1 2981 100 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 2 2956 35 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 3 963 27 CHRONIC MYELOMONOCYTIC LEUKEMIA: INSIGHTS INTO BIOLOGY, PROGNOSTIC FACTORS, AND TREATMENT. PURPOSE OF REVIEW: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOLOGICAL MALIGNANCY CHARACTERIZED BY BOTH DYSPLASTIC AND PROLIFERATIVE FEATURES, WITH AN INHERENT RISK FOR LEUKEMIC TRANSFORMATION. WITH THE HELP OF THIS REVIEW, WE AIM TO SUMMARIZE KEY CONCEPTS WITH REGARDS TO CMML BIOLOGY, DIAGNOSIS, RISK STRATIFICATION, AND THERAPEUTICS. RECENT FINDINGS: BASED ON RECENT STUDIES, CMML IS HALLMARKED BY A RELATIVELY LOW GENETIC COMPLEXITY, WHICH CONTRASTS WITH A COMPELLING PHENOTYPICAL HETEROGENEITY, LARGELY DRIVEN BY EPIGENETIC MECHANISMS. RECENT ADVANCES IN THE CHARACTERIZATION OF CMML BIOLOGY HAS LED TO AN IMPROVEMENT IN RISK-STRATIFICATION, BY MEANS OF INCORPORATING PROGNOSTICALLY RELEVANT GENE MUTATIONS. THIS, HOWEVER, HAS NOT SIGNIFICANTLY IMPACTED AVAILABLE THERAPIES AND OUTCOMES CONTINUE TO REMAIN POOR. ADVANCES IN CMML BIOLOGY HAVE BETTER EXPLAINED THE PHENOTYPIC HETEROGENEITY, WHILE CONTINUING TO DEFINE THE GENETIC AND EPIGENETIC LANDSCAPE. IN SPITE OF RECENT ADVANCES, LIMITED EFFECTIVE THERAPIES EXIST AND DEVELOPING RATIONALLY DERIVED THERAPEUTIC APPROACHES IS MUCH NEEDED. 2019 4 3565 26 IMPACT OF GENETIC POLYMORPHISMS AND BIOMARKERS ON THE EFFECTIVENESS AND TOXICITY OF TREATMENT OF CHRONIC MYELOID LEUKEMIA AND ACUTE MYELOID LEUKEMIA. MOST MALIGNANT HEMATOLOGICAL DISEASES ARE GENERALLY A CONSEQUENCE OF ACQUIRED MUTATIONS OR REARRANGEMENTS IN CELL REPLICATION PROCESSES. ACUTE MYELOID LEUKEMIA (AML) IS A CLINICALLY AND MOLECULARLY HETEROGENEOUS DISEASE THAT RESULTS FROM ACQUIRED GENETIC AND EPIGENETIC ALTERATIONS IN HEMATOPOIETIC PROGENITOR CELLS. DESPITE THE ADVANCES MADE IN UNDERSTANDING THE PATHOGENESIS OF THIS DISEASE, THE OVERALL SURVIVAL OF PATIENTS REMAINS VERY LOW DUE TO THE HIGH RELAPSE RATE. PHARMACOGENETICS AND MASSIVE SEQUENCING STUDIES HAVE ALLOWED THE IDENTIFICATION OF NEW RECURRENT MUTATIONS WITH SIGNIFICANT PROGNOSTIC IMPACT IN AML; FURTHERMORE, IT SEEMS LIKELY THAT WHOLE GENOME SEQUENCING WILL SOON BECOME A STANDARD DIAGNOSTIC TEST, WHICH WILL ALLOW THE MOLECULAR DIAGNOSIS OF PATIENTS. THEREFORE, IT IS NECESSARY TO DEVELOP MOLECULAR TARGETS THAT OPEN NEW THERAPEUTIC PERSPECTIVES AND ALLOW INDIVIDUALIZED TREATMENT OF PATIENTS WITH THIS AGGRESSIVE DISEASE. CHRONIC MYELOID LEUKEMIA (CML) IS THE FIRST NEOPLASTIC DISEASE FOR WHICH A CHARACTERISTIC GENETIC ALTERATION WAS DESCRIBED. IT HAS, BY DEFINITION, A GENETIC MARKER, THE BCR::ABL1 REARRANGEMENT, AS A CONSEQUENCE OF THE T9;22(Q34;Q11) TRANSLOCATION. ITS STUDY IS ESSENTIAL FOR THE DIAGNOSIS OF THIS ENTITY AND ALSO FOR MONITORING THE RESPONSE TO TREATMENT. DRUGS KNOWN AS TYROSINE KINASE INHIBITORS (TKIS) THAT TARGET THE BCR::ABL1 PROTEIN (ORAL TARGETED THERAPY) ARE THE CONVENTIONAL TREATMENT OF CML, REPRESENTING A CHANGE OF PARADIGM IN THE MANAGEMENT OF ONCOHEMATOLOGICAL PATIENTS. 2022 5 5284 25 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 6 957 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 7 1304 31 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 8 384 31 AN EVOLUTIONARY PERSPECTIVE ON CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) SHARES WITH OTHER MYELOID DISEASES A NUMBER OF SOMATIC GENE MUTATIONS. THESE MUTATIONS CAN NOW BE INTEGRATED WITHIN THE FRAMEWORK OF EVOLUTION THEORY TO ADDRESS THE MECHANISMS OF THE DISEASE. SEVERAL EVIDENCES INDICATE THAT THE DISEASE EMERGES IN ADULT HEMATOPOIETIC STEM CELLS (HSC) THROUGH THE AGE-DEPENDENT ACCUMULATION OF DNA DAMAGE, LEADING STOCHASTICALLY TO A DRIVER MUTATION THAT CONFERS A COMPETITIVE ADVANTAGE TO THE CELL. A MUTATION IN TET2 GENE COULD BE ONE OF THESE DRIVER MUTATIONS PROVOKING THE EMERGENCE OF CLONALITY. AFTER A LONG LATENCY, SECONDARY LESIONS, SUCH AS MUTATIONS IN THE SRSF2 GENE, CONTRIBUTE TO PROGRESSION TO FULL-BLOWN MALIGNANCY, WITH ABNORMAL DIFFERENTIATION. ADDITIONAL MUTATIONS ACCUMULATE AND BRANCHING ARISING MOSTLY THROUGH MITOTIC RECOMBINATION GENERATES CLONAL HETEROGENEITY. MODIFICATIONS IN THE MICROENVIRONMENT PROBABLY AFFECT THIS CLONAL DYNAMICS, WHEREAS EPIGENETIC ALTERATIONS, SUCH AS HYPERMETHYLATION OF THE TIF1GAMMA GENE PROMOTER, MAY GENERATE PHENOTYPIC DIVERSIFICATION OF OTHERWISE CLONAL POPULATIONS. THE PRESERVED ALTHOUGH DEREGULATED MYELOID DIFFERENTIATION THAT CHARACTERIZES CMML, WITH GRANULOMONOCYTE EXPANSION AND VARIOUS CYTOPENIAS, MAY DEPEND ON EARLY CLONAL DOMINANCE IN THE HEMATOPIETIC CELL HIERARCHY. PROGRESSION TO ACUTE MYELOID LEUKEMIA OBSERVED IN 25-30% OF THE PATIENTS MAY ARISE FROM THE MASSIVE EXPANSION OF A CLONE WITH NOVEL GENETIC LESIONS, PROVIDING A HIGH FITNESS TO PREVIOUSLY MINOR SUBCLONES WHEN IN CHRONIC PHASE OF THE DISEASE. THIS REVIEW DISCUSSES THE VARIOUS MODELS OF DISEASE EMERGENCE AND PROGRESSION AND HOW THIS RECENT KNOWLEDGE COULD DRIVE RATIONAL THERAPEUTIC STRATEGIES. 2013 9 2652 23 EPIGENOMICS OF LEUKEMIA: FROM MECHANISMS TO THERAPEUTIC APPLICATIONS. LEUKEMOGENESIS IS A MULTISTEP PROCESS IN WHICH SUCCESSIVE TRANSFORMATIONAL EVENTS ENHANCE THE ABILITY OF A CLONAL POPULATION ARISING FROM HEMATOPOIETIC PROGENITOR CELLS TO PROLIFERATE, DIFFERENTIATE AND SURVIVE. CLINICALLY AND PATHOLOGICALLY, LEUKEMIA IS SUBDIVIDED INTO FOUR MAIN CATEGORIES: CHRONIC LYMPHOCYTIC LEUKEMIA, CHRONIC MYELOID LEUKEMIA, ACUTE LYMPHOCYTIC LEUKEMIA AND ACUTE MYELOID LEUKEMIA. LEUKEMIA HAS BEEN PREVIOUSLY CONSIDERED ONLY AS A GENETIC DISEASE. HOWEVER, IN RECENT YEARS, SIGNIFICANT ADVANCES HAVE BEEN MADE IN THE ELUCIDATION OF THE LEUKEMOGENESIS-ASSOCIATED PROCESSES. THUS, WE HAVE COME TO UNDERSTAND THAT EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNA ARE INVOLVED IN THE PERMANENT CHANGES OF GENE EXPRESSION CONTROLLING THE LEUKEMIA PHENOTYPE. IN THIS ARTICLE, WE WILL FOCUS ON THE EPIGENETIC DEFECTS ASSOCIATED WITH LEUKEMIA AND THEIR IMPLICATIONS AS BIOMARKERS FOR DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC APPLICATIONS. 2011 10 4681 18 NEW OPTIONS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROME. MYELODYSPLASTIC SYNDROME (MDS) IS A HETEROGENEOUS GROUP OF PROGRESSIVE CHRONIC HEMATOPOIETIC DISORDERS, USUALLY PRESENTING AS REFRACTORY ANEMIA OR CYTOPENIA, WITH AN APPROXIMATELY 25% RISK OF PROGRESSION TOWARD ACUTE MYELOID LEUKAEIMA (AML), AND NO PROVEN CURATIVE TREATMENT. NOVEL BIOLOGICAL TREATMENT STRATEGIES TARGETING BOTH THE MALIGNANT BLOOD CELL AND ITS MICROENVIRONMENT CAN OVERCOME RESISTANCE TO CURRENT THERAPIES, AND REPRESENT A PROMISING TREATMENT PARADIGM FOR IMPROVING PATIENT OUTCOME. MANY OF THESE AGENTS HAVE MULTIPLE BIOLOGIC ACTIVITIES. THE OBJECTIVE OF THIS ARTICLE IS TO PRESENT A COMPARATIVE REVIEW OF CLASSIFICATION SYSTEMS IN MDS AND TO DISCUSS THE EVOLVING TRENDS IN THE TREATMENT OF MDS (IMMUNOSUPPRESIVE THERAPY, IMMUNOMODULATORY DRUGS, ARSENIC TRIOXIDE, PROTEASOME INHIBITORS, EPIGENETIC THERAPY). 2005 11 2237 32 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 12 1039 32 CLINICAL AND BIOLOGICAL IMPLICATIONS OF DRIVER MUTATIONS IN MYELODYSPLASTIC SYNDROMES. MYELODYSPLASTIC SYNDROMES (MDS) ARE A HETEROGENEOUS GROUP OF CHRONIC HEMATOLOGICAL MALIGNANCIES CHARACTERIZED BY DYSPLASIA, INEFFECTIVE HEMATOPOIESIS AND A VARIABLE RISK OF PROGRESSION TO ACUTE MYELOID LEUKEMIA. SEQUENCING OF MDS GENOMES HAS IDENTIFIED MUTATIONS IN GENES IMPLICATED IN RNA SPLICING, DNA MODIFICATION, CHROMATIN REGULATION, AND CELL SIGNALING. WE SEQUENCED 111 GENES ACROSS 738 PATIENTS WITH MDS OR CLOSELY RELATED NEOPLASMS (INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA AND MDS-MYELOPROLIFERATIVE NEOPLASMS) TO EXPLORE THE ROLE OF ACQUIRED MUTATIONS IN MDS BIOLOGY AND CLINICAL PHENOTYPE. SEVENTY-EIGHT PERCENT OF PATIENTS HAD 1 OR MORE ONCOGENIC MUTATIONS. WE IDENTIFY COMPLEX PATTERNS OF PAIRWISE ASSOCIATION BETWEEN GENES, INDICATIVE OF EPISTATIC INTERACTIONS INVOLVING COMPONENTS OF THE SPLICEOSOME MACHINERY AND EPIGENETIC MODIFIERS. COUPLED WITH INFERENCES ON SUBCLONAL MUTATIONS, THESE DATA SUGGEST A HYPOTHESIS OF GENETIC "PREDESTINATION," IN WHICH EARLY DRIVER MUTATIONS, TYPICALLY AFFECTING GENES INVOLVED IN RNA SPLICING, DICTATE FUTURE TRAJECTORIES OF DISEASE EVOLUTION WITH DISTINCT CLINICAL PHENOTYPES. DRIVER MUTATIONS HAD EQUIVALENT PROGNOSTIC SIGNIFICANCE, WHETHER CLONAL OR SUBCLONAL, AND LEUKEMIA-FREE SURVIVAL DETERIORATED STEADILY AS NUMBERS OF DRIVER MUTATIONS INCREASED. THUS, ANALYSIS OF ONCOGENIC MUTATIONS IN LARGE, WELL-CHARACTERIZED COHORTS OF PATIENTS ILLUSTRATES THE INTERCONNECTIONS BETWEEN THE CANCER GENOME AND DISEASE BIOLOGY, WITH CONSIDERABLE POTENTIAL FOR CLINICAL APPLICATION. 2013 13 358 31 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML. 2013 14 2547 19 EPIGENETICS IN MYELOID MALIGNANCIES. MYELOID HEMATOLOGICAL MALIGNANCIES ARE AMONG THE EPIGENETICALLY BEST CHARACTERIZED NEOPLASMS. THE COMPARATIVELY LOW NUMBER OF RECURRING BALANCED AND UNBALANCED CHROMOSOMAL ABNORMALITIES AS WELL AS COMMON GENETIC MUTATIONS HAS ENABLED SCIENTISTS TO RELATE EPIGENETIC STATES TO THESE. THE EASE OF ACCESSING MALIGNANT CELLS THROUGH BONE MARROW ASPIRATION HAS CERTAINLY CONTRIBUTED TO THE FAST EXPANSION OF KNOWLEDGE. EVEN SO, THE CLINICAL AND PATHOGENETIC RELEVANCE OF EPIGENETIC CHANGES IS STILL NOT KNOWN, AND THE FIELD WILL CERTAINLY EVOLVE VERY FAST WITH THE DEVELOPMENT OF NEW ANALYTIC TECHNIQUES. THE FIRST EXAMPLE OF SUCCESSFUL EPIGENETIC THERAPY IS SEEN IN MYELOID MALIGNANCIES, IN THE HIGH-RISK MYELODYSPLASTIC SYNDROMES (MDS) WHICH ARE ROUTINELY TREATED WITH THE DEMETHYLATING AGENT AZACYTIDINE.THIS CHAPTER WILL CONCENTRATE ON DESCRIBING THE EPIGENETIC CHANGES IN ACUTE MYELOID LEUKEMIA (AML), CHRONIC MYELOID LEUKEMIA (CML) AND MDS. AN OVERVIEW OF CLINICAL RELEVANCE AND EPIGENETIC THERAPEUTIC APPROACHES IS ALSO MADE. 2012 15 3575 35 IMPACT OF MOLECULAR PROFILING ON THE MANAGEMENT OF PATIENTS WITH MYELOFIBROSIS. MYELOFIBROSIS (MF) IS A CHRONIC MYELOPROLIFERATIVE NEOPLASM (MPN) CHARACTERIZED BY A HIGHLY HETEROGENEOUS CLINICAL COURSE, WHICH CAN BE COMPLICATED BY SEVERE CONSTITUTIONAL SYMPTOMS, MASSIVE SPLENOMEGALY, PROGRESSIVE BONE MARROW FAILURE, CARDIOVASCULAR EVENTS, AND DEVELOPMENT OF ACUTE LEUKEMIA. CONSTITUTIVE SIGNALING THROUGH THE JAK-STAT PATHWAY PLAYS A FUNDAMENTAL ROLE IN ITS PATHOGENESIS, GENERALLY DUE TO ACTIVATING MUTATIONS OF JAK2, CALR AND MPL GENES (I.E., THE MPN DRIVER MUTATIONS), PRESENT IN MOST MF PATIENTS. NEXT GENERATION SEQUENCING (NGS) PANEL TESTING HAS SHOWN THAT ADDITIONAL SOMATIC MUTATIONS CAN ALREADY BE DETECTED AT THE TIME OF DIAGNOSIS IN MORE THAN HALF OF PATIENTS, AND THAT THEY ACCUMULATE ALONG THE DISEASE COURSE. THESE MUTATIONS, MOSTLY AFFECTING EPIGENETIC MODIFIERS OR SPLICEOSOME COMPONENTS, MAY COOPERATE WITH MPN DRIVERS TO FAVOR CLONAL DOMINANCE OR INFLUENCE THE CLINICAL PHENOTYPE, AND SOME, SUCH AS HIGH MOLECULAR RISK MUTATIONS, CORRELATE WITH A MORE AGGRESSIVE CLINICAL COURSE WITH POOR TREATMENT RESPONSE. THE CURRENT MAIN ROLE OF MOLECULAR PROFILING IN CLINICAL PRACTICE IS PROGNOSTICATION, PRINCIPALLY FOR SELECTING HIGH-RISK PATIENTS WHO MAY BE CANDIDATES FOR TRANSPLANTATION, THE ONLY CURATIVE TREATMENT FOR MF TO DATE. TO THIS END, CONTEMPORARY PROGNOSTIC MODELS INCORPORATING MOLECULAR DATA ARE USEFUL TOOLS TO DISCRIMINATE DIFFERENT RISK CATEGORIES. ASIDE FROM CERTAIN CLINICAL SITUATIONS, DECISIONS REGARDING MEDICAL TREATMENT ARE NOT BASED ON PATIENT MOLECULAR PROFILING, YET THIS APPROACH MAY BECOME MORE RELEVANT IN NOVEL TREATMENT STRATEGIES, SUCH AS THE USE OF VACCINES AGAINST THE MUTANT FORMS OF JAK2 OR CALR, OR DRUGS DIRECTED AGAINST ACTIONABLE MOLECULAR TARGETS. 2022 16 2582 29 EPIGENETICS OF MYELODYSPLASTIC SYNDROMES. MYELODYSPLASTIC SYNDROMES (MDS) ARE CLONAL DISEASES OF THE ELDERLY CHARACTERIZED BY CHRONIC CYTOPENIAS, DYSPLASIA AND A VARIABLE RISK OF PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML). ABERRANT METHYLATION OF TUMOR-SUPPRESSOR GENE PROMOTERS HAS BEEN ESTABLISHED FOR MANY YEARS AND RECENTLY TRACKED TO THE MOST IMMATURE CELLS OF MDS, SUGGESTING THAT THESE ALTERATIONS ARE DRIVERS OF MDS PATHOGENESIS. IN RECENT YEARS, RECURRENT SOMATIC MUTATIONS IN GENES ENCODING PROTEINS INVOLVED IN DNA METHYLATION AND DEMETHYLATION AND IN COVALENT HISTONE MODIFICATIONS HAVE BEEN REPORTED IN MYELOID MALIGNANCIES, INCLUDING MDS. WHOLE-GENOME EPIGENETIC PROFILES OF MDS ARE ALSO EMERGING. IN PARALLEL WITH THESE ADVANCES IN THE MOLECULAR PATHOGENESIS OF MDS, CLINICAL TRIALS HAVE ESTABLISHED HYPOMETHYLATING AGENTS (HMAS) AS THE MAINSTAY OF THERAPY IN THE ADVANCED FORMS OF THE DISEASE. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF THE MOLECULAR MACHINERY INVOLVED IN EPIGENETIC REGULATION, DISCUSS HOW EPIGENETIC ALTERATIONS ARISE IN MDS AND CONTRIBUTE TO ITS PATHOGENESIS AND THEN DISCUSS THE MODE OF ACTION OF HMAS IN MDS. 2014 17 1076 27 CLONAL HEMATOPOIESIS IN MYELOPROLIFERATIVE NEOPLASMS CONFERS A PREDISPOSITION TO BOTH THROMBOSIS AND CANCER. PURPOSE OF REVIEW: THIS REVIEW FOCUSES ON VASCULAR COMPLICATIONS ASSOCIATED WITH CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPN) AND MORE SPECIFICALLY AIMS TO DISCUSS THE CLINICAL AND BIOLOGICAL EVIDENCE SUPPORTING THE EXISTENCE OF A LINK BETWEEN CLONAL HEMATOPOIESIS, CARDIOVASCULAR EVENTS (CVE), AND SOLID CANCER (SC). RECENT FINDINGS: THE MPN NATURAL HISTORY IS DRIVEN BY UNCONTROLLED CLONAL MYELOPROLIFERATION SUSTAINED BY ACQUIRED SOMATIC MUTATIONS IN DRIVER (JAK2, CALR, AND MPL) AND NON-DRIVER GENES, INVOLVING EPIGENETIC (E.G., TET2, DNMT3A) REGULATORS, CHROMATIN REGULATOR GENES (E.G., ASXL1, EZH2), AND SPLICING MACHINERY GENES (E.G., SF3B1). THE GENOMIC ALTERATIONS AND ADDITIONAL THROMBOSIS ACQUIRED RISK FACTORS ARE DETERMINANTS FOR CVE. THERE IS EVIDENCE THAT CLONAL HEMATOPOIESIS CAN ELICIT A CHRONIC AND SYSTEMIC INFLAMMATION STATUS THAT ACTS AS DRIVING FORCE FOR THE DEVELOPMENT OF THROMBOSIS, MPN EVOLUTION, AND SECOND CANCER (SC). THIS NOTION MAY EXPLAIN THE MECHANISM THAT LINKS ARTERIAL THROMBOSIS IN MPN PATIENTS AND SUBSEQUENT SOLID TUMORS. IN THE LAST DECADE, CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP) HAS BEEN DETECTED IN THE GENERAL POPULATION PARTICULARLY IN THE ELDERLY AND INITIALLY FOUND IN MYOCARDIAL INFARCTION AND STROKE, RISING THE HYPOTHESIS THAT THE INFLAMMATORY STATUS CHIP-ASSOCIATED COULD CONFER PREDISPOSITION TO BOTH CARDIOVASCULAR DISEASES AND CANCER. IN SUMMARY, CLONAL HEMATOPOIESIS IN MPN AND CHIP CONFER A PREDISPOSITION TO CARDIOVASCULAR EVENTS AND CANCER THROUGH CHRONIC AND SYSTEMIC INFLAMMATION. THIS ACQUISITION COULD OPEN NEW AVENUES FOR ANTITHROMBOTIC THERAPY BOTH IN MPNS AND IN GENERAL POPULATION BY TARGETING BOTH CLONAL HEMATOPOIESIS AND INFLAMMATION. 2023 18 1674 25 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 19 4551 28 MUTATIONAL HIERARCHIES IN MYELODYSPLASTIC SYNDROMES DYNAMICALLY ADAPT AND EVOLVE UPON THERAPY RESPONSE AND FAILURE. CLONAL EVOLUTION IS BELIEVED TO BE A MAIN DRIVER FOR PROGRESSION OF VARIOUS TYPES OF CANCER AND IMPLICATED IN FACILITATING RESISTANCE TO DRUGS. HOWEVER, THE HIERARCHICAL ORGANIZATION OF MALIGNANT CLONES IN THE HEMATOPOIESIS OF MYELODYSPLASTIC SYNDROMES (MDS) AND ITS IMPACT ON RESPONSE TO DRUG THERAPY REMAIN POORLY UNDERSTOOD. USING HIGH-THROUGHPUT SEQUENCING OF PATIENT AND XENOGRAFTED CELLS, WE EVALUATED THE INTRATUMORAL HETEROGENEITY (N= 54) AND RECONSTRUCTED MUTATIONAL TRAJECTORIES (N = 39) IN PATIENTS SUFFERING FROM MDS (N = 52) AND CHRONIC MYELOMONOCYTIC LEUKEMIA-1 (N = 2). WE IDENTIFIED LINEAR AND ALSO BRANCHING EVOLUTION PATHS AND CONFIRMED ON A PATIENT-SPECIFIC LEVEL THAT SOMATIC MUTATIONS IN EPIGENETIC REGULATORS AND RNA SPLICING GENES FREQUENTLY CONSTITUTE ISOLATED DISEASE-INITIATING EVENTS. USING HIGH-THROUGHPUT EXOME- AND/OR DEEP-SEQUENCING, WE ANALYZED 103 CHRONOLOGICALLY ACQUIRED SAMPLES FROM 22 PATIENTS COVERING A CUMULATIVE OBSERVATION TIME OF 75 YEARS MDS DISEASE PROGRESSION. OUR DATA REVEALED HIGHLY DYNAMIC SHAPING OF COMPLEX OLIGOCLONAL ARCHITECTURES, SPECIFICALLY UPON TREATMENT WITH LENALIDOMIDE AND OTHER DRUGS. DESPITE INITIAL CLINICAL RESPONSE TO TREATMENT, PATIENTS' MARROW PERSISTENTLY REMAINED CLONAL WITH RAPID OUTGROWTH OF FOUNDER-, SUB-, OR EVEN FULLY INDEPENDENT CLONES, INDICATING AN INCREASED DYNAMIC RATE OF CLONAL TURNOVER. THE EMERGENCE AND DISAPPEARANCE OF SPECIFIC CLONES FREQUENTLY CORRELATED WITH CHANGES OF CLINICAL PARAMETERS, HIGHLIGHTING THEIR DISTINCT AND FAR-REACHING FUNCTIONAL PROPERTIES. INTRIGUINGLY, INCREASINGLY COMPLEX MUTATIONAL TRAJECTORIES ARE FREQUENTLY ACCOMPANIED BY CLINICAL PROGRESSION DURING THE COURSE OF DISEASE. THESE DATA SUBSTANTIATE A NEED FOR REGULAR BROAD MOLECULAR MONITORING TO GUIDE CLINICAL TREATMENT DECISIONS IN MDS. 2016 20 1078 32 CLONAL NON-MALIGNANT HEMATOLOGICAL DISORDERS: UNRAVELING MOLECULAR PATHOGENIC MECHANISMS TO DEVELOP NOVEL TARGETED THERAPEUTICS. CLONAL NON-MALIGNANT HEMATOLOGICAL DISORDERS ARE A HETEROGENEOUS GROUP OF DISEASES THAT ARE PARTICULARLY CHALLENGING FOR HEMATOLOGISTS. INDEED, MOST OBVIOUS AND FREQUENT HEMATOLOGICAL DISEASES INCLUDE A BROAD SPECTRUM OF MALIGNANCIES, SUCH AS LEUKEMIAS, LYMPHOMAS, MYELOMA, AND OTHER MYELOPROLIFERATIVE OR LYMPHOPROLIFERATIVE DISORDERS. IN RECENT YEARS, ALL THESE DISEASES HAVE BEEN CATEGORIZED BY THE WHO ACCORDING TO A NOVEL CLASSIFICATION OF MYELOID AND LYMPHOID MALIGNANCIES, WHICH TAKES IN ACCOUNT THE OUTSTANDING PROGRESS IN OUR UNDERSTANDING OF MOLECULAR DEFECTS UNDERLYING HEMATOLOGICAL MALIGNANCIES. REGARDLESS OF A NUMBER OF NOVEL TECHNOLOGIES, HEMATOLOGISTS CONTINUE TO DEAL DAILY WITH CONDITIONS WHERE A CLEAR DIAGNOSIS OF A MALIGNANCY IS MISSING: THIS IS THE CASE OF SEVERAL CLONAL HEMATOLOGICAL DISORDERS, WHICH ARE CONSIDERED BONA FIDE NON-MALIGNANT. SOME MYELODYSPLASTIC SYNDROMES, CHRONIC T AND NK DISORDERS OF GRANULAR LYMPHOCYTES, MYELOFIBROSIS, MONOCLONAL GAMMOPATHIES, MONOCLONAL B-CEL LYMPHOCYTOSIS, MASTOCYTOSIS AND PAROXYSMAL NOCTURNAL HEMOGLOBINURIA ARE PARADIGMATIC EXAMPLES OF HOW CLONAL DISORDERS ARE CLEARLY DIFFERENT FROM CANCERS, EVEN IF THEY MAY SHARE WITH HEMATOLOGICAL MALIGNANCIES SIMILAR MOLECULAR, GENETIC, EPIGENETIC AND IMMUNOLOGICAL PROCESSES. INDEED, IT IS NOT ENTIRELY CLEAR WHETHER IN INDIVIDUAL CONDITIONS SUCH PATHOGENIC MECHANISMS MAY REPRESENT INITIAL STEP(S) OF MALIGNANT TRANSFORMATION, MAKING A BRIDGE BETWEEN THESE CLONAL NON-MALIGNANT DISORDERS AND TYPICAL HEMATOLOGICAL CANCERS. SOME OF THESE NON-MALIGNANT DISORDERS IMPLY SPECIFIC PATHOGENIC MECHANISMS AND/OR CLINICAL COURSE, AND SO THEY HAVE BEEN DEFINITELY ESTABLISHED WITH THEIR OWN BIOLOGICAL AND CLINICAL IDENTITY. HOWEVER, THE OBVIOUS QUESTION WHETHER SOME OF THESE CLONAL NON-MALIGNANT HEMATOLOGICAL DISEASES FORM SOME A KIND OF DISEASE-CONTINUUM WITH THEIR CORRESPONDING MALIGNANT COUNTERPART IS STILL TO BE ANSWERED. 2014