1 6847 186 [MOLECULAR DIAGNOSIS OF CHRONIC MYELOPROLIFERATIVE DISEASES AND MYELODYSPLASTIC SYNDROMES]. HISTOMORPHOLOGICAL EVALUATION OF BONE MARROW TREPHINES AND SMEARS REPRESENTS THE MAJOR APPROACH TO DIAGNOSE THE CHRONIC MYELOPROLIFERATIVE DISEASES (CMPD) AND THE MYELODYSPLASTIC SYNDROMES (MDS). HOWEVER, RISING INSIGHTS INTO MOLECULAR PATHOGENESIS OF HUMAN DISEASES STRENGTHEN THE ATTEMPT OF PATHOLOGISTS TO DEFINE AND TO DETECT UNDERLYING DEFECTS BEYOND THE MICROSCOPE. SINCE DISCOVERY OF THE PHILADELPHIA CHROMOSOME IN CHRONIC MYELOID LEUKEMIA AS THE FIRST SPECIFIC MOLECULAR ABNORMALITY EVER DETECTED IN A HUMAN NEOPLASIA THE GAIN OF KNOWLEDGE OF MOLECULAR PATHOMECHANISMS IN PHILADELPHIA CHROMOSOME NEGATIVE (PH-) CMPD WAS RATHER SPARSE. A DECISIVE BREAKTHROUGH IN PH CMPD WAS THE FINDING OF JAK2 (V617F) DERIVED FROM A SOMATIC POINT MUTATION IN THE MAJORITY OF PATIENTS WITH POLYCYTHEMIA VERA (P.VERA) AND HALF OF PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF). IT THEREFORE CAN NOT BE OVERESTIMATED THAT DETECTION OF JAK2 (V617F) IN A SUSPECTIVE MYELOPROLIFERATION NOW ENABLES A CLEARCUT DISCRIMINATION OF A TRUE PH CMPD FROM A REACTIVE STATE, E.G. P.VERA FROM REACTIVE ERYTHROCYTOSIS. INTERESTINGLY, A BASIC PRINCIPLE OF MOLECULAR DEFECTS DEMONSTRABLE IN CMPD AND RELATED DISORDERS SEEMS TO BE THE INVOLVEMENT OF GENES WITH KINASE ACTIVITIES. SOME OF THOSE GENES WILL BE DISCUSSED IN MORE DETAIL. IN PRIMARY MDS, KARYOTYPING VIA CLASSICAL CYTOGENETICS IS THE PREDOMINANT MOLECULAR APPROACH TO ESTIMATE PROGNOSIS, E.G. -Y, DEL(5Q) AND DEL(20Q) REPRESENT FAVOURABLE ANOMALIES. INDEED, IN 5Q- SYNDROMES KARYOTYPING ENABLES DEFINITE SUBTYPING AND ALLOWS CLINICIANS AND PATIENTS TO EXPECT A GOOD PROGNOSIS. UNTIL NOW, DOZENS OF MOLECULAR ABNORMALITIES SUCH AS MUTATIONS IN AML1, FLT3 AND RAS AS WELL AS EPIGENETIC ALTERATIONS OF GENES HAVE BEEN IDENTIFIED TO VARIOUS DEGREES IN MDS SUBTYPES. SOME OF THEM SEEM TO BE INVOLVED IN DISEASE INITIATION ("MASTER EVENT") AND OTHERS MIGHT INDICATE DISEASE PROGRESSION. HOWEVER, EVEN THOUGH USEFUL FOR FURTHER DISSECTION OF MOLECULAR PATHOMECHANISMS THE MAJORITY OF ABERRATIONS CURRENTLY DOES NOT SERVE AS POTENT MARKERS IN THE DAILY ROUTINE. NEVERTHELESS, IN CMPD AND MDS THE IMPORTANCE OF MOLECULAR ANALYSES FOR DIAGNOSIS, ESTIMATION OF PROGNOSIS, AND DISEASE MONITORING WILL FURTHER INCREASE IN A FORESEEABLE PERIOD OF TIME. 2007 2 3565 39 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 3 6852 39 [MYELOPROLIFERATIVE NEOPLASMS: UPDATES ON MOLECULAR PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT STRATEGIES]. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CHRONIC HEMATOPOIETIC STEM CELL DISORDERS, INCLUDING POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTOSIS, AND PRIMARY MYELOFIBROSIS. THE JAK2V617F MUTATION WAS IDENTIFIED IN 2005, FOLLOWED BY THE DISCOVERY OF THE JAK2 EXON12, MPNW515 MUTATION, AND CALR MUTATION. ABOUT 90% OF PATIENTS WITH BCR/ABL NEGATIVE MPNS HAVE BEEN SHOWN TO HAVE ONE OF THESE DRIVER MUTATIONS. IN ADDITION, MUTATIONS IN EPIGENETIC REGULATORS AND RNA SPLICING GENES WERE FOUND TO CO-EXIST WITH DRIVER MUTATIONS AND TO PLAY CRITICAL ROLES IN THE DISEASE PROGRESSION OF MPNS. CURRENTLY, EVALUATIONS OF THESE GENE MUTATIONS ARE ESSENTIAL FOR THE DIAGNOSIS OF MPNS, AND ARE ALSO NECESSARY FOR ESTIMATING THE CLINICAL COURSE AND THE RISK OF DISEASE PROGRESSION. GUIDELINES FOR THE MANAGEMENT OF MPNS WERE BASED ON THE RESULTS OF LARGE CLINICAL TRIALS. FURTHERMORE, RECENT ADVANCEMENTS IN UNDERSTANDING THE PATHOGENESIS OF MPNS ARE ANTICIPATED TO PROMOTE THE DEVELOPMENT OF MPN-TARGETED THERAPIES SUCH AS JAK2 INHIBITORS. CLINICAL TRIALS FOR PATIENTS WITH PMF AND PV HAVE CONFIRMED THE EFFICACIES OF JAK2 INHIBITORS. 2016 4 1043 43 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 5 2981 26 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 6 4681 23 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 7 255 39 ADVANCES IN MYELOFIBROSIS: A CLINICAL CASE APPROACH. PRIMARY MYELOFIBROSIS IS A MEMBER OF THE MYELOPROLIFERATIVE NEOPLASMS, A DIVERSE GROUP OF BONE MARROW MALIGNANCIES. SYMPTOMS OF MYELOFIBROSIS, PARTICULARLY THOSE ASSOCIATED WITH SPLENOMEGALY (ABDOMINAL DISTENTION AND PAIN, EARLY SATIETY, DYSPNEA, AND DIARRHEA) AND CONSTITUTIONAL SYMPTOMS, REPRESENT A SUBSTANTIAL BURDEN TO PATIENTS. MOST PATIENTS EVENTUALLY DIE FROM THE DISEASE, WITH A MEDIAN SURVIVAL RANGING FROM APPROXIMATELY 5-7 YEARS. MUTATIONS IN JANUS KINASE 2 (JAK2), A KINASE THAT IS ESSENTIAL FOR THE NORMAL DEVELOPMENT OF ERYTHROCYTES, GRANULOCYTES, AND PLATELETS, NOTABLY THE V617F MUTATION, HAVE BEEN IDENTIFIED IN APPROXIMATELY 50% OF PATIENTS WITH MYELOFIBROSIS. THE APPROVAL OF A JAK2 INHIBITOR IN 2011 HAS IMPROVED THE OUTLOOK OF MANY PATIENTS WITH MYELOFIBROSIS AND HAS CHANGED THE TREATMENT LANDSCAPE. THIS ARTICLE FOCUSES ON SOME OF THE IMPORTANT ISSUES IN CURRENT MYELOFIBROSIS TREATMENT MANAGEMENT, INCLUDING DIFFERENTIATION OF MYELOFIBROSIS FROM ESSENTIAL THROMBOCYTHEMIA AND POLYCYTHEMIA VERA, UP-DATED DATA ON THE RESULTS OF JAK2 INHIBITOR THERAPY, THE ROLE OF EPIGENETIC MECHANISMS IN MYELOFIBROSIS PATHOGENESIS, INVESTIGATIONAL THERAPIES FOR MYELOFIBROSIS, AND ADVANCES IN HEMATOPOIETIC STEM CELL TRANSPLANT. THREE MYELOFIBROSIS CASES ARE INCLUDED TO UNDERSCORE THE ISSUES IN DIAGNOSING AND TREATING THIS COMPLEX DISEASE. 2013 8 358 37 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 9 3575 44 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 10 6618 36 UNDERSTANDING AND MONITORING CHRONIC MYELOID LEUKEMIA BLAST CRISIS: HOW TO BETTER MANAGE PATIENTS. CHRONIC MYELOID LEUKEMIA (CML) IS TRIGGERED PRIMARILY BY THE T(9;22) (Q34.13; Q11.23) TRANSLOCATION. THIS RECIPROCAL CHROMOSOMAL TRANSLOCATION LEADS TO THE FORMATION OF THE BCR-ABL FUSION GENE. PATIENTS IN THE CHRONIC PHASE (CP) EXPERIENCE A GOOD CURATIVE EFFECT WITH TYROSINE KINASE INHIBITORS. HOWEVER, CASES ARE TREATMENT REFRACTORY, WITH A DISMAL PROGNOSIS, WHEN THE DISEASE HAS PROGRESSED TO THE ACCELERATED PHASE (AP) OR BLAST PHASE (BP). UNTIL NOW, FEW REPORTS HAVE PROVIDED A COMPREHENSIVE DESCRIPTION OF THE MECHANISMS INVOLVED AT DIFFERENT MOLECULAR LEVELS. INDEED, THE UNDERLYING PATHOGENESIS OF CML EVOLUTION COMPRISES GENETIC ABERRATIONS, CHROMOSOMAL TRANSLOCATIONS (EXCEPT FOR THE PHILADELPHIA CHROMOSOME), TELOMERE BIOLOGY, AND EPIGENETIC ANOMALIES. HEREIN, WE PROVIDE KNOWLEDGE OF THE BIOLOGY RESPONSIBLE FOR BLAST TRANSFORMATION OF CML AT SEVERAL LEVELS, SUCH AS GENETICS, TELOMERE BIOLOGY, AND EPIGENETIC ANOMALIES. BECAUSE OF THE LIMITED TREATMENT OPTIONS AVAILABLE AND POOR OUTCOMES, ONLY THE THERAPEUTIC RESPONSE IS MONITORED REGULARLY, WHICH INVOLVES BCR-ABL TRANSCRIPT LEVEL ASSESSMENT AND IMMUNOLOGIC SURVEILLANCE, WITH THE OPTIMAL TREATMENT STRATEGY FOR PATIENTS IN CP ADAPTED TO EVALUATE DISEASE RECURRENCE OR PROGRESSION. OVERALL, SELECTING OPTIMAL TREATMENT ENDPOINTS TO PREDICT SURVIVAL AND SUCCESSFUL TFR IMPROVES THE QUALITY OF LIFE OF PATIENTS. THUS, IDENTIFYING RISK FACTORS AND DEVELOPING RISK-ADAPTED THERAPEUTIC OPTIONS MAY CONTRIBUTE TO A BETTER OUTCOME FOR ADVANCED-PHASE PATIENTS. 2021 11 3747 45 INSIGHTS INTO THE MOLECULAR GENETICS OF MYELOPROLIFERATIVE NEOPLASMS. THE MOLECULAR BIOLOGY OF THE BCR-ABL1-NEGATIVE CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPNS) HAS WITNESSED UNPRECEDENTED ADVANCES SINCE THE DISCOVERY OF THE ACQUIRED JAK2 V617F MUTATION IN 2005. DESPITE THE HIGH PREVALENCE OF JAK2 V617F IN POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET), AND PRIMARY MYELOFIBROSIS (PMF), AND THE COMMON FINDING OF DYSREGULATED JAK-STAT SIGNALING IN THESE DISORDERS, IT IS NOW APPRECIATED THAT MPN PATHOGENESIS CAN REFLECT THE ACQUISITION OF MULTIPLE GENETIC MUTATIONS THAT ALTER SEVERAL BIOLOGIC PATHWAYS, INCLUDING EPIGENETIC CONTROL OF GENE EXPRESSION. ALTHOUGH CERTAIN GENE MUTATIONS ARE IDENTIFIED AT HIGHER FREQUENCIES WITH DISEASE EVOLUTION TO THE BLAST PHASE, MPN INITIATION AND PROGRESSION ARE NOT EXPLAINED BY A SINGLE, TEMPORAL PATTERN OF CLONAL CHANGES. A COMPLEX INTERPLAY BETWEEN ACQUIRED MOLECULAR ABNORMALITIES AND HOST GENETIC BACKGROUND, IN ADDITION TO THE TYPE AND ALLELIC BURDEN OF MUTATIONS, CONTRIBUTES TO THE PHENOTYPIC HETEROGENEITY OF MPNS. AT THE POPULATION LEVEL, AN INHERITED PREDISPOSITION TO DEVELOPING MPNS IS LINKED TO A RELATIVELY COMMON JAK2-ASSOCIATED HAPLOTYPE (REFERRED TO AS '46/1'), BUT IT EXHIBITS A RELATIVELY LOW PENETRANCE. THIS REVIEW DETAILS THE CURRENT STATE OF KNOWLEDGE OF THE MOLECULAR GENETICS OF THE CLASSIC MPNS PV, ET, AND PMF AND DISCUSSES THE CLINICAL IMPLICATIONS OF THESE FINDINGS. 2012 12 1076 28 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 13 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 14 4566 28 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 1164 26 CONTRIBUTION OF CHRONIC MYELOID LEUKAEMIA (CML) AS A DISEASE MODEL TO DEFINE AND STUDY CLONAL HETEROGENEITY. ALTHOUGH TUMOUR CELL INTRA-CLONAL HETEROGENEITY HAS BEEN KNOWN FOR MANY YEARS, ITS APPLICATION IN THE ONCOLOGY CLINICAL PRACTICE (PATIENT MANAGEMENT, PROGNOSIS, ETC.) REMAINS LIMITED. FOR THIS, CHRONIC MYELOID LEUKAEMIA (CML) IS A REMARKABLE MODEL. BASIC RESEARCH STUDIES REVEALED THE HETEROGENEITY OF THE INITIAL CLONE, AND LED TO THE HYPOTHESIS OF THE EXISTENCE OF LEUKEMIC STEM CELLS. NEVERTHELESS, THE INDISPUTABLE EVIDENCE OF THE INTRA-CLONAL HETEROGENEITY ROLE IN THE THERAPEUTIC RESPONSE CAME FROM THE OUTCOMES OF THE TREATMENT WITH TYROSINE KINASE INHIBITORS (THE FIRST TARGETED THERAPY IN MEDICINE) COMBINED WITH THE EARLY AND RIGOROUS CLINICAL AND MOLECULAR MONITORING OF THESE PATIENTS. CML MANAGEMENT ALREADY TAKES THIS HETEROGENEITY INTO ACCOUNT FOR PERSONALIZED PATIENT FOLLOW-UP. THE ADVENTURE CONTINUES WITH THE OBJECTIVES OF BETTER TAILORING THE TREATMENT AND OF CURING THE DISEASE IN MOST OF THE PATIENTS. 2019 16 2652 28 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 17 732 29 CANCER DRUG RESISTANCE: THE CENTRAL ROLE OF THE KARYOTYPE. CURRENT GENETIC AND EPIGENETIC THEORIES OF CANCER-SPECIFIC DRUG RESISTANCE DO NOT ADEQUATELY EXPLAIN: (I) THE KARYOTYPIC CHANGES THAT COINCIDE WITH RESISTANCE, (II) THE HIGH RATES AT WHICH CANCER CELLS ACQUIRE AND ENHANCE RESISTANCE COMPARED TO THE RATES OF CONVENTIONAL MUTATION, (III) THE WIDE RANGES OF RESISTANCE SUCH AS MULTIDRUG RESISTANCE, (IV) THE FREQUENT OCCURRENCE OF INTRINSIC DRUG RESISTANCE. WE HAVE RECENTLY PROPOSED, THAT SPECIFIC KARYOTYPIC ALTERATIONS ARE SUFFICIENT FOR DRUG RESISTANCE VIA NEW TRANSCRIPTOMES OF COOPERATIVE GENES, INDEPENDENT OF GENE MUTATION. THIS MECHANISM GENERATES NEW PHENOTYPES JUST LIKE TRISOMY 21 GENERATES DOWN SYNDROME. THESE KARYOTYPIC CHANGES ARE GENERATED BY CANCER-SPECIFIC ANEUPLOIDY AUTOCATALYTICALLY, BECAUSE ANEUPLOIDY DESTABILIZES THE KARYOTYPE BY MISBALANCING TEAMS OF PROTEINS THAT SYNTHESIZE, REPAIR AND SEGREGATE CHROMOSOMES. EVIDENCE FOR THIS CHROMOSOMAL MECHANISM IS AS FOLLOWS: (I) RESISTANCE IS PROPORTIONAL TO THE NUMBER OF CLONAL CHROMOSOMAL ALTERATIONS COMPARED TO DRUG-SENSITIVE PRECURSORS. (II) THE HIGH RATES AT WHICH CANCER CELLS ACQUIRE DRUG RESISTANCE ARE COMPARABLE WITH THE RATES, AS HIGH AS 10(-2) PER CELL GENERATION, AT WHICH THEIR KARYOTYPES CHANGE-DIMMING HOPES FOR GENE-SPECIFIC THERAPIES. (III) MULTIDRUG RESISTANCE PROBABLY REFLECTS UN-SELECTED TRANSCRIPTOMES OF KARYOTYPES SELECTED FOR RESISTANCE AGAINST SPECIFIC DRUGS. (IV) INTRINSIC DRUG RESISTANCE PROBABLY REFLECTS UNSELECTED TRANSCRIPTOMES OF KARYOTYPES SELECTED FOR ONCOGENICITY. WE ALSO ADDUCE EVIDENCE THAT RESISTANCE OF CHRONIC MYELOID LEUKEMIA AGAINST THE DRUG IMATINIB IS CHROMOSOMAL, ALTHOUGH IT IS WIDELY BELIEVED TO BE DUE TO MUTATION OF A KINASE. 2007 18 2548 31 EPIGENETICS IN MYELOPROLIFERATIVE NEOPLASMS. THE MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE A GROUP OF ACQUIRED CLONAL DISORDERS WHERE MUTATIONS DRIVE PROLIFERATIVE DISEASE RESULTING IN INCREASED BLOOD COUNTS AND IN SOME CASES END-STAGE MYELOFIBROSIS. EPIGENETIC CHANGES ARE THE REVERSIBLE MODIFICATIONS TO DNA- AND RNA-ASSOCIATED PROTEINS THAT IMPACT GENE ACTIVITY WITHOUT CHANGING THE DNA SEQUENCE. THIS REVIEW SUMMARIZES MECHANISMS OF EPIGENETIC CHANGES AND THE NUCLEOSOME. THE DRIVERS AND EPIGENETIC REGULATORS IN MPNS ARE OUTLINED. IN MPNS, DISTINCT PATTERNS OF EPIGENETIC DYSREGULATION HAVE BEEN SEEN IN CHRONIC AND IN ADVANCED PHASES. METHYLATION AGE AND HISTONE MODIFICATION ARE ALTERED IN MPNS AND BY FURTHER TREATMENT. THE ALTERATIONS FOUND IN METHYLATION AGE IN MPNS AND WITH TREATMENT ARE DISCUSSED, AND THE CHANGES IN HISTONE MODIFICATION WITH JANUS KINASE (JAK) INHIBITION ARE EVALUATED. CURRENTLY AVAILABLE THERAPEUTIC AREAS WHERE THE EPIGENOME CAN BE ALTERED ARE OUTLINED. THUS, WE REVIEW THE CURRENT KNOWLEDGE AND UNDERSTANDING OF EPIGENETICS IN MPN AND CONSIDER FURTHER MANAGEMENT OPTIONS. UNDERSTANDING THE EPIGENOME AND ITS ALTERATION IN MPNS AND EPIGENETIC CHANGES ASSOCIATED WITH THE PROGRESSION OF DISEASE WILL LEAD TO ADVANCES IN THERAPEUTIC OPTIONS. 2023 19 2547 29 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 20 963 23 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