1 4565 106 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 2 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 3 4557 26 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 4 959 39 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 5 957 31 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 6 2956 29 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 7 4680 38 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 8 2237 35 EPIGENETIC MODIFIERS IN MYELOID MALIGNANCIES: THE ROLE OF HISTONE DEACETYLASE INHIBITORS. MYELOID HEMATOLOGICAL MALIGNANCIES ARE CLONAL BONE MARROW NEOPLASMS, COMPRISING OF ACUTE MYELOID LEUKEMIA (AML), THE MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), THE MYELOPROLIFERATIVE NEOPLASMS (MPN) AND SYSTEMIC MASTOCYTOSIS (SM). THE FIELD OF EPIGENETIC REGULATION OF NORMAL AND MALIGNANT HEMATOPOIESIS IS RAPIDLY GROWING. IN RECENT YEARS, HETEROZYGOUS SOMATIC MUTATIONS IN GENES ENCODING EPIGENETIC REGULATORS HAVE BEEN FOUND IN ALL SUBTYPES OF MYELOID MALIGNANCIES, SUPPORTING THE RATIONALE FOR TREATMENT WITH EPIGENETIC MODIFIERS. HISTONE DEACETYLASE INHIBITORS (HDACI) ARE EPIGENETIC MODIFIERS THAT, IN VITRO, HAVE BEEN SHOWN TO INDUCE GROWTH ARREST, APOPTOTIC OR AUTOPHAGIC CELL DEATH, AND TERMINAL DIFFERENTIATION OF MYELOID TUMOR CELLS. THESE EFFECTS WERE OBSERVED BOTH AT THE BULK TUMOR LEVEL AND IN THE MOST IMMATURE CD34(+)38(-) CELL COMPARTMENTS CONTAINING THE LEUKEMIC STEM CELLS. THUS, THERE IS A STRONG RATIONALE SUPPORTING HDACI THERAPY IN MYELOID MALIGNANCIES. HOWEVER, DESPITE INITIAL PROMISING RESULTS IN PHASE I TRIALS, HDACI IN MONOTHERAPY AS WELL AS IN COMBINATION WITH OTHER DRUGS, HAVE FAILED TO IMPROVE RESPONSES OR SURVIVAL. THIS REVIEW PROVIDES AN OVERVIEW OF THE RATIONALE FOR HDACI IN MYELOID MALIGNANCIES, CLINICAL RESULTS AND SPECULATIONS ON WHY CLINICAL TRIALS HAVE THUS FAR NOT MET THE EXPECTATIONS, AND HOW THIS MAY BE IMPROVED IN THE FUTURE. 2018 9 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 10 1674 29 DRIVER MUTATIONS IN LEUKEMIA PROMOTE DISEASE PATHOGENESIS THROUGH A COMBINATION OF CELL-AUTONOMOUS AND NICHE MODULATION. STUDIES OF PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) HAVE LED TO THE IDENTIFICATION OF MUTATIONS THAT AFFECT DIFFERENT CELLULAR PATHWAYS. SOME OF THESE HAVE BEEN CLASSIFIED AS PRELEUKEMIC, AND A STEPWISE EVOLUTION PROGRAM WHEREBY CELLS ACQUIRE ADDITIONAL MUTATIONS HAS BEEN PROPOSED IN THE DEVELOPMENT OF AML. HOW THE TIMING OF ACQUISITION OF THESE MUTATIONS AND THEIR IMPACT ON TRANSFORMATION AND THE BONE MARROW (BM) MICROENVIRONMENT OCCURS HAS ONLY RECENTLY BEGUN TO BE INVESTIGATED. WE SHOW THAT CONSTITUTIVE AND EARLY LOSS OF THE EPIGENETIC REGULATOR, TET2, WHEN COMBINED WITH CONSTITUTIVE ACTIVATION OF FLT3, RESULTS IN TRANSFORMATION OF CHRONIC MYELOMONOCYTIC LEUKEMIA-LIKE OR MYELOPROLIFERATIVE NEOPLASM-LIKE PHENOTYPE TO AML, WHICH IS MORE PRONOUNCED IN DOUBLE-MUTANT MICE RELATIVE TO MICE CARRYING MUTATIONS IN SINGLE GENES. FURTHERMORE, WE SHOW THAT IN PRELEUKEMIC AND LEUKEMIC MICE THERE ARE ALTERATIONS IN THE BM NICHE AND SECRETED CYTOKINES, WHICH CREATES A PERMISSIVE ENVIRONMENT FOR THE GROWTH OF MUTATION-BEARING CELLS RELATIVE TO NORMAL CELLS. 2020 11 4442 28 MOLECULAR GENETICS OF MDS/MPN OVERLAP SYNDROMES. THE MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE A HETEROGENOUS GROUP OF MYELOID MALIGNANCIES HALLMARKED BY CLINICOPATHOLOGIC FEATURES THAT OVERLAP WITH MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. FORMALLY RECOGNIZED BY THE WORLD HEALTH ORGANIZATION, THIS GROUP INCLUDES THE ENTITIES CHRONIC MYELOMONOCYTIC LEUKEMIA, JUVENILE MYELOMONOCYTIC LEUKEMIA, ATYPICAL CHRONIC MYELOID LEUKEMIA, MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS AND MDS/MPN, UNCLASSIFIABLE. ADVANCEMENTS IN NEXT GENERATION SEQUENCING HAVE BEGUN TO UNRAVEL THE MOLECULAR UNDERPINNINGS OF THESE DISEASES, IDENTIFYING AN ARRAY OF RECURRENTLY MUTATED GENES INVOLVED IN EPIGENETIC REGULATION, RNA SPLICING, TRANSCRIPTION, AND CELL SIGNALING. DESPITE MOLECULAR OVERLAP WITH OTHER MYELOID MALIGNANCIES, EACH ENTITY DISPLAYS A UNIQUE SPECTRUM OF SOMATIC MUTATIONS SUPPORTING THEIR UNIQUE PATHOBIOLOGY AND CLINICAL FEATURES. IMPORTANTLY, MOLECULAR PROFILING IS BECOMING AN INTEGRAL TOOL UTILIZED IN ROUTINE CLINICAL PRACTICE. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF OVERLAP SYNDROMES AND DETAILS THE IMPACT OF SOMATIC MUTATIONS IN DIAGNOSTIC, PROGNOSTIC, AND THERAPEUTIC DECISION-MAKING. 2020 12 2981 23 GENETIC COMPLEXITY OF CHRONIC MYELOMONOCYTIC LEUKEMIA. IN RECENT YEARS CMML HAS RECEIVED INCREASED ATTENTION AS THE MOST COMMONLY OBSERVED MDS/MPN OVERLAP SYNDROME. RENEWED INTEREST HAS OCCURRED IN PART DUE TO WIDESPREAD ADOPTION OF NEXT-GENERATION SEQUENCING PANELS THAT HELP RENDER THE DIAGNOSIS IN THE ABSENCE OF MORPHOLOGIC DYSPLASIA. ALTHOUGH MOST CMML PATIENTS EXHIBIT SOMATIC MUTATIONS IN EPIGENETIC MODIFIERS, SPLICEOSOME COMPONENTS, TRANSCRIPTION FACTORS AND SIGNAL TRANSDUCTION GENES, IT IS INCREASINGLY CLEAR THAT A SMALL SUBSET HARBORS AN INHERITED PREDISPOSITION TO CMML AND OTHER MYELOID NEOPLASMS. MORE INTRIGUING IS THE FACT THAT THE MUTATIONAL SPECTRUM OBSERVED IN CMML IS FOUND IN OTHER TYPES OF MYELOID LEUKEMIAS, BEGGING THE QUESTION OF HOW SIMILAR GENETIC BACKGROUNDS CAN LEAD TO SUCH DIVERGENT CLINICAL PHENOTYPES. IN THIS REVIEW WE PRESENT A CONTEMPORARY SNAPSHOT OF THE GENETIC COMPLEXITY INHERENT TO CMML, EXPLORE THE RELATIONSHIP BETWEEN GENOTYPE-PHENOTYPE AND PRESENT A STEPWISE MODEL OF CMML PATHOGENESIS AND PROGRESSION. 2021 13 5782 23 SPLICING ANOMALIES IN MYELOPROLIFERATIVE NEOPLASMS: PAVING THE WAY FOR NEW THERAPEUTIC VENUES. SINCE THE DISCOVERY OF SPLICEOSOME MUTATIONS IN MYELOID MALIGNANCIES, ABNORMAL PRE-MRNA SPLICING, WHICH HAS BEEN WELL STUDIED IN VARIOUS CANCERS, HAS ATTRACTED NOVEL INTEREST IN HEMATOLOGY. HOWEVER, DESPITE THE COMMON OCCURRENCE OF SPLICEOSOME MUTATIONS IN MYELO-PROLIFERATIVE NEOPLASMS (MPN), NOT MUCH IS KNOWN REGARDING THE CHARACTERIZATION AND MECHANISMS OF SPLICING ANOMALIES IN MPN. IN THIS ARTICLE, WE REVIEW THE CURRENT SCIENTIFIC LITERATURE REGARDING "SPLICING AND MYELOPROLIFERATIVE NEOPLASMS". WE FIRST ANALYSE THE CLINICAL SERIES REPORTING SPLICEOSOME MUTATIONS IN MPN AND THEIR CLINICAL CORRELATES. WE THEN PRESENT THE CURRENT KNOWLEDGE ABOUT MOLECULAR MECHANISMS BY WHICH THESE MUTATIONS PARTICIPATE IN THE PATHOGENESIS OF MPN OR OTHER MYELOID MALIGNANCIES. BESIDE SPLICEOSOME MUTATIONS, SPLICING ANOMALIES HAVE BEEN DESCRIBED IN MYELOPROLIFERATIVE NEOPLASMS, AS WELL AS IN ACUTE MYELOID LEUKEMIAS, A DREADFUL COMPLICATION OF THESE CHRONIC DISEASES. BASED ON SPLICING ANOMALIES REPORTED IN CHRONIC MYELOGENOUS LEUKEMIA AS WELL AS IN ACUTE LEUKEMIA, AND THE MECHANISMS PRESIDING SPLICING DEREGULATION, WE PROPOSE THAT ABNORMAL SPLICING PLAYS A MAJOR ROLE IN THE EVOLUTION OF MYELOPROLIFERATIVE NEOPLASMS AND MAY BE THE TARGET OF SPECIFIC THERAPEUTIC STRATEGIES. 2020 14 4566 21 MYELOID SOMATIC MUTATION PANEL TESTING IN MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATIVE NEOPLASMS ARE CHARACTERISED BY SOMATIC MUTATIONS IN PATHWAYS THAT REGULATE CELL PROLIFERATION, EPIGENETIC MODIFICATIONS, RNA SPLICING OR DNA REPAIR. ASSESSMENT OF THE MUTATIONAL PROFILE ASSISTS DIAGNOSIS AND CLASSIFICATION, BUT ALSO AIDS ASSESSMENT OF PROGNOSIS, AND MAY GUIDE THE USE OF EMERGING TARGETED THERAPIES. THE MOST PRACTICAL WAY TO PROVIDE INFORMATION ON NUMEROUS GENETIC VARIANTS IS BY USING MASSIVELY PARALLEL SEQUENCING, COMMONLY IN THE FORM OF DISEASE SPECIFIC NEXT GENERATION SEQUENCING (NGS) PANELS. THIS REVIEW SUMMARISES THE DIAGNOSTIC AND PROGNOSTIC VALUE OF SOMATIC MUTATION TESTING IN PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: POLYCYTHAEMIA VERA, ESSENTIAL THROMBOCYTHAEMIA, PRIMARY MYELOFIBROSIS, CHRONIC NEUTROPHILIC LEUKAEMIA, SYSTEMIC MASTOCYTOSIS, AND CHRONIC EOSINOPHILIC LEUKAEMIA. NGS PANEL TESTING IS INCREASING IN ROUTINE PRACTICE AND PROMISES TO IMPROVE THE ACCURACY AND EFFICIENCY OF PATHOLOGICAL DIAGNOSIS AND PROGNOSIS. 2021 15 6885 37 [RNA SPLICING DYSREGULATION IN HEMATOLOGICAL MALIGNANCIES]. RECURRENT MUTATIONS IN GENES ENCODING KEY SPLICING FACTORS, SF3B1, SRSF2, U2AF1, AND ZRSR2 HAVE BEEN FOUND IN A VARIETY OF CANCERS, PARTICULARLY IN HEMATOLOGIC MALIGNANCIES, INCLUDING MYELODYSPLASTIC SYNDROMES, CHRONIC MYELOMONOCYTIC LEUKEMIA, ACUTE MYELOID LEUKEMIA, AND CHRONIC LYMPHOCYTIC LEUKEMIA. GLOBAL MIS-SPLICING OF MRNAS TARGETED BY ABERRANT SPLICING FACTORS PARTLY CONTRIBUTES TO LEUKEMOGENESIS THROUGH DECREASE PROTEIN EXPRESSION OF TUMOR SUPPRESSORS AND EPIGENETIC MODIFIERS, CAUSED BY MRNAS DEGRADATION OF ABERRANTLY SPLICED. SOME OF THE MIS-SPLICED MRNAS INFLUENCE INTRACELLULAR ONCOGENIC PATHWAYS AND CELLULAR PROCESSES THROUGH A DYSREGULATED EXPRESSION OF ASSOCIATED PROTEINS, WHEREAS OTHERS INFLUENCE THE FUNCTION OF CO-MUTATED GENES SUCH AS ABERRANT TRANSCRIPTIONAL REGULATORS. SPLICEOSOMAL DISRUPTION IS COMMON IN MANY CANCERS, MAKING SPLICEOSOME AN APPEALING THERAPEUTIC TARGET. THE FINDINGS THAT SPLICEOSOMAL MUTANT CELLS RELY ON WILD-TYPE SPLICING MACHINERY FOR SURVIVAL AND THAT SPLICING FACTOR MUTATIONS OCCUR IN A MUTUALLY EXCLUSIVE MANNER STRONGLY SUGGEST THAT INHIBITING WILD-TYPE SPLICING MACHINERY CAUSES SYNTHETIC LETHALITY IN CANCER CELLS WITH THESE MUTATIONS. WE DISCUSS THE CHARACTERISTICS AND ONCOGENIC MECHANISMS OF SPLICING FACTOR MUTATIONS, AS WELL AS THE DEVELOPMENT OF NOVEL TREATMENT STRATEGIES TARGETING ABERRANT SPLICING FACTORS IN HEMATOLOGIC MALIGNANCIES. 2023 16 1043 34 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 1304 27 DEFECTS IN SPLICEOSOMAL MACHINERY: A NEW PATHWAY OF LEUKAEMOGENESIS. PROPER SPLICING OF PRE-MRNA IS REQUIRED FOR PROTEIN SYNTHESIS AND THEREFORE IS A FUNDAMENTAL CELLULAR FUNCTION. THE DISCOVERY OF A VARIETY OF SOMATIC SPLICEOSOMAL MUTATIONS IN HAEMATOLOGICAL MALIGNANCIES, INCLUDING MYELOID NEOPLASMS AND CHRONIC LYMPHOCYTIC LEUKAEMIA HAS POINTED TO A NEW LEUKAEMOGENIC PATHWAY INVOLVING SPLICEOSOMAL DYSFUNCTION. THEORETICALLY, SPLICEOSOMAL MUTATIONS CAN LEAD TO ACTIVATION OF INCORRECT SPLICE SITES, INTRON RETENTION OR ABERRANT ALTERNATIVE SPLICING OCCURRING IN PATTERNS GENERATED BY MUTATIONS OF INDIVIDUAL SPLICEOSOMAL PROTEINS. SUCH EVENTS CAN PRODUCE A DEFECTIVE BALANCE BETWEEN PROTEIN ISOFORMS LEADING TO FUNCTIONAL CONSEQUENCES INCLUDING DEFECTIVE REGULATION OF PROLIFERATION AND DIFFERENTIATION. THE OBSERVED PATTERN OF OCCURRENCE OF HIGHLY SPECIFIC MISSENSE MUTATIONS, COUPLED WITH THE LACK OF NONSENSE MUTATIONS AND DELETIONS, IMPLIES A GAIN-OF-FUNCTION OR BETTER GAIN-OF-DYSFUNCTION MECHANISM. INCORRECT SPLICING OF DOWNSTREAM GENES, SUCH AS TUMOUR SUPPRESSOR GENES, MAY RESULT IN HAPLOINSUFFICIENT EXPRESSION THROUGH NONSENSE-MEDIATED MRNA DECAY. THUS, SPLICEOSOMAL MUTATIONS MAY, DEPENDING ON THE PATTERN OF AFFECTED PROTEINS, LEAD TO SIMILAR FUNCTIONAL EFFECTS ON TUMOUR SUPPRESSOR GENES AS CHROMOSOMAL DELETIONS, EPIGENETIC SILENCING OR INACTIVATING/HYPOMORPHIC MUTATIONS. THE PROGNOSTIC VALUE OF THE MOST COMMON MUTATIONS AND THEIR PHENOTYPIC ASSOCIATION IN THE CLINICAL SETTING IS CURRENTLY UNDER INVESTIGATION. IT IS LIKELY THAT SPLICEOSOMAL MUTATIONS MAY INDICATE SENSITIVITY TO SPLICEOSOME INHIBITORS APPLIED IN THE FORM OF A SYNTHETIC LETHAL APPROACH. THIS REVIEW DISCUSSES THE MOST CURRENT ASPECTS OF SPLICEOSOMAL RESEARCH IN THE CONTEXT OF HAEMATOLOGICAL MALIGNANCIES. 2012 18 2781 28 EZH2 IN MYELOID MALIGNANCIES. OUR UNDERSTANDING OF THE SIGNIFICANCE OF EPIGENETIC DYSREGULATION IN THE PATHOGENESIS OF MYELOID MALIGNANCIES HAS GREATLY ADVANCED IN THE PAST DECADE. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS THE CATALYTIC CORE COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), WHICH IS RESPONSIBLE FOR GENE SILENCING THROUGH TRIMETHYLATION OF H3K27. EZH2 DYSREGULATION IS HIGHLY TUMORIGENIC AND HAS BEEN OBSERVED IN VARIOUS CANCERS, WITH EZH2 ACTING AS AN ONCOGENE OR A TUMOR-SUPPRESSOR DEPENDING ON CELLULAR CONTEXT. WHILE LOSS-OF-FUNCTION MUTATIONS OF EZH2 FREQUENTLY AFFECT PATIENTS WITH MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS, MYELODYSPLASTIC SYNDROME AND MYELOFIBROSIS, CASES OF CHRONIC MYELOID LEUKEMIA (CML) SEEM TO BE LARGELY CHARACTERIZED BY EZH2 OVEREXPRESSION. A VARIETY OF OTHER FACTORS FREQUENTLY ABERRANT IN MYELOID LEUKEMIA CAN AFFECT PRC2 FUNCTION AND DISEASE PATHOGENESIS, INCLUDING ADDITIONAL SEX COMBS LIKE 1 (ASXL1) AND SPLICING GENE MUTATIONS. AS THE GENETIC BACKGROUND OF MYELOID MALIGNANCIES IS LARGELY HETEROGENEOUS, IT IS NOT SURPRISING THAT EZH2 MUTATIONS ACT IN CONJUNCTION WITH OTHER ABERRATIONS. SINCE EZH2 MUTATIONS ARE CONSIDERED TO BE EARLY EVENTS IN DISEASE PATHOGENESIS, THEY ARE OF THERAPEUTIC INTEREST TO RESEARCHERS, THOUGH TARGETING OF EZH2 LOSS-OF-FUNCTION DOES PRESENT UNIQUE CHALLENGES. PRELIMINARY RESEARCH INDICATES THAT COMBINED TYROSINE KINASE INHIBITOR (TKI) AND EZH2 INHIBITOR THERAPY MAY PROVIDE A STRATEGY TO ELIMINATE THE RESIDUAL DISEASE BURDEN IN CML TO ALLOW PATIENTS TO REMAIN IN TREATMENT-FREE REMISSION. 2020 19 5284 26 PROPOSALS FOR CLINICAL TRIALS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOLOGIC MALIGNANCY OF MOSTLY OLDER INDIVIDUALS THAT EXHIBITS BOTH MYELODYSPLASTIC AND MYELOPROLIFERATIVE FEATURES. CMML PRESENTATION AND OUTCOME ARE VARIABLE, REFLECTING GENETIC AND CLINICAL HETEROGENEITY. HYPOMETHYLATING AGENTS ARE THE MAINSTAY OF THERAPY BUT INDUCE COMPLETE REMISSIONS IN LESS THAN 20% OF PATIENTS AND DO NOT PROLONG SURVIVAL COMPARED TO HYDROXYUREA. ALLOGENEIC STEM CELL TRANSPLANT (ASCT) IS POTENTIALLY CURATIVE, BUT FEW PATIENTS QUALIFY DUE TO ADVANCED AGE AND/OR COMORBIDITIES. WORK OF THE PAST SEVERAL YEARS HAS IDENTIFIED KEY MOLECULAR PATHWAYS THAT DRIVE DISEASE PROLIFERATION AND TRANSFORMATION TO ACUTE LEUKEMIA, INCLUDING JAK/STAT AND MAPK SIGNALING AND EPIGENETIC DYSREGULATION. THERE IS INCREASINGLY COMPELLING EVIDENCE THAT INFLAMMATION IS A MAJOR DRIVER OF CMML PROGRESSION. THUS FAR HOWEVER, THIS MECHANISTIC KNOWLEDGE HAS NOT YET BEEN TRANSLATED INTO IMPROVED OUTCOMES, SUGGESTING THAT FUNDAMENTALLY NEW APPROACHES ARE REQUIRED. IN THIS REVIEW, WE DISCUSS THE DISEASE COURSE, NEW CLASSIFICATIONS, AND CURRENT TREATMENT LANDSCAPE OF CMML. WE REVIEW ONGOING CLINICAL STUDIES AND DISCUSS OPTIONS FOR RATIONALLY BASED FUTURE CLINICAL TRIALS. 2023 20 1947 31 EPIGENETIC ABNORMALITIES IN MYELOPROLIFERATIVE NEOPLASMS: A TARGET FOR NOVEL THERAPEUTIC STRATEGIES. THE MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE A GROUP OF CLONAL HEMATOLOGICAL MALIGNANCIES CHARACTERIZED BY A HYPERCELLULAR BONE MARROW AND A TENDENCY TO DEVELOP THROMBOTIC COMPLICATIONS AND TO EVOLVE TO MYELOFIBROSIS AND ACUTE LEUKEMIA. UNLIKE CHRONIC MYELOGENOUS LEUKEMIA, WHERE A SINGLE DISEASE-INITIATING GENETIC EVENT HAS BEEN IDENTIFIED, A MORE COMPLICATED SERIES OF GENETIC MUTATIONS APPEAR TO BE RESPONSIBLE FOR THE BCR-ABL1-NEGATIVE MPNS WHICH INCLUDE POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA, AND PRIMARY MYELOFIBROSIS. RECENT STUDIES HAVE REVEALED A NUMBER OF EPIGENETIC ALTERATIONS THAT ALSO LIKELY CONTRIBUTE TO DISEASE PATHOGENESIS AND DETERMINE CLINICAL OUTCOME. INCREASING EVIDENCE INDICATES THAT ALTERATIONS IN DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA EXPRESSION PATTERNS CAN COLLECTIVELY INFLUENCE GENE EXPRESSION AND POTENTIALLY CONTRIBUTE TO MPN PATHOGENESIS. EXAMPLES INCLUDE MUTATIONS IN GENES ENCODING PROTEINS THAT MODIFY CHROMATIN STRUCTURE (EZH2, ASXL1, IDH1/2, JAK2V617F, AND IKZF1) AS WELL AS EPIGENETIC MODIFICATION OF GENES CRITICAL FOR CELL PROLIFERATION AND SURVIVAL (SUPPRESSORS OF CYTOKINE SIGNALING, POLYCYTHEMIA RUBRA VERA-1, CXC CHEMOKINE RECEPTOR 4, AND HISTONE DEACETYLASE (HDAC)). THESE EPIGENETIC LESIONS SERVE AS NOVEL TARGETS FOR EXPERIMENTAL THERAPEUTIC INTERVENTIONS. CLINICAL TRIALS ARE CURRENTLY UNDERWAY EVALUATING HDAC INHIBITORS AND DNA METHYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF PATIENTS WITH MPNS. 2011