1 5799 108 STEPPING OUT OF ANTIQUITY: AN UPDATE ON EMERGING DRUGS FOR THE TREATMENT OF POLYCYTHEMIA VERA. INTRODUCTION: POLYCYTHEMIA VERA IS A CHRONIC HEMATOLOGIC MALIGNANCY FREQUENTLY PRESENTED WITH CONSTITUTIONAL SYMPTOMS AND ASSOCIATED WITH AN INCREASED RISK OF THROMBOSIS, HEMORRHAGE, AND PROGRESSION TO MYELOFIBROSIS OR ACUTE MYELOID LEUKEMIA. CURRENT TREATMENT STRATEGIES REDUCE THROMBOHEMORRHAGIC RISK BY CONTROLLING BLOOD COUNTS AND INHIBITING PLATELETS, BUT OFTEN FAIL TO ADDRESS DISEASE-RELATED SYMPTOMS OR BIOLOGICALLY MODIFY THE DISEASE.AREAS COVERED: WE REVIEW THE CURRENT PARADIGM FOR TREATING POLYCYTHEMIA VERA, HIGHLIGHT AREAS OF UNMET NEED, REVIEW THERAPEUTIC AGENTS IN LATE STAGE CLINICAL DEVELOPMENT, AND PROVIDE AN OVERARCHING VIEW OF HOW THESE EMERGING AGENT MAY FIT INTO THE FUTURE ARMAMENTARIUM OF POLYCYTHEMIA VERA TREATMENTS.EXPERT OPINION: THE SHIFT FROM FOCUSING SOLELY ON SECONDARY PREVENTION OF THROMBOHEMORRHAGIC EVENTS TO A COMPREHENSIVE TREATMENT STRATEGY THAT ADDITIONALLY AIMS TO IMPROVE QUALITY OF LIFE AND PREVENT DISEASE PROGRESSION HAS RESULTED IN A RAPIDLY EVOLVING THERAPEUTIC LANDSCAPE THAT PROMISES TO MOVE THE TREATMENT OF POLYCYTHEMIA VERA OUT OF ANTIQUITY INTO THE MODERN AGE. 2021 2 5448 24 REPRESSION OF HDAC5 BY ACETATE RESTORES HYPOTHALAMIC-PITUITARY-OVARIAN FUNCTION IN TYPE 2 DIABETES MELLITUS. TYPE 2 DIABETES MELLITUS (T2DM) ACCOUNTS FOR 90-95 % OF WORLDWIDE DIABETES CASES AND IS PRIMARILY CHARACTERIZED BY INSULIN RESISTANCE. ITS PROGRESSION AS A CHRONIC METABOLIC DISEASE HAS BEEN LARGELY ASSOCIATED WITH FEMALE REPRODUCTIVE ABNORMALITIES, INCLUDING OVARIAN DYSFUNCTION WITH CONSEQUENT INFERTILITY. EPIGENETIC MODIFICATIONS HAVE BEEN SUGGESTED AS A POSSIBLE LINK TO METABOLIC COMORBIDITIES. WE THEREFORE HYPOTHESIZED THAT SHORT CHAIN FATTY ACIDS, ACETATE (ACA), A POTENTIAL HISTONE DEACETYLASE INHIBITOR (HDAC) AMELIORATES HYPOTHALAMIC-PITUITARY-OVARIAN (HPO) DYSFUNCTION IN T2DM. FEMALE WISTAR RATS WEIGHING 160-190 G WERE ALLOTTED INTO THREE GROUPS (N = 6/GROUP): CONTROL (VEHICLE; PO), T2D AND T2D + ACA (200 MG/KG; PO). T2DM WAS INDUCED BY FRUCTOSE ADMINISTRATION (10 %; W/V) FOR 6 WEEKS AND SINGLE DOSE OF STREPTOZOTOCIN (35 MG/KG; IP). THE PRESENT DATA SHOWED THAT IN ADDITION TO INSULIN RESISTANCE, INCREASED FASTING BLOOD GLUCOSE AND INSULIN, T2DM INDUCED ELEVATED PLASMA, HYPOTHALAMIC AND OVARIAN TRIGLYCERIDE, LIPID PEROXIDATION, TNF-ALPHA AND GLUTATHIONE DEPLETION. ASIDE, T2DM ALSO LED TO INCREASED PLASMA LACTATE PRODUCTION AND GAMMA-GLUTAMYL TRANSFERASE AS WELL AS DECREASED GONADOTROPINS/17BETA-ESTRADIOL. HISTOLOGICALLY, HYPOTHALAMUS, PITUITARY AND OVARIES REVEALED DISRUPTED NEURONAL CELLS/MODERATE HEMORRHAGE, ALTERED MORPHOLOGY/VASCULAR CONGESTIONS, AND DEGENERATED ANTRAL FOLLICLE/GRAAFIAN FOLLICLE WITH MILD FIBROSIS AND INFILTRATED INFLAMMATORY CELLS RESPECTIVELY IN T2D ANIMALS. INTERESTINGLY, THESE ALTERATIONS WERE ACCOMPANIED BY ELEVATED PLASMA/HYPOTHALAMIC HDAC5 AND ATTENUATED WHEN TREATED WITH ACETATE. THE PRESENT RESULTS DEMONSTRATE THAT T2DM INDUCES HPO DYSFUNCTION, WHICH IS ACCOMPANIED BY ELEVATED CIRCULATING/HYPOTHALAMIC HDAC5. THE RESULTS IN ADDITION SUGGEST THAT ACETATE RESTORES HPO FUNCTION IN T2DM BY SUPPRESSION OF HDAC5 AND ENHANCEMENT OF INSULIN SENSITIVITY. 2021 3 6856 33 [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 4 5257 42 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 5 680 19 BRAIN INJURY IN CHRONICALLY VENTILATED PRETERM NEONATES: COLLATERAL DAMAGE RELATED TO VENTILATION STRATEGY. BRAIN INJURY IS A FREQUENT COMORBIDITY IN CHRONICALLY VENTILATED PRETERM INFANTS. HOWEVER, THE MOLECULAR BASIS OF THE BRAIN INJURY REMAINS INCOMPLETELY UNDERSTOOD. THIS ARTICLE DISCUSSES THE SUBTLE (DIFFUSE) FORM OF BRAIN INJURY THAT HAS WHITE MATTER AND GRAY MATTER LESIONS WITHOUT GERMINAL MATRIX HEMORRHAGE-INTRAVENTRICULAR HEMORRHAGE, POSTHEMORRHAGIC HYDROCEPHALUS, OR CYSTIC PERIVENTRICULAR LEUKOMALACIA. THIS ARTICLE SYNTHESIZES DATA THAT SUGGEST THAT DIFFUSE LESIONS TO WHITE MATTER AND GRAY MATTER ARE COLLATERAL DAMAGE RELATED TO VENTILATOR STRATEGY. EVIDENCE IS INTRODUCED FROM THE 2 LARGE-ANIMAL, PHYSIOLOGIC MODELS OF EVOLVING NEONATAL CHRONIC LUNG DISEASE THAT SUGGEST THAT AN EPIGENETIC MECHANISM MAY UNDERLIE THE COLLATERAL DAMAGE. 2012 6 3025 26 GENETICS AND PATHOPHYSIOLOGY OF GRANULOMATOSIS WITH POLYANGIITIS (GPA) AND ITS MAIN AUTOANTIGEN PROTEINASE 3. GRANULOMATOSIS WITH POLYANGIITIS (GPA) IS A SEVERE AUTOIMMUNE DISEASE AND ONE OF THE SMALL VESSEL ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED VASCULITIDES. ALTHOUGH ITS ETIOLOGY AND PATHOPHYSIOLOGY ARE STILL WIDELY UNKNOWN, IT IS ACCEPTED THAT INFECTIONS, ENVIRONMENTAL FACTORS, EPIGENETIC MODIFICATIONS, AND A GENETIC PREDISPOSITION PROVIDE THE BASIS FOR THIS SYSTEMIC DISORDER. GPA TYPICALLY EVOLVES INTO TWO PHASES: AN INITIAL PHASE CHARACTERIZED BY EAR, NOSE AND THROAT (ENT) MANIFESTATIONS, SUCH AS CHRONIC SINUSITIS AND OTITIS, ULCERATION OF THE ORAL CAVITY AND PHARYNX, AS WELL AS PULMONARY NODULES AND A SEVERE GENERALIZED PHASE, DEFINED BY THE OCCURRENCE OF RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS, PULMONARY HEMORRHAGE, AND ARTHRITIS. ANCAS, DIRECTED AGAINST THE NEUTROPHILIC ENZYMES PROTEINASE 3 AND MYELOPEROXIDASE, ARE PRESENT IN UP TO 90% OF THE AFFECTED PATIENTS IN THE SYSTEMIC PHASE. AS THE HUMORAL IMMUNITY IS PREDOMINANTLY DIRECTED AGAINST NEUTROPHILIC ANTIGENS, IT IS APPARENT THAT NEUTROPHILS PLAY A CRITICAL ROLE IN GPA BOTH AS TARGET AND EFFECTOR CELLS. ALTHOUGH GPA PATHOGENESIS IS NOT WELL KNOWN, SOME SUSCEPTIBILITY GENES AND LOCI HAVE BEEN IDENTIFIED BY CANDIDATE GENE APPROACHES, GENOME-WIDE ASSOCIATION STUDIES, AND META-ANALYSES, AS WELL AS FAMILIAL ASSOCIATION STUDIES. SUCH GENES ARE CTLA4, PTPN22, COL11A2, SERPINA1, AND THE MHC CLASS II GENE CLUSTER. THIS REVIEW HIGHLIGHTS THE CLINICAL, PATHOPHYSIOLOGICAL, AND GENETIC BACKGROUND OF GPA AND AIMS TO GIVE AN OVERVIEW OF RECENT EFFORTS TO IDENTIFY GPA SUSCEPTIBILITY GENES. WE POINT OUT THE GENETIC BASIS OF THE MAIN AUTOANTIGEN PR3 AND WHY IT IS SO DIFFICULT TO ESTABLISH A MURINE GPA MODEL. 2016 7 5953 26 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 8 5697 29 SIMILARITIES IN PATHOGENETIC MECHANISMS UNDERLYING THE BIDIRECTIONAL RELATIONSHIP BETWEEN ENDOMETRIOSIS AND PELVIC INFLAMMATORY DISEASE. BACKGROUND: ENDOMETRIOSIS IS A COMMON INFLAMMATORY DISEASE CHARACTERIZED BY THE PRESENCE OF ENDOMETRIAL CELLS OUTSIDE OF THE UTERINE CAVITY. ENDOMETRIOSIS AFFECTS 10% OF WOMEN OF REPRODUCTIVE AGE AND SIGNIFICANTLY REDUCES THEIR QUALITY OF LIFE AS A RESULT OF CHRONIC PELVIC PAIN AND INFERTILITY. BIOLOGIC MECHANISMS, INCLUDING PERSISTENT INFLAMMATION, IMMUNE DYSFUNCTION, AND EPIGENETIC MODIFICATIONS, HAVE BEEN PROPOSED AS THE PATHOGENESIS OF ENDOMETRIOSIS. IN ADDITION, ENDOMETRIOSIS CAN POTENTIALLY BE ASSOCIATED WITH AN INCREASED RISK OF PELVIC INFLAMMATORY DISEASE (PID). CHANGES IN THE VAGINAL MICROBIOTA ASSOCIATED WITH BACTERIAL VAGINOSIS (BV) RESULT IN PID OR A SEVERE FORM OF ABSCESS FORMATION, TUBO-OVARIAN ABSCESS (TOA). THIS REVIEW AIMS TO SUMMARIZE THE PATHOPHYSIOLOGY OF ENDOMETRIOSIS AND PID AND TO DISCUSS WHETHER ENDOMETRIOSIS MAY PREDISPOSE TO PID AND VICE VERSA. METHODS: PAPERS PUBLISHED BETWEEN 2000 AND 2022 IN THE PUBMED AND GOOGLE SCHOLAR DATABASES WERE INCLUDED. RESULTS: AVAILABLE EVIDENCE SUPPORTS THAT WOMEN WITH ENDOMETRIOSIS ARE AT INCREASED RISK OF COMORBID PID AND VICE VERSA, SUPPORTING THAT ENDOMETRIOSIS AND PID ARE LIKELY TO COEXIST. THERE IS A BIDIRECTIONAL RELATIONSHIP BETWEEN ENDOMETRIOSIS AND PID THAT SHARES A SIMILAR PATHOPHYSIOLOGY, WHICH INCLUDES THE DISTORTED ANATOMY FAVORABLE TO BACTERIA PROLIFERATION, HEMORRHAGE FROM ENDOMETRIOTIC LESIONS, ALTERATIONS TO THE REPRODUCTIVE TRACT MICROBIOME, AND IMPAIRED IMMUNE RESPONSE MODULATED BY ABERRANT EPIGENETIC PROCESSES. HOWEVER, WHETHER ENDOMETRIOSIS PREDISPOSES TO PID OR VICE VERSA HAS NOT BEEN IDENTIFIED. CONCLUSIONS: THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF THE PATHOGENESIS OF ENDOMETRIOSIS AND PID AND DISCUSSES THE SIMILARITIES BETWEEN THEM. 2023 9 3129 42 GIVINOSTAT: AN EMERGING TREATMENT FOR POLYCYTHEMIA VERA. INTRODUCTION: POLYCYTHEMIA VERA (PV), A PHILADELPHIA CHROMOSOME-NEGATIVE MYELOPROLIFERATIVE NEOPLASM, IS CHARACTERIZED BY PANMYELOSIS, PANCYTOSIS, AND A JAK2 MUTATION. PATIENTS ARE AT INCREASED RISK OF THROMBOHEMORRHAGIC EVENTS, AND PROGRESSION TO MYELOFIBROSIS OR ACUTE LEUKEMIA. CURRENT TREATMENTS INCLUDE ASPIRIN, PHLEBOTOMY, AND CYTOREDUCTIVE DRUGS (MOST COMMONLY HYDROXYUREA). GIVINOSTAT IS A POTENT, CLASS I/II HISTONE DEACETYLASE (HDAC) INHIBITOR THAT IS IN PHASE I/II CLINICAL TRIALS IN PV. GIVINOSTAT WAS WELL TOLERATED AND YIELDED PROMISING CLINICO-HEMATOLOGICAL RESPONSES. A PHASE III STUDY OF GIVINOSTAT VERSUS HYDROXYUREA IN HIGH-RISK PV PATIENTS IS PLANNED. AREAS COVERED: WE PRESENT AN OVERVIEW OF PV, CURRENT TREATMENT GUIDELINES, AND THE PUTATIVE MECHANISM(S) OF ACTION OF GIVINOSTAT. WE DISCUSS THE PRECLINICAL AND CLINICAL STUDIES OF GIVINOSTAT IN PV AND BRIEFLY REVIEW APPROVED AND INVESTIGATIONAL COMPETITOR COMPOUNDS. EXPERT OPINION: HDAC INHIBITORS HAVE LONG BEEN KNOWN TO BE ACTIVE IN PV, BUT CHRONIC TOXICITIES CAN BE CHALLENGING. GIVINOSTAT, HOWEVER, IS ACTIVE AND WELL TOLERATED, AND IS ENTERING A PIVOTAL PHASE III RANDOMIZED TRIAL. GIVINOSTAT OFFERS THE POSSIBILITY OF REPLACING HYDROXYUREA AS THE STANDARD FIRST-LINE CYTOREDUCTIVE CHOICE FOR PV PATIENTS. THIS WOULD COMPLETELY CHANGE THE CURRENT THERAPEUTIC PARADIGM AND GUIDELINES FOR PV MANAGEMENT. ALTHOUGH SURROGATE CLINICAL STUDY ENDPOINTS MAY SUFFICE FOR REGULATORY PURPOSES, THROMBOSIS REDUCTION AND PREVENTION OF DISEASE PROGRESSION REMAIN MOST IMPORTANT TO PATIENTS AND CLINICIANS. 2020 10 255 31 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 11 3111 22 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 12 3747 29 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 13 6852 25 [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 14 6561 26 TRANSGLUTAMINASE IS A THERAPEUTIC TARGET FOR OXIDATIVE STRESS, EXCITOTOXICITY AND STROKE: A NEW EPIGENETIC KID ON THE CNS BLOCK. TRANSGLUTAMINASES (TGS) ARE MULTIFUNCTIONAL, CALCIUM-DEPENDENT ENZYMES THAT HAVE BEEN RECENTLY IMPLICATED IN STROKE PATHOPHYSIOLOGY. CLASSICALLY, THESE ENZYMES ARE THOUGHT TO PARTICIPATE IN CELL INJURY AND DEATH IN CHRONIC NEURODEGENERATIVE CONDITIONS VIA THEIR ABILITY TO CATALYZE COVALENT, NONDEGRADABLE CROSSLINKS BETWEEN PROTEINS OR TO INCORPORATE POLYAMINES INTO PROTEIN SUBSTRATES. ACCUMULATING LINES OF INQUIRY INDICATE THAT SPECIFIC TG ISOFORMS CAN SHUTTLE INTO THE NUCLEUS WHEN THEY SENSE PATHOLOGIC CHANGES IN CALCIUM OR OXIDATIVE STRESS, BIND TO CHROMATIN AND THEREBY TRANSDUCE THESE CHANGES INTO TRANSCRIPTIONAL REPRESSION OF GENES INVOLVED IN METABOLIC OR OXIDANT ADAPTATION. HERE, WE REVIEW THE EVIDENCE THAT SUPPORTS PRINCIPALLY A ROLE FOR ONE ISOFORM OF THIS FAMILY, TG2, IN CELL INJURY AND DEATH ASSOCIATED WITH HEMORRHAGIC OR ISCHEMIC STROKE. WE ALSO OUTLINE AN EVOLVING MODEL IN WHICH TG2 IS A CRITICAL MEDIATOR BETWEEN PATHOLOGIC SIGNALING AND EPIGENETIC MODIFICATIONS THAT LEAD TO GENE REPRESSION. ACCORDINGLY, THE SALUTARY EFFECTS OF TG INHIBITORS IN STROKE MAY DERIVE FROM THEIR ABILITY TO RESTORE HOMEOSTASIS BY REMOVING INAPPROPRIATE DEACTIVATION OF ADAPTIVE GENETIC PROGRAMS BY OXIDATIVE STRESS OR EXTRASYNAPTIC GLUTAMATE RECEPTOR SIGNALING. 2013 15 1947 30 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 16 6442 28 THERAPEUTIC APPROACHES IN MYELOFIBROSIS AND MYELODYSPLASTIC/MYELOPROLIFERATIVE OVERLAP SYNDROMES. THE DISCOVERY OF JAK2 (V617F) A DECADE AGO LED TO OPTIMISM FOR A RAPIDLY DEVELOPING TREATMENT REVOLUTION IN PH(-) MYELOPROLIFERATIVE NEOPLASMS. UNLIKE BCR-ABL, HOWEVER, JAK2 WAS FOUND TO HAVE A MORE HETEROGENEOUS ROLE IN CARCINOGENESIS. THEREFORE, FOR YEARS, DEVELOPMENT OF NEW THERAPIES WAS SLOW, DESPITE STANDARD TREATMENT OPTIONS THAT DID NOT ADDRESS THE OVERWHELMING SYMPTOM BURDEN IN PATIENTS WITH PRIMARY MYELOFIBROSIS (MF), POST-ESSENTIAL THROMBOCYTHEMIA MF, POST-POLYCYTHEMIA VERA MF, AND MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) SYNDROMES. JAK-STAT INHIBITORS HAVE CHANGED THIS, DRASTICALLY AMELIORATING SYMPTOMS AND ULTIMATELY BEGINNING TO SHOW EVIDENCE OF IMPACT ON SURVIVAL. NOW, THE GENETIC FOUNDATIONS OF MYELOFIBROSIS AND MDS/MPN ARE RAPIDLY BEING ELUCIDATED AND CONTRIBUTING TO TARGETED THERAPY DEVELOPMENT. THIS HAS BEEN EMPOWERED THROUGH UPDATED RESPONSE CRITERIA FOR MDS/MPN AND REFINED PROGNOSTIC SCORING SYSTEMS IN THESE DISEASES. THE AIM OF THIS ARTICLE IS TO SUMMARIZE CONCISELY THE CURRENT AND RATIONALLY DESIGNED INVESTIGATIONAL THERAPEUTICS DIRECTED AT JAK-STAT, HEDGEHOG, PI3K-AKT, BONE MARROW FIBROSIS, TELOMERASE, AND ROGUE EPIGENETIC SIGNALING. THE REVOLUTION IN IMMUNOTHERAPY AND NOVEL TREATMENTS AIMED AT PREVIOUSLY UNTARGETED SIGNALING PATHWAYS PROVIDES HOPE FOR CONSIDERABLE ADVANCEMENT IN THERAPY OPTIONS FOR THOSE WITH CHRONIC MYELOID DISEASE. 2016 17 83 19 A NOVEL EPIGENETIC MARKER, TEN-ELEVEN TRANSLOCATION FAMILY MEMBER 2 (TET2), IS IDENTIFIED IN THE INTRACTABLE EPILEPTIC BRAIN AND REGULATES ATP BINDING CASSETTE SUBFAMILY B MEMBER 1 (ABCB1) IN THE BLOOD-BRAIN BARRIER. DRUG-RESISTANT EPILEPSY (DRE) IS A CHRONIC CONDITION DERIVED FROM SPONTANEOUS CHANGES AND REGULATORY EFFECTS IN THE EPILEPTIC BRAIN. AS DEMETHYLATION FACTORS, TEN-ELEVEN TRANSLOCATION (TET) FAMILY MEMBERS HAVE BECOME A FOCUS IN RECENT STUDIES OF NEUROLOGICAL DISORDERS. HERE, WE QUANTIFIED AND LOCALIZED TET1, TET2 AND 5-HYDROXYMETHYLCYTOSINE (5-HMC) IN THE TEMPORAL LOBE CORTEX OF DRE PATIENTS (N = 27) AND TRAUMATIC BRAIN HEMORRHAGE CONTROLS (N = 10) BY IMMUNOCHEMICAL STAINING. TET2 AND ATP BINDING CASSETTE SUBFAMILY B MEMBER 1 (ABCB1) EXPRESSION PATTERNS WERE DETERMINED IN THE ISOLATED BRAIN CAPILLARIES OF DRE PATIENTS. TET2 EXPRESSION WAS SIGNIFICANTLY INCREASED IN THE TEMPORAL CORTICAL TISSUE OF DRE PATIENTS WITH OR WITHOUT HIPPOCAMPAL SCLEROSIS (HS) COMPARED TO CONTROL PATIENTS, WHILE TET1 AND 5-HMC SHOWED NO DIFFERENCES IN EXPRESSION. WE ALSO FOUND THAT A PARTICULARLY STRONG EXPRESSION OF TET2 IN THE VASCULAR TISSUE OF DRE PATIENTS. ABCB1 AND TET2 HAVE EVIDENTLY HIGHER EXPRESSION IN THE VASCULAR ENDOTHELIUM FROM THE NEOCORTEX OF DRE PATIENTS. IN BLOOD-BRAIN BARRIER (BBB) MODEL, TET2 DEPLETION CAN CAUSE ATTENUATED EXPRESSION AND FUNCTION OF ABCB1. DATA FROM A COHORT STUDY AND EXPERIMENTS IN A BBB MODEL SUGGEST THAT TET2 HAS A SPECIFIC REGULATORY EFFECT ON ABCB1, WHICH MAY SERVE AS A POTENTIAL MECHANISM AND TARGET IN DRE. 2022 18 4554 23 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 19 4748 28 NOVEL MUTATIONS AND THEIR FUNCTIONAL AND CLINICAL RELEVANCE IN MYELOPROLIFERATIVE NEOPLASMS: JAK2, MPL, TET2, ASXL1, CBL, IDH AND IKZF1. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ORIGINATE FROM GENETICALLY TRANSFORMED HEMATOPOIETIC STEM CELLS THAT RETAIN THE CAPACITY FOR MULTILINEAGE DIFFERENTIATION AND EFFECTIVE MYELOPOIESIS. BEGINNING IN EARLY 2005, A NUMBER OF NOVEL MUTATIONS INVOLVING JANUS KINASE 2 (JAK2), MYELOPROLIFERATIVE LEUKEMIA VIRUS (MPL), TET ONCOGENE FAMILY MEMBER 2 (TET2), ADDITIONAL SEX COMBS-LIKE 1 (ASXL1), CASITAS B-LINEAGE LYMPHOMA PROTO-ONCOGENE (CBL), ISOCITRATE DEHYDROGENASE (IDH) AND IKAROS FAMILY ZINC FINGER 1 (IKZF1) HAVE BEEN DESCRIBED IN BCR-ABL1-NEGATIVE MPNS. HOWEVER, NONE OF THESE MUTATIONS WERE MPN SPECIFIC, DISPLAYED MUTUAL EXCLUSIVITY OR COULD BE TRACED BACK TO A COMMON ANCESTRAL CLONE. JAK2 AND MPL MUTATIONS APPEAR TO EXERT A PHENOTYPE-MODIFYING EFFECT AND ARE DISTINCTLY ASSOCIATED WITH POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA AND PRIMARY MYELOFIBROSIS; THE CORRESPONDING MUTATIONAL FREQUENCIES ARE APPROXIMATELY 99, 55 AND 65% FOR JAK2 AND 0, 3 AND 10% FOR MPL MUTATIONS. THE INCIDENCE OF TET2, ASXL1, CBL, IDH OR IKZF1 MUTATIONS IN THESE DISORDERS RANGES FROM 0 TO 17%; THESE LATTER MUTATIONS ARE MORE COMMON IN CHRONIC (TET2, ASXL1, CBL) OR JUVENILE (CBL) MYELOMONOCYTIC LEUKEMIAS, MASTOCYTOSIS (TET2), MYELODYSPLASTIC SYNDROMES (TET2, ASXL1) AND SECONDARY ACUTE MYELOID LEUKEMIA, INCLUDING BLAST-PHASE MPN (IDH, ASXL1, IKZF1). THE FUNCTIONAL CONSEQUENCES OF MPN-ASSOCIATED MUTATIONS INCLUDE UNREGULATED JAK-STAT (JANUS KINASE/SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION) SIGNALING, EPIGENETIC MODULATION OF TRANSCRIPTION AND ABNORMAL ACCUMULATION OF ONCOPROTEINS. HOWEVER, IT IS NOT CLEAR AS TO WHETHER AND HOW THESE ABNORMALITIES CONTRIBUTE TO DISEASE INITIATION, CLONAL EVOLUTION OR BLASTIC TRANSFORMATION. 2010 20 4322 30 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