BLAST TRANSFORMATION DURING FOLLOW-UP (P = .0007 FOR SRSF2; P = .0063 FOR U2AF1 AND IDH1/2). CONCLUSION: UNLIKE FREQUENT ARCH/CHIP ALTERATIONS (TET2, ASXL1, DNMT3A), MUTATIONS IN SRSF2, IDH1/2, AND U2AF1 WHEN MANIFEST ALREADY AT FIRST PRESENTATION PROVIDE AN INDEPENDENT RISK FACTOR FOR RAPID BLAST TRANSFORMATION OF MPN. 2021 14 4748 37 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 15 1266 43 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 16 960 39 CHRONIC MYELOMONOCYTIC LEUKEMIA: 2016 UPDATE ON DIAGNOSIS, RISK STRATIFICATION, AND MANAGEMENT. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. DIAGNOSIS IS BASED ON THE PRESENCE OF PERSISTENT (>3 MONTHS) PERIPHERAL BLOOD MONOCYTOSIS (>1 X 10(9) /L), ALONG WITH BONE MARROW DYSPLASIA. CLONAL CYTOGENETIC ABNORMALITIES OCCUR IN APPROXIMATELY 20-30% OF PATIENTS, WHILE >90% HAVE GENE MUTATIONS. MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT; WITH ONLY ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. TWO MOLECULARLY INTEGRATED, CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE; THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) AND THE MOLECULAR MAYO MODEL (MMM). THE GFM MODEL SEGREGATES PATIENTS INTO 3 GROUPS BASED ON: AGE >65 YEARS, WBC >15 X 10(9) /L, ANEMIA, PLATELETS <100 X 10(9) /L, AND ASXL1 MUTATION STATUS, WITH RESPECTIVE MEDIAN SURVIVALS OF 56 (LOW), 27.4 (INTERMEDIATE), AND 9.2 (HIGH) MONTHS. THE MMM IS BASED ON ASXL1 MUTATIONAL STATUS, ABSOLUTE MONOCYTE COUNT >10 X 10(9) /L, HEMOGLOBIN <10 G/DL, PLATELETS <100 X 109/L AND CIRCULATING IMMATURE MYELOID CELLS. THIS MODEL STRATIFIES PATIENTS INTO FOUR GROUPS; HIGH (>/=3 RISK FACTORS), INTERMEDIATE-2 (2 RISK FACTORS), INTERMEDIATE-1 (1 RISK FACTOR) AND LOW (NO RISK FACTORS), WITH MEDIAN SURVIVALS OF 16, 31, 59, AND 97 MONTHS, RESPECTIVELY. HYPOMETHYLATING AGENTS SUCH AS 5-AZACITIDINE AND DECITABINE ARE COMMONLY USED, WITH OVERALL RESPONSE RATES OF APPROXIMATELY 30-40% AND COMPLETE REMISSION RATES OF APPROXIMATELY 7-17%. ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY POTENTIALLY CURATIVE OPTION, BUT IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY. INDIVIDUALIZED THERAPY, INCLUDING EPIGENETIC MODIFIERS AND SMALL MOLECULE INHIBITORS, ARE EXCITING PROSPECTS. AM. J. HEMATOL. 91:632-642, 2016. (C) 2016 WILEY PERIODICALS, INC. 2016 17 3872 35 JUVENILE MYELOMONOCYTIC LEUKEMIA-A COMPREHENSIVE REVIEW AND RECENT ADVANCES IN MANAGEMENT. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A RARE PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP DISEASE. JMML IS ASSOCIATED WITH MUTATIONS IN THE RAS PATHWAY GENES RESULTING IN THE MYELOID PROGENITORS BEING SENSITIVE TO GRANULOCYTE MONOCYTE COLONY-STIMULATING FACTOR (GM-CSF). KARYOTYPE ABNORMALITIES AND ADDITIONAL EPIGENETIC ALTERATIONS CAN ALSO BE FOUND IN JMML. NEUROFIBROMATOSIS AND NOONAN'S SYNDROME HAVE A PREDISPOSITION FOR JMML. IN A FEW PATIENTS, THE RAS GENES (NRAS, KRAS, AND PTPN11) ARE MUTATED AT THE GERMLINE AND THIS USUALLY RESULTS IN A TRANSIENT MYELOPROLIFERATIVE DISORDER WITH A GOOD PROGNOSIS. JMML WITH SOMATIC RAS MUTATION BEHAVES AGGRESSIVELY. JMML PRESENTS WITH CYTOPENIAS AND LEUKEMIC INFILTRATION INTO ORGANS. THE LABORATORY FINDINGS INCLUDE HYPERLEUKOCYTOSIS, MONOCYTOSIS, INCREASED HEMOGLOBIN-F LEVELS, AND CIRCULATING MYELOID PRECURSORS. THE BLAST CELLS IN THE PERIPHERAL BLOOD/BONE-MARROW ASPIRATE ARE LESS THAN 20% AND THE ABSENCE OF THE BCR-ABL TRANSLOCATION HELPS TO DIFFERENTIATE FROM CHRONIC MYELOID LEUKEMIA. JMML SHOULD BE DIFFERENTIATED FROM IMMUNODEFICIENCIES, VIRAL INFECTIONS, INTRAUTERINE INFECTIONS, HEMOPHAGOLYMPHOHISTIOCYTOSIS, OTHER MYELOPROLIFERATIVE DISORDERS, AND LEUKEMIAS. CHEMOTHERAPY IS EMPLOYED AS A BRIDGE TO HSCT, EXCEPT IN FEW WITH LESS AGGRESSIVE DISEASE, IN WHICH CHEMOTHERAPY ALONE CAN RESULT IN LONG TERM REMISSION. AZACITIDINE HAS SHOWN PROMISE AS A SINGLE AGENT TO STABILIZE THE DISEASE. THE PROGNOSIS OF JMML IS POOR WITH ABOUT 50% OF PATIENTS SURVIVING AFTER AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). ALLOGENEIC HSCT IS THE ONLY KNOWN CURE FOR JMML TO DATE. MYELOABLATIVE CONDITIONING IS MOST COMMONLY USED WITH GRAFT VERSUS HOST DISEASE (GVHD) PROPHYLAXIS TAILORED TO THE AGGRESSIVENESS OF THE DISEASE. RELAPSES ARE COMMON EVEN AFTER HSCT AND A SECOND HSCT CAN SALVAGE A THIRD OF THESE PATIENTS. NOVEL OPTIONS IN THE TREATMENT OF JMML E.G., HYPOMETHYLATING AGENTS, MEK INHIBITORS, JAK INHIBITORS, TYROSINE KINASE INHIBITORS, ETC. ARE BEING EXPLORED. 2021 18 961 35 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 19 1083 31 CNL AND ACML SHOULD BE CONSIDERED AS A SINGLE ENTITY BASED ON MOLECULAR PROFILES AND OUTCOMES. CHRONIC NEUTROPHILIC LEUKEMIA (CNL) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) ARE RARE MYELOID DISORDERS THAT ARE CHALLENGING WITH REGARD TO DIAGNOSIS AND CLINICAL MANAGEMENT. TO STUDY THE SIMILARITIES AND DIFFERENCES BETWEEN THESE DISORDERS, WE UNDERTOOK A MULTICENTER INTERNATIONAL STUDY OF ONE OF THE LARGEST CASE SERIES (CNL, N = 24; ACML, N = 37 CASES, RESPECTIVELY), FOCUSING ON THE CLINICAL AND MUTATIONAL PROFILES (N = 53 WITH MOLECULAR DATA) OF THESE DISEASES. WE FOUND NO DIFFERENCES IN CLINICAL PRESENTATIONS OR OUTCOMES OF BOTH ENTITIES. AS PREVIOUSLY DESCRIBED, BOTH CNL AND ACML SHARE A COMPLEX MUTATIONAL PROFILE WITH MUTATIONS IN GENES INVOLVED IN EPIGENETIC REGULATION, SPLICING, AND SIGNALING PATHWAYS. APART FROM CSF3R, ONLY EZH2 AND TET2 WERE DIFFERENTIALLY MUTATED BETWEEN THEM. THE MOLECULAR PROFILES SUPPORT THE NOTION OF CNL AND ACML BEING A CONTINUUM OF THE SAME DISEASE THAT MAY FIT BEST WITHIN THE MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS. WE IDENTIFIED 4 HIGH-RISK MUTATED GENES, SPECIFICALLY CEBPA (BETA = 2.26, HAZARD RATIO [HR] = 9.54, P = .003), EZH2 (BETA = 1.12, HR = 3.062, P = .009), NRAS (BETA = 1.29, HR = 3.63, P = .048), AND U2AF1 (BETA = 1.75, HR = 5.74, P = .013) USING MULTIVARIATE ANALYSIS. OUR FINDINGS UNDERSCORE THE RELEVANCE OF MOLECULAR-RISK CLASSIFICATION IN CNL/ACML AS WELL AS THE IMPORTANCE OF CSF3R MUTATIONS IN THESE DISEASES. 2023 20 4557 27 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