1  3872 175 JUVENILE MYELOMONOCYTIC LEUKEMIA-A COMPREHENSIVE REVIEW AND RECENT ADVANCES IN MANAGEMENT. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A RARE PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP DISEASE. JMML IS ASSOCIATED WITH MUTATIONS IN THE RAS PATHWAY GENES RESULTING IN THE MYELOID PROGENITORS BEING SENSITIVE TO GRANULOCYTE MONOCYTE COLONY-STIMULATING FACTOR (GM-CSF). KARYOTYPE ABNORMALITIES AND ADDITIONAL EPIGENETIC ALTERATIONS CAN ALSO BE FOUND IN JMML. NEUROFIBROMATOSIS AND NOONAN'S SYNDROME HAVE A PREDISPOSITION FOR JMML. IN A FEW PATIENTS, THE RAS GENES (NRAS, KRAS, AND PTPN11) ARE MUTATED AT THE GERMLINE AND THIS USUALLY RESULTS IN A TRANSIENT MYELOPROLIFERATIVE DISORDER WITH A GOOD PROGNOSIS. JMML WITH SOMATIC RAS MUTATION BEHAVES AGGRESSIVELY. JMML PRESENTS WITH CYTOPENIAS AND LEUKEMIC INFILTRATION INTO ORGANS. THE LABORATORY FINDINGS INCLUDE HYPERLEUKOCYTOSIS, MONOCYTOSIS, INCREASED HEMOGLOBIN-F LEVELS, AND CIRCULATING MYELOID PRECURSORS. THE BLAST CELLS IN THE PERIPHERAL BLOOD/BONE-MARROW ASPIRATE ARE LESS THAN 20% AND THE ABSENCE OF THE BCR-ABL TRANSLOCATION HELPS TO DIFFERENTIATE FROM CHRONIC MYELOID LEUKEMIA. JMML SHOULD BE DIFFERENTIATED FROM IMMUNODEFICIENCIES, VIRAL INFECTIONS, INTRAUTERINE INFECTIONS, HEMOPHAGOLYMPHOHISTIOCYTOSIS, OTHER MYELOPROLIFERATIVE DISORDERS, AND LEUKEMIAS. CHEMOTHERAPY IS EMPLOYED AS A BRIDGE TO HSCT, EXCEPT IN FEW WITH LESS AGGRESSIVE DISEASE, IN WHICH CHEMOTHERAPY ALONE CAN RESULT IN LONG TERM REMISSION. AZACITIDINE HAS SHOWN PROMISE AS A SINGLE AGENT TO STABILIZE THE DISEASE. THE PROGNOSIS OF JMML IS POOR WITH ABOUT 50% OF PATIENTS SURVIVING AFTER AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). ALLOGENEIC HSCT IS THE ONLY KNOWN CURE FOR JMML TO DATE. MYELOABLATIVE CONDITIONING IS MOST COMMONLY USED WITH GRAFT VERSUS HOST DISEASE (GVHD) PROPHYLAXIS TAILORED TO THE AGGRESSIVENESS OF THE DISEASE. RELAPSES ARE COMMON EVEN AFTER HSCT AND A SECOND HSCT CAN SALVAGE A THIRD OF THESE PATIENTS. NOVEL OPTIONS IN THE TREATMENT OF JMML E.G., HYPOMETHYLATING AGENTS, MEK INHIBITORS, JAK INHIBITORS, TYROSINE KINASE INHIBITORS, ETC. ARE BEING EXPLORED.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  4562  60 MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROMES: A FOCUSED REVIEW. MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) OVERLAP SYNDROMES ARE UNIQUE MYELOID NEOPLASMS, WITH OVERLAPPING FEATURES OF MDS AND MPN. THEY CONSIST OF FOUR ADULT ONSET ENTITIES INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), MDS/MPN-RING SIDEROBLASTS-THROMBOCYTOSIS (MDS/MPN-RS-T), BCR-ABL1 NEGATIVE ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) AND MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U); WITH JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) BEING THE ONLY PEDIATRIC ONSET ENTITY. AMONG THESE OVERLAP NEOPLASMS, CMML IS THE MOST FREQUENT AND IS HALLMARKED BY THE PRESENCE OF SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS WITH RECURRENT MUTATIONS INVOLVING TET2 (60%), SRSF2 (50%) AND ASXL1 (40%); WITH RAS PATHWAY MUTATIONS AND JAK2V617F BEING RELATIVELY ENRICHED IN PROLIFERATIVE CMML SUBTYPES (WBC >/=13 X 109/L). CMML USUALLY PRESENTS IN THE 7TH DECADE OF LIFE, WITH A MALE PREPONDERANCE AND IS ASSOCIATED WITH A MEDIAN OVERALL SURVIVAL OF <36 MONTHS. ADVERSE PROGNOSTICATORS IN CMML INCLUDE INCREASING AGE, HIGH WBC, PRESENCE OF CIRCULATING IMMATURE MYELOID CELLS, ANEMIA, THROMBOCYTOPENIA AND TRUNCATING ASXL1 MUTATIONS. WHILE ALLOGENEIC STEM CELL TRANSPLANTATION REMAINS THE ONLY CURATIVE OPTION, GIVEN THE LATE ONSET OF THIS NEOPLASM AND HIGH FREQUENCY OF COMORBIDITIES, MOST PATIENTS REMAIN INELIGIBLE. HYPOMETHYLATING AGENTS SUCH AS AZACITIDINE, DECITABINE AND ORAL DECITABINE/CEDAZURIDINE HAVE BEEN US FDA APPROVED FOR THE MANAGEMENT OF CMML, WITH OVERALL RESPONSE RATES OF 40-50% AND COMPLETE REMISSION RATES OF <20%. WHILE THESE AGENTS EPIGENETICALLY RESTORE HEMATOPOIESIS IN A SUBSET OF RESPONDING PATIENTS, THEY DO NOT IMPACT MUTATIONAL ALLELE BURDENS AND EVENTUAL DISEASE PROGRESSION TO AML REMAINS INEVITABLE. NEWER TREATMENT MODALITIES EXPLOITING EPIGENETIC, SIGNALING AND SPLICING ABNORMALITIES COMMONLY SEEN IN CMML ARE MUCH NEEDED.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
3  4964  28 PATHOGENETIC AND CLINICAL ASPECTS OF ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIDES. ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODIES (ANCA) TARGETING PROTEINASE 3 (PR3) AND MYELOPEROXIDASE EXPRESSED BY INNATE IMMUNE CELLS (NEUTROPHILS AND MONOCYTES) ARE SALIENT DIAGNOSTIC AND PATHOGENIC FEATURES OF SMALL VESSEL VASCULITIS, COMPRISING GRANULOMATOSIS WITH POLYANGIITIS (GPA), MICROSCOPIC POLYANGIITIS, AND EOSINOPHILIC GPA. GENETIC STUDIES SUGGEST THAT ANCA-ASSOCIATED VASCULITIDES (AAV) CONSTITUTE SEPARATE DISEASES, WHICH SHARE COMMON IMMUNOLOGICAL AND PATHOLOGICAL FEATURES, BUT ARE OTHERWISE HETEROGENEOUS. THE SUCCESSFUL THERAPEUTIC USE OF ANTI-CD20 ANTIBODIES EMPHASIZES THE PROMINENT ROLE OF ANCA AND POSSIBLY OTHER AUTOANTIBODIES IN THE PATHOGENESIS OF AAV. HOWEVER, TO ELUCIDATE CAUSAL EFFECTS IN AAV, A BETTER UNDERSTANDING OF THE COMPLEX INTERPLAY LEADING TO THE EMERGENCE OF B LYMPHOCYTES THAT PRODUCE PATHOGENIC ANCA REMAINS A CHALLENGE. DIFFERENT SCENARIOS SEEM POSSIBLE; E.G., THE BREAK OF TOLERANCE INDUCED BY A SHIFT FROM NON-PATHOGENIC TOWARD PATHOGENIC AUTOANTIGEN EPITOPES IN INFLAMED TISSUE. THIS REVIEW GIVES A BRIEF OVERVIEW ON CURRENT KNOWLEDGE ABOUT GENETIC AND EPIGENETIC FACTORS, BARRIER DYSFUNCTION AND CHRONIC NON-RESOLVING INFLAMMATION, NECRO-INFLAMMATORY AUTO-AMPLIFICATION OF CELLULAR DEATH AND INFLAMMATION, ALTERED AUTOANTIGEN PRESENTATION, ALTERNATIVE COMPLEMENT PATHWAY ACTIVATION, ALTERATIONS WITHIN PERIPHERAL AND INFLAMED TISSUE-RESIDING T- AND B-CELL POPULATIONS, ECTOPIC LYMPHOID TISSUE NEOFORMATION, THE CHARACTERIZATION OF PR3-SPECIFIC T-CELLS, PROPERTIES OF ANCA, LINKS BETWEEN AUTOIMMUNE DISEASE AND INFECTION-TRIGGERED PATHOLOGY, AND ANIMAL MODELS IN AAV.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4  3025  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5  2697  27 EX VIVO MODELS OF CHRONIC GRANULOMATOUS DISEASE. INDUCED PLURIPOTENT STEM CELLS (IPSCS) ARE PLURIPOTENT STEM CELLS THAT CAN BE ESTABLISHED FROM DEDIFFERENTIATION OF ALL SOMATIC CELL TYPES BY EPIGENETIC PHENOMENA. IPSCS CAN BE DIFFERENTIATED INTO ANY MATURE CELLS LIKE NEURONS, HEPATOCYTES, OR PANCREATIC CELLS THAT HAVE NOT BEEN EASILY AVAILABLE TO DATE. THUS, IPSCS ARE WIDELY USED FOR DISEASE MODELING, DRUG DISCOVERY, AND CELL THERAPY DEVELOPMENT. HERE, WE DESCRIBE A PROTOCOL TO OBTAIN HUMAN MATURE AND FUNCTIONAL NEUTROPHILS AND MACROPHAGES AS EX VIVO MODELS OF X-LINKED CHRONIC GRANULOMATOUS DISEASE (X-CGD). THIS METHOD CAN BE APPLIED TO MODEL THE OTHER GENETIC FORMS OF CGD. WE ALSO DESCRIBE METHODS FOR TESTING THE CHARACTERISTICS AND FUNCTIONS OF NEUTROPHILS AND MACROPHAGES BY MORPHOLOGY, PHAGOCYTOSIS ASSAY, RELEASE OF GRANULE MARKERS OR CYTOKINES, CELL SURFACE MARKERS, AND NADPH OXIDASE ACTIVITY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  4530  32 MULTILAYER INTRACLONAL HETEROGENEITY IN CHRONIC MYELOMONOCYTIC LEUKEMIA. THE FUNCTIONAL DIVERSITY OF CELLS THAT COMPOSE MYELOID MALIGNANCIES, I.E., THE RESPECTIVE ROLES OF GENETIC AND EPIGENETIC HETEROGENEITY IN THIS DIVERSITY, REMAINS POORLY UNDERSTOOD. THIS QUESTION IS ADDRESSED IN CHRONIC MYELOMONOCYTIC LEUKEMIA, A MYELOID NEOPLASM IN WHICH CLINICAL DIVERSITY CONTRASTS WITH LIMITED GENETIC HETEROGENEITY. TO GENERATE INDUCED PLURIPOTENT STEM CELL CLONES, WE REPROGRAMMED CD34(+) CELLS COLLECTED FROM A PATIENT WITH A CHRONIC MYELOMONOCYTIC LEUKEMIA IN WHICH WHOLE EXOME SEQUENCING OF PERIPHERAL BLOOD MONOCYTE DNA HAD IDENTIFIED 12 GENE MUTATIONS, INCLUDING A MUTATION IN KDM6A AND TWO HETEROZYGOUS MUTATIONS IN TET2 IN THE FOUNDING CLONE AND A SECONDARY KRAS(G12D) MUTATION. CD34(+) CELLS FROM AN AGE-MATCHED HEALTHY DONOR WERE ALSO REPROGRAMMED. WE CAPTURED A PART OF THE GENETIC HETEROGENEITY OBSERVED IN THE PATIENT, I.E. WE ANALYZED FIVE CLONES WITH TWO GENETIC BACKGROUNDS, WITHOUT AND WITH THE KRAS(G12D) MUTATION. HEMATOPOIETIC DIFFERENTIATION OF THESE CLONES RECAPITULATED THE MAIN FEATURES OF THE PATIENT'S DISEASE, INCLUDING OVERPRODUCTION OF GRANULOMONOCYTES AND DYSMEGAKARYOPOIESIS. THESE ANALYSES ALSO DISCLOSED SIGNIFICANT DISCREPANCIES IN THE BEHAVIOR OF HEMATOPOIETIC CELLS DERIVED FROM INDUCED PLURIPOTENT STEM CELL CLONES WITH SIMILAR GENETIC BACKGROUND, CORRELATING WITH LIMITED EPIGENETIC CHANGES. THESE ANALYSES SUGGEST THAT, BEYOND THE CODING MUTATIONS, SEVERAL LEVELS OF INTRACLONAL HETEROGENEITY MAY PARTICIPATE IN THE YET UNEXPLAINED CLINICAL HETEROGENEITY OF THE DISEASE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
7   384  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8   255  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9  6394  39 THE ROLE OF THE HOST-NEUTROPHIL BIOLOGY. NEUTROPHILIC POLYMORPHONUCLEAR LEUKOCYTES (NEUTROPHILS) ARE MYELOID CELLS PACKED WITH LYSOSOMAL GRANULES (HENCE ALSO CALLED GRANULOCYTES) THAT CONTAIN A FORMIDABLE ANTIMICROBIAL ARSENAL. THEY ARE TERMINALLY DIFFERENTIATED CELLS THAT PLAY A CRITICAL ROLE IN ACUTE AND CHRONIC INFLAMMATION, AS WELL AS IN THE RESOLUTION OF INFLAMMATION AND WOUND HEALING. NEUTROPHILS EXPRESS A DENSE ARRAY OF SURFACE RECEPTORS FOR MULTIPLE LIGANDS, RANGING FROM INTEGRINS TO SUPPORT THEIR EGRESS FROM BONE MARROW INTO THE CIRCULATION AND FROM THE CIRCULATION INTO TISSUES, TO CYTOKINE/CHEMOKINE RECEPTORS THAT DRIVE THEIR NAVIGATION TO THE SITE OF INFECTION OR TISSUE DAMAGE AND ALSO PRIME THEM FOR A SECOND STIMULUS, TO PATTERN RECOGNITION RECEPTORS AND IMMUNOGLOBULIN RECEPTORS TO FACILITATE THE DESTRUCTION AND REMOVAL OF INFECTIVE AGENTS OR DEBRIDEMENT OF DAMAGED TISSUES. WHEN AFFERENT NEUTROPHIL SIGNALS ARE PROPORTIONATE AND COORDINATED THEY WILL PHAGOCYTOSE OPSONIZED AND UNOPSONIZED BACTERIA, ACTIVATING THE NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE (RESPIRATORY BURST) TO GENERATE REACTIVE OXYGEN SPECIES, WHICH AUGMENT THE PROTEOLYTIC DESTRUCTION OF MICROBES SECURED WITHIN THE PHAGOSOME. A HIGHLY ORCHESTRATED PROCESS OF APOPTOSIS FOLLOWS, FORMING MEMBRANE-BOUND SUBSTRUCTURES THAT ARE REMOVED BY MACROPHAGES. NEUTROPHILS ARE CAPABLE OF VARIOUS OTHER FORMS OF PROGRAMMED CELL DEATH, SUCH AS NETOSIS AND PYROPTOTIC CELL DEATH, AS WELL AS NONPROGRAMMED CELL DEATH BY NECROSIS. IN RECENT YEARS, RESEARCH HAS REVEALED THAT NEUTROPHILS ARE CAPABLE OF FAR MORE SUBTLE CELL-CELL INTERACTIONS THAN PREVIOUSLY THOUGHT POSSIBLE. THIS INCLUDES SYNTHESIS OF VARIOUS INFLAMMATORY MEDIATORS AND ALSO MYELOID CELL TRAINING WITHIN BONE MARROW, WHERE EPIGENETIC AND METABOLIC SIGNALS ASSOCIATED WITH RETURNING NEUTROPHILS THAT UNDERGO REVERSE EGRESS FROM TISSUES INTO THE VASCULATURE AND BACK TO BONE MARROW PROGRAM A HYPERREACTIVE SUBSET OF NEUTROPHILS DURING MYELOPOIESIS THAT ARE CAPABLE OF HYPERSENSITIVE REACTIONS TO MICROBIAL AGGRESSORS. THESE CHARACTERISTICS ARE EVIDENT IN VARIOUS NEUTROPHIL SUBSETS/SUBPOPULATIONS, CREATING BROAD HETEROGENEITY IN THE BEHAVIOR AND BIOLOGICAL REPERTOIRE OF THESE SEEMINGLY SCHIZOPHRENIC IMMUNE CELLS. MOREOVER, NEUTROPHILS ARE CRITICAL EFFECTOR CELLS OF ADAPTIVE AND INNATE IMMUNITY, BINDING TO OPSONIZED BACTERIA AND DESTROYING THEM BY EXTRACELLULAR AND INTRACELLULAR METHODS. THE FORMER CREATES SUBSTANTIAL COLLATERAL HOST TISSUE DAMAGE, AS THEY ARE LESS SPECIFIC THAN T-CYTOTOXIC CELL-KILLING MECHANISMS, AND IN CONDITIONS SUCH AS PERI-IMPLANTITIS, WHERE PLASMA CELLS AND NEUTROPHILS DOMINATE THE IMMUNE INFILTRATE, BONE AND TISSUE DESTRUCTION ARE RAPID AND APPEAR RELENTLESS. FINALLY, THE ROLE OF NEUTROPHILS AS CONDUITS FOR PERIODONTAL-SYSTEMIC DISEASE CONNECTIONS AND FOR OXIDATIVE DAMAGE TO ACT AS A CAUSAL LINK BETWEEN THE TWO HAS ONLY RECENTLY BEEN REALIZED. IN THIS CHAPTER, WE ATTEMPT TO EXPAND ON THESE ISSUES, EMPHASIZING THE CONTRIBUTIONS OF EUROPEAN SCIENTISTS THROUGHOUT A DETAILED APPRAISAL OF THE BENEFITS AND SIDE EFFECTS OF NEUTROPHILIC INFLAMMATION AND IMMUNE FUNCTION.	2023	

10   962  53 CHRONIC MYELOMONOCYTIC LEUKEMIA: FOCUS ON CLINICAL PRACTICE. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER WITH FEATURES THAT OVERLAP THOSE OF MYELODYSPLASTIC SYNDROMES (MDSS) AND MYELOPROLIFERATIVE NEOPLASMS (MPNS). CHRONIC MYELOMONOCYTIC LEUKEMIA OFTEN RESULTS IN PERIPHERAL BLOOD MONOCYTOSIS AND HAS AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKEMIA. CLONAL CYTOGENETIC CHANGES ARE SEEN IN APPROXIMATELY 30% OF PATIENTS, AND MOLECULAR ABNORMALITIES ARE SEEN IN MORE THAN 90%. GENE MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT, WITH NONSENSE AND FRAMESHIFT ASXL1 MUTATIONS BEING THE ONLY MUTATIONS IDENTIFIED THUS FAR TO HAVE AN INDEPENDENT NEGATIVE PROGNOSTIC EFFECT ON OVERALL SURVIVAL. CONTEMPORARY MOLECULARLY INTEGRATED PROGNOSTIC MODELS (INCLUSIVE OF ASXL1 MUTATIONS) INCLUDE THE MOLECULAR MAYO MODEL AND THE GROUPE FRANCAIS DES MYELODYSPLASIES MODEL. GIVEN THE LACK OF FORMAL TREATMENT AND RESPONSE CRITERIA, MANAGEMENT OF CMML IS OFTEN EXTRAPOLATED FROM MDS AND MPN, WITH ALLOGENEIC STEM CELL TRANSPLANT BEING THE ONLY CURATIVE OPTION. HYDROXYUREA AND OTHER CYTOREDUCTIVE AGENTS HAVE BEEN USED TO CONTROL MPN-LIKE FEATURES, WHILE EPIGENETIC MODIFIERS SUCH AS HYPOMETHYLATING AGENTS HAVE BEEN USED FOR MDS-LIKE FEATURES. GIVEN THE RELATIVELY POOR RESPONSE TO THESE AGENTS AND THE INHERENT RISKS ASSOCIATED WITH HEMATOPOIETIC STEM CELL TRANSPLANT, NEWER DRUGS EXPLOITING MOLECULAR AND EPIGENETIC ABNORMALITIES IN CMML ARE BEING DEVELOPED. THE CREATION OF CMML-SPECIFIC RESPONSE CRITERIA IS A MUCH NEEDED STEP IN ORDER TO IMPROVE CLINICAL OUTCOMES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11   961  45 CHRONIC MYELOMONOCYTIC LEUKEMIA: A GENETIC AND CLINICAL UPDATE. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER, CHARACTERIZED BY PERIPHERAL BLOOD MONOCYTOSIS AND OVERLAPPING FEATURES BETWEEN MYELODYSPLASTIC SYNDROMES (MDS) AND MYELOPROLIFERATIVE NEOPLASMS (MPNS). CLONAL CYTOGENETIC CHANGES ARE SEEN IN UP TO 30 % PATIENTS, WHILE APPROXIMATELY 90 % HAVE DETECTABLE MOLECULAR ABNORMALITIES. MOST PATIENTS ARE DIAGNOSED IN THE SEVENTH DECADE OF LIFE. GENE MUTATIONS IN TEN-ELEVEN TRANSLOCATION (TET) ONCOGENE FAMILY MEMBER 2 (TET2) (60 %), SRSF2 (50 %), ASXL1 (40 %), AND RAS (20-30 %) ARE FREQUENT, WITH ONLY FRAME SHIFT AND NONSENSE ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. WITH THE LACK OF FORMAL GUIDELINES, MANAGEMENT AND RESPONSE CRITERIA ARE OFTEN EXTRAPOLATED FROM MDS AND MPN. CONTEMPORARY MOLECULARLY INTEGRATED CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) MODEL AND THE MOLECULAR MAYO MODEL, BOTH INCORPORATING ASXL1 MUTATIONAL STATUS. HYPOMETHYLATING AGENTS AND ALLOGENEIC STEM CELL TRANSPLANT REMAIN THE TWO MOST COMMONLY USED TREATMENT STRATEGIES, WITH SUBOPTIMAL RESULTS. CLINICAL TRIALS EXPLOITING EPIGENETIC AND SIGNAL PATHWAY ABNORMALITIES, FREQUENT IN CMML, OFFER HOPE AND PROMISE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12  1053  30 CLINICAL IMPLICATIONS OF INTERFERON-GAMMA GENETIC AND EPIGENETIC VARIANTS. INTERFERON-GAMMA (IFN-GAMMA) IS AN INTEGRAL AND CRITICAL MOLECULE OF THE IMMUNE SYSTEM, WITH MULTIPLE FUNCTIONS, MOSTLY RELATED TO THE T HELPER TYPE 1 (TH1) RESPONSE TO INFECTION. IT IS CRITICAL FOR DEFENCE AGAINST MYCOBACTERIAL INFECTION AND IS OF INCREASING INTEREST IN DEFENCE AGAINST FUNGI. IN THIS ARTICLE, WE REVIEW THE GENETIC AND EPIGENETIC VARIANTS AFFECTING IFN-GAMMA EXPRESSION AND INVESTIGATE ITS ROLE IN DISEASE, WITH AN EMPHASIS ON FUNGAL DISEASES SUCH AS INVASIVE AND CHRONIC PULMONARY ASPERGILLOSIS. OVER 347 IFN-GAMMA GENE VARIANTS HAVE BEEN DESCRIBED, IN MULTIPLE ETHNIC POPULATIONS. MANY APPEAR TO CONFER A SUSCEPTIBILITY TO DISEASE, ESPECIALLY TUBERCULOSIS (TB) AND HEPATITIS, BUT ALSO SOME NON-INFECTIOUS CONDITIONS SUCH AS APLASTIC ANAEMIA, CERVICAL CANCER AND PSORIASIS. SEVERAL EPIGENETIC MODIFICATIONS ARE ALSO DESCRIBED, INCREASING IFN-GAMMA EXPRESSION IN TH1 LYMPHOCYTES AND REDUCING IFN-GAMMA EXPRESSION IN TH2 LYMPHOCYTES. RECOMBINANT IFN-GAMMA ADMINISTRATION IS LICENSED FOR THE PROPHYLAXIS OF INFECTION (BACTERIAL AND FUNGAL) IN PATIENTS WITH THE PHAGOCYTE FUNCTIONAL DEFICIENCY SYNDROME CHRONIC GRANULOMATOUS DISEASE, ALTHOUGH THE BENEFITS APPEAR LIMITED. INTERFERON-GAMMA THERAPY IS GIVEN TO PATIENTS WITH PROFOUND DEFECTS IN IFN-GAMMA AND INTERLEUKIN-12 PRODUCTION AND APPEARS TO BE BENEFICIAL FOR PATIENTS WITH INVASIVE ASPERGILLOSIS AND CRYPTOCOCCAL MENINGITIS, BUT THE STUDIES ARE NOT DEFINITIVE. A HIGH PROPORTION OF PATIENTS WITH CHRONIC PULMONARY ASPERGILLOSIS ARE POOR PRODUCERS OF IFN-GAMMA IN RESPONSE TO MULTIPLE STIMULI AND COULD ALSO BENEFIT FROM IFN-GAMMA ADMINISTRATION. THE INVESTIGATION AND MANAGEMENT OF PATIENTS WITH POSSIBLE OR DEMONSTRATED IFN-GAMMA DEFICIENCY IN ADULTHOOD IS POORLY STUDIED AND COULD BE GREATLY ENHANCED WITH THE INTEGRATION OF GENETIC DATA.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  2277  41 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14   957  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15  5790  35 SRSF2-P95 HOTSPOT MUTATION IS HIGHLY ASSOCIATED WITH ADVANCED FORMS OF MASTOCYTOSIS AND MUTATIONS IN EPIGENETIC REGULATOR GENES. MASTOCYTOSIS IS A RARE AND CHRONIC DISEASE WITH PHENOTYPES RANGING FROM INDOLENT TO SEVERE. PROGNOSIS FOR THIS DISEASE IS VARIABLE AND VERY FEW BIOMARKERS TO PREDICT DISEASE EVOLUTION OR OUTCOME ARE CURRENTLY KNOWN. WE HAVE PERFORMED COMPREHENSIVE SCREENING IN OUR LARGE COHORT OF MASTOCYTOSIS PATIENTS FOR MUTATIONS PREVIOUSLY FOUND IN OTHER MYELOID DISEASES AND THAT COULD SERVE AS PROGNOSTIC INDICATORS. KIT, SRSF2-P95 AND TET2 MUTATIONS WERE BY FAR THE MOST FREQUENT, DETECTED IN 81%, 24% AND 21% OF PATIENTS, RESPECTIVELY. WHERE TET2 AND SRSF2-P95 MUTATION BOTH CORRELATED WITH ADVANCED DISEASE PHENOTYPES, SRSF2-P95 HOTSPOT MUTATION WAS FOUND ALMOST EXCLUSIVELY IN PATIENTS DIAGNOSED WITH ASSOCIATED CLONAL HEMATOLOGIC NON-MAST CELL DISEASE. STATISTICALLY, TET2 AND SRSF2-P95 MUTATIONS WERE HIGHLY ASSOCIATED, SUGGESTING A MECHANISTIC LINK BETWEEN THESE TWO FACTORS. FINALLY, ANALYSIS OF BOTH CLONAL AND SORTED CELL POPULATIONS FROM PATIENTS CONFIRMS THE PRESENCE OF THESE MUTATIONS IN THE MAST CELL COMPONENT OF THE DISEASE, SUGGESTS AN ONTOLOGICAL MUTATION HIERARCHY AND PROVIDES EVIDENCE FOR THE EXPANSION OF MULTIPLE CLONES. THIS HIGHLIGHTS THE PROGNOSTIC POTENTIAL OF SUCH APPROACHES, IF APPLIED SYSTEMATICALLY, FOR DELINEATING THE ROLES OF SPECIFIC MUTATIONS IN PREDISPOSING AND/OR DRIVING DISTINCT DISEASE PHENOTYPES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16   959  36 CHRONIC MYELOMONOCYTIC LEUKEMIA AND ATYPICAL CHRONIC MYELOID LEUKEMIA: NOVEL PATHOGENETIC LESIONS. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) ARE DISTINCT, YET RELATED, ENTITIES OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) CHARACTERIZED BY MORPHOLOGIC DYSPLASIA WITH ACCUMULATION OF MONOCYTES OR NEUTROPHILS, RESPECTIVELY. OUR UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CMML AND ACML HAS ADVANCED, MAINLY DUE TO THE APPLICATION OF NOVEL TECHNOLOGIES SUCH AS ARRAY-BASED KARYOTYPING AND NEXT-GENERATION SEQUENCING. IN ADDITION TO PREVIOUSLY KNOWN RECURRENT ABERRATIONS, SOMATIC UNIPARENTAL DISOMY AFFECTING CHROMOSOMES 3, 4, 7, AND 11 FREQUENTLY OCCURS IN CMML. NOVEL SOMATIC MUTATIONS OF GENES, INCLUDING THOSE ASSOCIATED WITH PROLIFERATION SIGNALING (CBL, RAS, RUNX1, JAK2 (V617F)) AND WITH MODIFICATION OF EPIGENETIC STATUS (TET2, ASXL1, UTX, EZH2) HAVE BEEN FOUND. VARIOUS COMBINATIONS OF MUTATIONS SUGGEST A MULTISTEP PATHOGENESIS AND MAY ACCOUNT FOR CLINICAL HETEROGENEITY. MOST RECENTLY, SEVERAL SPLICEOSOME-ASSOCIATED-GENE MUTATIONS WERE REPORTED AND SRSF2 MUTATIONS ARE FREQUENTLY DETECTED IN CMML. THE PROGNOSTIC AND DIAGNOSTIC SIGNIFICANCE OF THESE MOLECULAR LESIONS, IN PARTICULAR THEIR VALUE AS BIOMARKERS OF RESPONSE OR RESISTANCE TO SPECIFIC THERAPIES, WHILE UNCERTAIN NOW IS LIKELY TO BE CLARIFIED AS LARGE SYSTEMATIC STUDIES COME TO COMPLETION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17  4442  33 MOLECULAR GENETICS OF MDS/MPN OVERLAP SYNDROMES. THE MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE A HETEROGENOUS GROUP OF MYELOID MALIGNANCIES HALLMARKED BY CLINICOPATHOLOGIC FEATURES THAT OVERLAP WITH MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. FORMALLY RECOGNIZED BY THE WORLD HEALTH ORGANIZATION, THIS GROUP INCLUDES THE ENTITIES CHRONIC MYELOMONOCYTIC LEUKEMIA, JUVENILE MYELOMONOCYTIC LEUKEMIA, ATYPICAL CHRONIC MYELOID LEUKEMIA, MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS AND MDS/MPN, UNCLASSIFIABLE. ADVANCEMENTS IN NEXT GENERATION SEQUENCING HAVE BEGUN TO UNRAVEL THE MOLECULAR UNDERPINNINGS OF THESE DISEASES, IDENTIFYING AN ARRAY OF RECURRENTLY MUTATED GENES INVOLVED IN EPIGENETIC REGULATION, RNA SPLICING, TRANSCRIPTION, AND CELL SIGNALING. DESPITE MOLECULAR OVERLAP WITH OTHER MYELOID MALIGNANCIES, EACH ENTITY DISPLAYS A UNIQUE SPECTRUM OF SOMATIC MUTATIONS SUPPORTING THEIR UNIQUE PATHOBIOLOGY AND CLINICAL FEATURES. IMPORTANTLY, MOLECULAR PROFILING IS BECOMING AN INTEGRAL TOOL UTILIZED IN ROUTINE CLINICAL PRACTICE. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF OVERLAP SYNDROMES AND DETAILS THE IMPACT OF SOMATIC MUTATIONS IN DIAGNOSTIC, PROGNOSTIC, AND THERAPEUTIC DECISION-MAKING.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18  3701  23 INFLAMMATORY RESPONSE TO REGULATED CELL DEATH IN GOUT AND ITS FUNCTIONAL IMPLICATIONS. GOUT, A CHRONIC INFLAMMATORY ARTHRITIS DISEASE, IS CHARACTERIZED BY HYPERURICEMIA AND CAUSED BY INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND METABOLIC FACTORS. ACUTE GOUT SYMPTOMS ARE TRIGGERED BY THE INFLAMMATORY RESPONSE TO MONOSODIUM URATE CRYSTALS, WHICH IS MEDIATED BY THE INNATE IMMUNE SYSTEM AND IMMUNE CELLS (E.G., MACROPHAGES AND NEUTROPHILS), THE NACHT, LRR, AND PYD DOMAINS-CONTAINING PROTEIN 3 (NLRP3) INFLAMMASOME ACTIVATION, AND PRO-INFLAMMATORY CYTOKINE (E.G., IL-1BETA) RELEASE. RECENT STUDIES HAVE INDICATED THAT THE MULTIPLE PROGRAMMED CELL DEATH PATHWAYS INVOLVED IN THE INFLAMMATORY RESPONSE INCLUDE PYROPTOSIS, NETOSIS, NECROPTOSIS, AND APOPTOSIS, WHICH INITIATE INFLAMMATORY REACTIONS. IN THIS REVIEW, WE EXPLORE THE CORRELATION AND INTERACTIONS AMONG THESE FACTORS AND THEIR ROLES IN THE PATHOGENESIS OF GOUT TO PROVIDE FUTURE RESEARCH DIRECTIONS AND POSSIBILITIES FOR IDENTIFYING POTENTIAL NOVEL THERAPEUTIC TARGETS AND ENHANCING OUR UNDERSTANDING OF GOUT PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19  3575  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  4838  39 ONCOGENIC N-RAS AND TET2 HAPLOINSUFFICIENCY COLLABORATE TO DYSREGULATE HEMATOPOIETIC STEM AND PROGENITOR CELLS. CONCURRENT GENETIC LESIONS EXIST IN A MAJORITY OF PATIENTS WITH HEMATOLOGIC MALIGNANCIES. AMONG THESE, SOMATIC MUTATIONS THAT ACTIVATE RAS ONCOGENES AND INACTIVATE THE EPIGENETIC MODIFIER TEN-ELEVEN TRANSLOCATION 2 (TET2) FREQUENTLY CO-OCCUR IN HUMAN CHRONIC MYELOMONOCYTIC LEUKEMIAS (CMMLS) AND ACUTE MYELOID LEUKEMIAS, SUGGESTING A COOPERATIVITY IN MALIGNANT TRANSFORMATION. TO TEST THIS, WE APPLIED A CONDITIONAL MURINE MODEL THAT ENDOGENOUSLY EXPRESSED ONCOGENIC NRAS(G12D) AND MONOALLELIC LOSS OF TET2 AND EXPLORED THE COLLABORATIVE ROLE SPECIFICALLY WITHIN HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS) AT DISEASE INITIATION. WE DEMONSTRATE THAT THE 2 MUTATIONS COLLABORATED TO ACCELERATE A TRANSPLANTABLE CMML-LIKE DISEASE IN VIVO, WITH AN OVERALL SHORTENED SURVIVAL AND INCREASED DISEASE PENETRANCE COMPARED WITH SINGLE MUTANTS. AT PRELEUKEMIC STAGE, N-RAS(G12D) AND TET2 HAPLOINSUFFICIENCY TOGETHER INDUCED BALANCED HEMATOPOIETIC STEM CELL (HSC) PROLIFERATION AND ENHANCED COMPETITIVENESS. NRAS(G12D/+)/TET2(+/-) HSCS DISPLAYED INCREASED SELF-RENEWAL IN PRIMARY AND SECONDARY TRANSPLANTATIONS, WITH SIGNIFICANTLY HIGHER RECONSTITUTION THAN SINGLE MUTANTS. STRIKINGLY, THE 2 MUTATIONS TOGETHER CONFERRED LONG-TERM RECONSTITUTION AND SELF-RENEWAL POTENTIAL TO MULTIPOTENT PROGENITORS, A POOL OF CELLS THAT USUALLY HAVE LIMITED SELF-RENEWAL COMPARED WITH HSCS. MOREOVER, HSPCS FROM NRAS(G12D/+)/TET2(+/-) MICE DISPLAYED INCREASED CYTOKINE SENSITIVITY IN RESPONSE TO THROMBOPOIETIN. THEREFORE, OUR STUDIES ESTABLISH A NOVEL TRACTABLE CMML MODEL AND PROVIDE INSIGHTS INTO HOW DYSREGULATED SIGNALING PATHWAYS AND EPIGENETIC MODIFIERS COLLABORATE TO MODULATE HSPC FUNCTION AND PROMOTE LEUKEMOGENESIS.	2018