1 5953 122 TARGETS IN MPNS AND POTENTIAL THERAPEUTICS. PHILADELPHIA-NEGATIVE CLASSICAL MYELOPROLIFERATIVE NEOPLASMS (MPNS), INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF), ARE CLONAL HEMOPATHIES THAT EMERGE IN THE HEMATOPOIETIC STEM CELL (HSC) COMPARTMENT. MPN DRIVER MUTATIONS ARE RESTRICTED TO SPECIFIC EXONS (14 AND 12) OF JANUS KINASE 2 (JAK2), THROMBOPOIETIN RECEPTOR (MPL/TPOR) AND CALRETICULIN (CALR) GENES, ARE INVOLVED DIRECTLY IN CLONAL MYELOPROLIFERATION AND GENERATE THE MPN PHENOTYPE. AS A RESULT, AN INCREASED NUMBER OF FULLY FUNCTIONAL ERYTHROCYTES, PLATELETS AND LEUKOCYTES IS OBSERVED IN THE PERIPHERAL BLOOD. NEVERTHELESS, THE COMPLEXITY AND HETEROGENEITY OF MPN CLINICAL PHENOTYPES CANNOT BE SOLELY EXPLAINED BY THE TYPE OF DRIVER MUTATION. OTHER FACTORS, SUCH AS ADDITIONAL SOMATIC MUTATIONS AFFECTING EPIGENETIC REGULATORS OR SPLICEOSOMES COMPONENTS, MUTANT ALLELE BURDENS AND MODIFIERS OF SIGNALING BY DRIVER MUTANTS, CLONAL ARCHITECTURE AND THE ORDER OF MUTATION ACQUISITION, SIGNALING EVENTS THAT OCCUR DOWNSTREAM OF A DRIVER MUTATION, THE PRESENCE OF SPECIFIC GERM-LINE VARIANTS, THE INTERACTION OF THE NEOPLASTIC CLONE WITH BONE MARROW MICROENVIRONMENT AND CHRONIC INFLAMMATION, ALL CAN MODULATE THE DISEASE PHENOTYPE, INFLUENCE THE MPN CLINICAL COURSE AND THEREFORE, MIGHT BE USEFUL THERAPEUTIC TARGETS. 2022 2 6856 46 [NOT AVAILABLE]. BIOLOGICAL ASPECTS OF JAK/STAT SIGNALING IN BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: MYELOPROLIFERATIVE DISORDERS MORE RECENTLY NAMED MYELOPROLIFERATIVE NEOPLASMS (MPN) DISPLAY SEVERAL CLINICAL ENTITIES: CHRONIC MYELOID LEUKEMIA (CML), THE CLASSICAL MPN INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET), PRIMARY MYELOFIBROSIS (PMF) AND ATYPICAL AND UNCLASSIFIABLE NMP. THE TERM MPN IS MOSTLY USED FOR CLASSICAL BCR-ABL-NEGATIVE (MYELOPROLIFERATIVE DISORDER) (ET, PV, PMF). THESE ARE CLONAL DISEASES RESULTING FROM THE TRANSFORMATION OF AN HEMATOPOIETIC STEM CELL AND LEADING TO AN ABNORMAL PRODUCTION OF MYELOID CELLS. THE GENETIC DEFECTS RESPONSIBLE FOR THE MYELOPROLIFERATIVE ABNORMALITIES ARE CALLED << DRIVER >> MUTATIONS AND ALL RESULT IN DEREGULATION OF THE CYTOKINE RECEPTOR / JAK2 / STAT AXIS. AMONG THEM, JAK2, THE THROMBOPOIETIN RECEPTOR (MPL) AND CALRETICULIN (CALR) MUTATIONS ARE FOUND IN AROUND 90% OF THE CASES. THESE DRIVER MPN MUTATIONS CAN BE ASSOCIATED WITH OTHER DRIVER MUTATIONS ALSO FOUND IN OTHER HEMATOLOGICAL MALIGNANCIES, ESPECIALLY IN PMFS. THESE ARE CHRONIC DISEASES WITH MAJOR RISKS BEING THROMBOSIS, HEMORRHAGE AND CYTOPENIAS FOR PMF AND THE LONG-TERM PROGRESSION TO MYELOFIBROSIS AND THE TRANSFORMATION TO LEUKEMIA. MOST RECENT THERAPEUTIC HAVE FOCUSED ON TARGETING THE JAK2 SIGNALING PATHWAY DIRECTLY BY INHIBITORS OF JAK2 OR INDIRECTLY. INTERFERON A ALLOWS IN SOME CASES HEMATOLOGIC AND MOLECULAR REMISSION PATIENTS. 2016 3 6852 38 [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 4680 48 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 5 3747 42 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 6 255 35 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 7 3111 34 GENOTYPE-PHENOTYPE INTERACTIONS IN THE MYELOPROLIFERATIVE NEOPLASMS. THE CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL DISORDERS CHARACTERIZED BY OVERPRODUCTION OF MATURE MYELOID CELLS. THEY SHARE ASSOCIATIONS WITH MOLECULAR ABNORMALITIES SUCH AS THE JAK2V617F MUTATION BUT ARE DISTINGUISHED BY IMPORTANT PHENOTYPIC DIFFERENCES. THIS REVIEW FIRST CONSIDERS THE FACTORS THAT MAY INFLUENCE PHENOTYPE IN JAK2-MUTATED MPNS, ESPECIALLY POLYCYTHEMIA VERA (PV) AND ESSENTIAL THROMBOCYTHEMIA (ET), AND THEN DISCUSSES THE MUTATIONS IMPLICATED IN JAK2-NEGATIVE MPNS SUCH AS IN MPL AND EPIGENETIC REGULATORS. CURRENT EVIDENCE SUPPORTS A MODEL WHERE ET AND PV ARE DISORDERS OF RELATIVELY LOW GENETIC COMPLEXITY, WHEREAS EVOLUTION TO MYELOFIBROSIS OR BLAST-PHASE DISEASE REFLECTS ACCUMULATION OF A HIGHER MUTATION BURDEN. 2012 8 1947 42 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 9 1043 48 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 10 1076 35 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 11 4322 46 MICRORNAS IN MYELOPROLIFERATIVE NEOPLASMS. THE CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPN), INCLUDING POLYCYTHAEMIA VERA (PV), ESSENTIAL THROMBOCYTHAEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF), ARE CLONAL STEM CELL DISORDERS CHARACTERIZED BY DYSREGULATED HAEMATOPOIETIC STEM CELL EXPANSION AND PRODUCTION OF RED CELLS, WHITE CELLS AND PLATELETS ALONE OR IN COMBINATION. AN ACQUIRED MUTATION JAK2(V617F) CAN BE FOUND IN ALL THREE DISORDERS AND SHOWS MANY OF THE PHENOTYPIC ABNORMALITIES OF THE DISEASES IN MURINE MODELS. THE DISEASE PHENOTYPE IS ALSO INFLUENCED BY OTHER UNKNOWN GENETIC OR EPIGENETIC FACTORS. MICRORNAS (MIRNA) ARE 18-24 NUCLEOTIDE SINGLE-STRANDED NON-PROTEIN-CODING RNAS THAT FUNCTION PRIMARILY AS GENE REPRESSORS BY BINDING TO THEIR TARGET MESSENGER RNAS. THERE IS GROWING EVIDENCE THAT MIRNAS REGULATE HAEMATOPOIESIS IN BOTH HAEMATOPOIETIC STEM CELLS AND COMMITTED PROGENITOR CELLS. HERE, WE REVIEW THE FIELD OF MIRNA BIOLOGY AND ITS REGULATORY ROLES IN NORMAL HAEMATOPOIESIS WITH AN EMPHASIS ON MIRNA DEREGULATIONS IN MPNS. CONTINUED RESEARCH INTO HOW MIRNAS IMPACT JAK2(V617F) CLONAL EXPANSION, DIFFERENTIAL HAEMATOPOIESIS AMONG DIFFERENT MPNS, DISEASE PROGRESSION AND LEUKAEMIA TRANSFORMATION WILL LEAD TO A BETTER UNDERSTANDING OF THE DEVELOPMENT OF THESE DISORDERS, THEIR CLINICAL MANIFESTATIONS, AND THEIR TREATMENT. 2013 12 4959 30 PATHOGENESIS OF MYELOPROLIFERATIVE DISORDERS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE A SET OF CHRONIC HEMATOPOIETIC NEOPLASMS WITH OVERLAPPING CLINICAL AND MOLECULAR FEATURES. RECENT YEARS HAVE WITNESSED CONSIDERABLE ADVANCES IN OUR UNDERSTANDING OF THEIR PATHOGENETIC BASIS. DUE TO THEIR PROTRACTED CLINICAL COURSE, THE EVOLUTION TO ADVANCED HEMATOLOGICAL MALIGNANCIES, AND THE ACCESSIBILITY OF NEOPLASTIC TISSUE, THE STUDY OF MPNS HAS PROVIDED A WINDOW INTO THE EARLIEST STAGES OF TUMORIGENESIS. WITH THE DISCOVERY OF MUTATIONS IN CALR, THE MAJORITY OF MPN PATIENTS NOW BEAR AN IDENTIFIABLE MARKER OF CLONAL DISEASE; HOWEVER, THE MECHANISM BY WHICH MUTATED CALR PERTURBS MEGAKARYOPOIESIS IS CURRENTLY UNRESOLVED. WE ARE BEGINNING TO UNDERSTAND BETTER THE ROLE OF JAK2(V617F) HOMOZYGOSITY, THE FUNCTION OF COMUTATIONS IN EPIGENETIC REGULATORS AND SPLICEOSOME COMPONENTS, AND HOW THESE MUTATIONS COOPERATE WITH JAK2(V617F) TO MODULATE MPN PHENOTYPE. 2016 13 5257 48 PROGRESSION OF MYELOPROLIFERATIVE NEOPLASMS (MPN): DIAGNOSTIC AND THERAPEUTIC PERSPECTIVES. CLASSICAL BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS (MPN) ARE A HETEROGENEOUS GROUP OF HEMATOLOGIC MALIGNANCIES, INCLUDING ESSENTIAL THROMBOCYTHEMIA (ET), POLYCYTHEMIA VERA (PV), AND PRIMARY MYELOFIBROSIS (PMF), AS WELL AS POST-PV-MF AND POST-ET-MF. PROGRESSION TO MORE SYMPTOMATIC DISEASE, SUCH AS OVERT MF OR ACUTE LEUKEMIA, REPRESENTS ONE OF THE MAJOR CAUSES OF MORBIDITY AND MORTALITY. THERE ARE CLINICALLY EVIDENT BUT ALSO SUBCLINICAL TYPES OF MPN PROGRESSION. CLINICALLY EVIDENT PROGRESSION INCLUDES EVOLUTION FROM ET TO PV, ET TO POST-ET-MF, PV TO POST-PV-MF, OR PRE-PMF TO OVERT PMF, AND TRANSFORMATION OF ANY OF THESE SUBTYPES TO MYELODYSPLASTIC NEOPLASMS OR ACUTE LEUKEMIA. THROMBOSIS, MAJOR HEMORRHAGE, SEVERE INFECTIONS, OR INCREASING SYMPTOM BURDEN (E.G., PRURITUS, NIGHT SWEATS) MAY HERALD PROGRESSION. SUBCLINICAL TYPES OF PROGRESSION MAY INCLUDE INCREASES IN THE EXTENT OF BONE MARROW FIBROSIS, INCREASES OF DRIVER GENE MUTATIONAL ALLELE BURDEN, AND CLONAL EVOLUTION. THE UNDERLYING CAUSES OF MPN PROGRESSION ARE DIVERSE AND CAN BE ATTRIBUTED TO GENETIC ALTERATIONS AND CHRONIC INFLAMMATION. PARTICULARLY, BYSTANDER MUTATIONS IN GENES ENCODING EPIGENETIC REGULATORS OR SPLICING FACTORS WERE ASSOCIATED WITH PROGRESSION. FINALLY, COMORBIDITIES SUCH AS SYSTEMIC INFLAMMATION, CARDIOVASCULAR DISEASES, AND ORGAN FIBROSIS MAY AUGMENT THE RISK OF PROGRESSION. THE AIM OF THIS REVIEW WAS TO DISCUSS TYPES AND MECHANISMS OF MPN PROGRESSION AND HOW THEIR KNOWLEDGE MIGHT IMPROVE RISK STRATIFICATION AND THERAPEUTIC INTERVENTION. IN VIEW OF THESE ASPECTS, WE DISCUSS THE POTENTIAL BENEFITS OF EARLY DIAGNOSIS USING MOLECULAR AND FUNCTIONAL IMAGING AND EXPLOITABLE THERAPEUTIC STRATEGIES THAT MAY PREVENT PROGRESSION, BUT ALSO HIGHLIGHT CURRENT CHALLENGES AND METHODOLOGICAL PITFALLS. 2021 14 4566 33 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 5782 21 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 16 924 39 CHRONIC INFLAMMATION AS A PROMOTOR OF MUTAGENESIS IN ESSENTIAL THROMBOCYTHEMIA, POLYCYTHEMIA VERA AND MYELOFIBROSIS. A HUMAN INFLAMMATION MODEL FOR CANCER DEVELOPMENT? THE PHILADELPHIA-NEGATIVE CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE ACQUIRED STEM CELL NEOPLASMS, IN WHICH A STEM CELL LESION INDUCES AN AUTONOMOUS PROLIFERATIVE ADVANTAGE. IN ADDITION TO THE JAK2V617 MUTATION SEVERAL OTHER MUTATIONS HAVE BEEN DESCRIBED. RECENTLY CHRONIC INFLAMMATION HAS BEEN PROPOSED AS A TRIGGER AND DRIVER OF CLONAL EVOLUTION IN MPNS. HEREIN, IT IS HYPOTHESIZED THAT SUSTAINED INFLAMMATION MAY ELICIT THE STEM CELL INSULT BY INDUCING A STATE OF CHRONIC OXIDATIVE STRESS WITH ELEVATED LEVELS OF REACTIVE OXYGEN SPECIES (ROS) IN THE BONE MARROW, THEREBY CREATING A HIGH-RISK MICROENVIRONMENT FOR INDUCTION OF MUTATIONS DUE TO THE PERSISTENT INFLAMMATION-INDUCED OXIDATIVE DAMAGE TO DNA IN HEMATOPOIETIC CELLS. ALTERATIONS IN THE EPIGENOME INDUCED BY THE CHRONIC INFLAMMATORY DRIVE MAY LIKELY ELICIT A "EPIGENETIC SWITCH" PROMOTING PERSISTENT INFLAMMATION. THE PERSPECTIVES OF CHRONIC INFLAMMATION AS THE DRIVER OF MUTAGENESIS IN MPNS ARE DISCUSSED, INCLUDING EARLY INTERVENTION WITH INTERFERON-ALPHA2 AND POTENT ANTI-INFLAMMATORY AGENTS (E.G. JAK1-2 INHIBITORS, HISTONE DEACETYLASE INHIBITORS, DNA-HYPOMETHYLATORS AND STATINS) TO DISRUPT THE SELF-PERPETUATING CHRONIC INFLAMMATION STATE AND ACCORDINGLY ELIMINATING A POTENTIAL TRIGGER OF CLONAL EVOLUTION AND DISEASE PROGRESSION WITH MYELOFIBROTIC AND LEUKEMIC TRANSFORMATION. 2013 17 3575 48 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 18 2277 31 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 19 957 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 20 4554 38 MUTATIONAL PROFILING IN MYELOFIBROSIS: IMPLICATIONS FOR MANAGEMENT. MUTATIONAL PROFILING, USUALLY BY TARGETED NEXT-GENERATION SEQUENCING, IS INCREASINGLY PERFORMED ON PATIENTS WITH MYELOPROLIFERATIVE NEOPLASM-ASSOCIATED MYELOFIBROSIS (MF), WHETHER PRIMARY (PMF) OR POST-POLYCYTHEMIA VERA/ESSENTIAL THROMBOCYTHEMIA (POST-PV/ET MF). "DRIVER" MUTATIONS IN JAK2, MPL AND INDELS IN CALR UNDERLIE THE VAST MAJORITY OF CASES OF PMF AND POST-ET MF; THE REMAINDER ( APPROXIMATELY 10%) LACK IDENTIFIABLE DRIVER MUTATIONS, BUT OTHER CLONAL MARKERS ARE USUALLY DETECTABLE. NEARLY ALL PATIENTS WITH POST-PV MF CARRY ACTIVATING JAK2 MUTATIONS. IN BOTH PMF AND POST-ET MF, TYPE 1/-LIKE CALR MUTATIONS CONFER A FAVORABLE PROGNOSIS. SINCE BOTH TYPE 1/-LIKE AND TYPE 2/-LIKE CALR MUTATIONS HAVE ESSENTIALLY THE SAME FUNCTIONAL CONSEQUENCE, THIS IS A SUBJECT OF INTENSE RESEARCH. ADDITIONAL, "NON-DRIVER" MUTATIONS, MOSTLY AFFECTING GENES ENCODING EPIGENETIC MODIFIERS OR SPLICEOSOME COMPONENTS, E.G., ASXL1, EZH2, TET2, DNMT3A, SRSF2 AND U2AF1, ARE FREQUENTLY FOUND; SOME OF THESE ARE ASSOCIATED WITH INFERIOR SURVIVAL AND HAVE BEEN INCORPORATED INTO PROGNOSTIC MODELS. SOME MUTATIONS, E.G., IDH1/2, ARE RELATIVELY INFREQUENT IN CHRONIC PHASE BUT ARE SUBSTANTIALLY MORE COMMON IN BLAST PHASE, AND ARE NOW THERAPEUTICALLY TARGETABLE. WHILE MUTATIONAL INFORMATION DOES NOT CURRENTLY INFLUENCE CHOICE OF DRUG THERAPY IN CHRONIC-PHASE MF, THE PRESENCE OF A "HIGH MOLECULAR RISK" GENOTYPE IS NOW ROUTINELY TAKEN INTO ACCOUNT FOR TRANSPLANT DECISION-MAKING. 2020