1 5911 111 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 2 4557 29 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 3 4555 34 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 4 2277 35 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 1070 29 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 6 4571 25 MYELOMONOCYTIC SKEWING IN CHRONIC MYELOMONOCYTIC LEUKEMIA: PHENOTYPIC, MOLECULAR AND BIOLOGIC FEATURES AND IMPACT ON SURVIVAL. BACKGROUND: MYELOMONOCYTIC SKEWING IS CONSIDERED AS A KEY PATHOPHYSIOLOGIC PHENOMENON IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), BUT ITS PREVALENCE AND POTENTIAL CORRELATION WITH PHENOTYPIC, GENOTYPIC, AND CLINICAL FEATURES ARE POORLY DEFINED. METHODS: SKEWED DIFFERENTIATION TOWARD THE MYELOMONOCYTIC OVER ERYTHROID COMMITMENT AS INDICATED BY AN INVERSE RATIO OF MYELOMONOCYTIC/ERYTHROID COLONIES WAS INVESTIGATED IN 146 PATIENTS WITH CMML BY SEMISOLID IN VITRO CULTURES. RESULTS: THERE WAS A HIGH PREVALENCE OF MYELOMONOCYTIC SKEWING IN PATIENTS WITH CMML (120/146, 82%); WHEREAS, THIS PHENOMENON WAS RARE IN NORMAL INDIVIDUALS (1/98, 1%). PATIENTS WITH CMML WITH MYELOMONOCYTIC SKEWING HAD HIGHER WHITE BLOOD CELL AND PERIPHERAL BLAST CELL COUNTS, AND LOWER PLATELET VALUES. THE NUMBER OF MUTATIONS IN GENES OF THE EPIGENETIC AND/OR SPLICING CATEGORY WAS HIGHER IN CMML PATIENTS WITH AS COMPARED WITH PATIENTS WITHOUT SKEWING. PATIENTS WITH MYELOMONOCYTIC SKEWING HAD MORE FREQUENTLY MUTATIONS IN RASOPATHY GENES AND HIGHER GROWTH FACTOR INDEPENDENT MYELOID COLONY FORMATION. INTERESTINGLY, THE LACK OF MYELOMONOCYTIC SKEWING DISCRIMINATED PATIENTS WITH CMML WITH A PARTICULARLY FAVORABLE PROGNOSIS (60 VS 19 MONTHS, P = .003) AND A MINIMAL RISK OF TRANSFORMATION. CONCLUSION: MYELOMONOCYTIC SKEWING AS DETERMINED BY SEMISOLID CULTURES CAN DISCRIMINATE SUBGROUPS OF PATIENTS WITH CMML WITH A DIFFERENT PHENOTYPE, A DIFFERENT GENOTYPE, AND A DIFFERENT PROGNOSIS. 2021 7 4485 30 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 8 1266 28 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 9 536 33 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 10 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 11 959 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 12 4549 28 MUTATION ANALYSIS OF THERAPY-RELATED MYELOID NEOPLASMS. WE ANALYZED THE GENETIC MUTATION STATUS OF 13 PATIENTS WITH THERAPY-RELATED MYELOID NEOPLASMS (T-MN). CONSISTENT WITH PREVIOUS REPORTS, T-MN CELLS PREFERENTIALLY ACQUIRED MUTATIONS IN TP53 AND EPIGENETIC MODIFYING GENES, INSTEAD OF MUTATIONS IN TYROSINE KINASE AND SPLICEOSOME GENES. FURTHERMORE, WE COMPARED THE MUTATION STATUS OF THREE T-MN CELLS WITH EACH OF THE INITIAL LYMPHOID MALIGNANT CELLS, AND IDENTIFIED COMMON MUTATIONS AMONG T-MN AND THE INITIAL MALIGNANT CELLS IN TWO PATIENTS. IN A PATIENT WHO DEVELOPED CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AFTER FOLLICULAR LYMPHOMA (FL), TET2 MUTATION WAS IDENTIFIED IN BOTH CMML AND FL CELLS. NOTABLY, THE TET2 MUTATION WAS ALSO IDENTIFIED IN PERIPHERAL BLOOD CELLS IN THE DISEASE-FREE PERIOD WITH THE SAME ALLELIC FREQUENCY AS CMML AND FL CELLS, BUT NOT IN A GERM-LINE CONTROL, INDICATING THAT THE TET2 MUTATION OCCURRED SOMATICALLY IN THE INITIATING CLONE FOR BOTH MALIGNANT CELLS. ON THE OTHER HAND, A GERM-LINE MYB MUTATION WAS IDENTIFIED IN A PATIENT WHO DEVELOPED MYELODYSPLASTIC SYNDROMES (MDS) AFTER FL. THESE RESULTS SUGGEST THAT GERM-LINE DEPOSITION AND CLONAL HEMATOPOIESIS ARE CLOSELY ASSOCIATED WITH T-MN SUSCEPTIBILITY; HOWEVER, FURTHER ANALYSIS IS NECESSARY TO CLARIFY THE MECHANISM REQUIRED TO PROVIDE THE INITIATING CLONE WITH LINEAGE COMMITMENT AND CLONAL EXPANSION. 2018 13 3560 30 IMPACT OF CLINICAL, CYTOGENETIC, AND MOLECULAR PROFILES ON LONG-TERM SURVIVAL AFTER TRANSPLANTATION IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A HETEROGENEOUS GROUP OF CLONAL HEMATOPOIETIC MALIGNANCIES WITH VARIABLE CLINICAL AND MOLECULAR FEATURES. WE ANALYZED LONG-TERM RESULTS OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH CMML AND DETERMINED CLINICAL AND MOLECULAR RISK FACTORS ASSOCIATED WITH OUTCOMES. DATA FROM 129 PATIENTS, AGED 7-74 (MEDIAN 55) YEARS, AT VARIOUS STAGES OF THE DISEASE AND TRANSPLANTED FROM RELATED OR UNRELATED DONORS WERE ANALYZED. USING A PANEL OF 75 GENES SOMATIC MUTATIONS PRESENT BEFORE HEMATOPOIETIC CELL TRANSPLANTATION WERE IDENTIFIED IN 52 PATIENTS. THE PROGRESSION-FREE SURVIVAL RATE AT 10 YEARS WAS 29%. THE MAJOR CAUSE OF DEATH WAS RELAPSE (32%), WHICH WAS SIGNIFICANTLY ASSOCIATED WITH ADVERSE CYTOGENETICS (HAZARD RATIO, 3.77; P=0.0002), CMML PROGNOSTIC SCORING SYSTEM (HAZARD RATIO, 14.3, P=0.01), AND MD ANDERSON PROGNOSTIC SCORES (HAZARD RATIO, 9.4; P=0.005). MORTALITY WAS ASSOCIATED WITH HIGH-RISK CYTOGENETICS (HAZARD RATIO, 1.88; P=0.01) AND HIGH HEMATOPOIETIC CELL TRANSPLANTATION COMORBIDITY INDEX (SCORE >/=4: HAZARD RATIO, 1.99; P=0.01). HIGH OVERALL MUTATION BURDEN (>/=10 MUTATIONS: HAZARD RATIO, 3.4; P=0.02), AND >/=4 MUTATED EPIGENETIC REGULATORY GENES (HAZARD RATIO 5.4; P=0.003) WERE LINKED TO RELAPSE. UNSUPERVISED CLUSTERING OF THE CORRELATION MATRIX REVEALED DISTINCT HIGH-RISK GROUPS WITH UNIQUE ASSOCIATIONS OF MUTATIONS AND CLINICAL FEATURES. CMML WITH A HIGH MUTATION BURDEN APPEARED TO BE DISTINCT FROM HIGH-RISK GROUPS DEFINED BY COMPLEX CYTOGENETICS. NEW TRANSPLANT STRATEGIES MUST BE DEVELOPED TO TARGET SPECIFIC DISEASE SUBGROUPS, STRATIFIED BY MOLECULAR PROFILING AND CLINICAL RISK FACTORS. 2020 14 1039 29 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 15 962 36 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 16 1043 30 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 17 957 26 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 18 5984 34 TET2, DNMT3A, IDH1, AND JAK2 MUTATION IN MYELOPROLIFERATIVE NEOPLASMS IN SOUTHERN IRAN. BACKGROUND: FIVE EPIGENETIC REGULATOR MUTATIONS ARE CONSIDERED IN MYELOPROLIFERATIVE NEOPLASMS (MPN) THAT HAVE PROGNOSTIC AND THERAPEUTIC VALUES. OBJECTIVE: WE AIMED TO EVALUATE THESE MUTATIONS IN MPNS AMONG THE IRANIAN POPULATION. METHODS: WE SELECTED 5 MUTATIONS IN 4 EPIGENETIC REGULATORY GENES [TET2, DNMT3A, IDH1 (RS147001633&RS121913499), AND JAK2)] AND EVALUATED 130 PATIENTS WITH MPNS INCLUDING 78 PHILADELPHIA CHROMOSOME NEGATIVE (49 ETS, 20 PVS, AND 9 PMFS) AND 52 PHILADELPHIA CHROMOSOME-POSITIVE PATIENTS AS WELL AS 51 HEALTHY CONTROLS. RESULTS: EIGHT PATIENTS (6.5%) CARRIED THE DNMT3A MUTATION, 35 (27%) WERE POSITIVE FOR TET2 MUTATION AND 64 (49.3%) HAD THE JAK2V617F MUTATION. IN THE HEALTHY CONTROLS, 16 (31.4%) CASES HAD THE TET2 MUTATION (15 HETEROZYGOTE + 1 HOMOZYGOTE) AND ONE HAD HETEROZYGOTE JAK2 MUTATION. THERE WAS NO STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN PATIENT GROUPS FOR ANY OF THESE MUTATIONS, EXCEPT FOR JAK2. THE JAK2 MUTATION RATE WAS 18 (90%), 25 (51%), 7 (77.8%), 14 (26.9%) IN POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA, PRIMARY MYELOFIBROSIS, AND CHRONIC MYELOCYTIC LEUKEMIA, RESPECTIVELY. PATIENTS AGED 60 AND OLDER WERE MORE LIKELY TO CARRY THE TET2 MUTATION (23% VS. 39% IN YOUNGER AND OLDER THAN 60 YEARS OLD INDIVIDUALS, P=0.025). IDH1 WAS NOT DETECTED AT ALL AND PV HAD THE HIGHEST TET2 MUTATION 7(35%). TWO PMF PATIENTS HAD A HISTORY OF BONE MARROW TRANSPLANTATION THAT WERE NEGATIVE FOR IDH1AND DNMT3A AND ONE WAS POSITIVE FOR TET2 MUTATION. CONCLUSION: IN THE NORMAL IRANIAN POPULATION, THE HETEROZYGOTE FORM OF TET2 MUTATION IS SIGNIFICANT, ESPECIALLY IN THE ELDERLY. NO ASSOCIATION WAS FOUND BETWEEN JAK2 AND TET2 MUTATIONS. BOTH OF THEM ARE MORE PREVALENT IN THE AGE GROUP OF 60 YEARS AND OLDER. DNMT3A MUTATION HAS A LOW PREVALENCE AND OCCURS IN BOTH POSITIVE AND NEGATIVE MPNS. 2021 19 32 34 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 20 5665 27 SF3B1, RUNX1 AND TP53 MUTATIONS SIGNIFICANTLY IMPACT THE OUTCOME OF PATIENTS WITH LOWER-RISK MYELODYSPLASTIC SYNDROME. INTRODUCTION: PROGNOSIS OF PATIENTS WITH MYELODYSPLASTIC SYNDROME (MDS), PARTICULARLY THE GROUP WITH LOWER-RISK DISEASE (LR-MDS) IS VERY HETEROGENEOUS. SEVERAL STUDIES HAVE DESCRIBED THE PROGNOSTIC VALUE OF RECURRENT SOMATIC MUTATIONS IN MDS INCLUDING ALL RISK CATEGORIES. RECENTLY, THE INCORPORATION OF GENOMIC DATA TO CLINICAL PARAMETERS DEFINED THE NEW MOLECULAR INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS-M). MATERIALS AND METHODS: IN THIS STUDY, WE EVALUATED THE IMPACT OF MOLECULAR PROFILE IN A SERIES OF 181 PATIENTS WITH LR-MDS AND NON-PROLIFERATIVE CHRONIC MYELOMONOCYTIC LEUKEMIA. RESULTS: EPIGENETIC REGULATORS (TET2, ASXL1) AND SPLICING (SF3B1) WERE THE MOST RECURRENT MUTATED PATHWAYS. IN UNIVARIATE ANALYSIS, RUNX1 OR TP53 MUTATIONS CORRELATED WITH LOWER MEDIAN OVERALL SURVIVAL (OS). IN CONTRAST, SF3B1 MUTATION WAS ASSOCIATED WITH PROLONGED MEDIAN OS [95 MONTHS (95% IC, 32-157) VS. 33 MONTHS (95% CI, 19-46) IN UNMUTATED PATIENTS (P < 0.01)]. IN A MULTIVARIATE COX REGRESSION MODEL, RUNX1 MUTATIONS INDEPENDENTLY ASSOCIATED WITH SHORTER OS, WHILE SF3B1 MUTATION RETAINED ITS FAVORABLE IMPACT ON OUTCOME (HR: 0.24, 95% CI, 0.1-0.5; P = 0.001). IN ADDITION, TP53 OR RUNX1 MUTATIONS WERE IDENTIFIED AS PREDICTIVE COVARIATES FOR THE PROBABILITY OF LEUKEMIC PROGRESSION (P < 0.001). CONCLUSION: INCORPORATION OF MOLECULAR TESTING IN LR-MDS IDENTIFIED A SUBSET OF PATIENTS WITH EXPECTED POORER OUTCOME, EITHER DUE TO LOWER SURVIVAL OR PROBABILITY OF LEUKEMIC PROGRESSION. 2022