1  4181 92 MESENCHYMAL STEM CELLS IN IMMUNE-MEDIATED BONE MARROW FAILURE SYNDROMES. IMMUNE-MEDIATED BONE MARROW FAILURE SYNDROMES (BMFS) ARE CHARACTERIZED BY INEFFECTIVE MARROW HAEMOPOIESIS AND SUBSEQUENT PERIPHERAL CYTOPENIAS. INEFFECTIVE HAEMOPOIESIS IS THE RESULT OF A COMPLEX MARROW DEREGULATION INCLUDING GENETIC, EPIGENETIC, AND IMMUNE-MEDIATED ALTERATIONS IN HAEMOPOIETIC STEM/PROGENITOR CELLS, AS WELL AS ABNORMAL HAEMOPOIETIC-TO-STROMAL CELL INTERACTIONS, WITH ABNORMAL RELEASE OF HAEMOPOIETIC GROWTH FACTORS, CHEMOKINES, AND INHIBITORS. MESENCHYMAL STEM/STROMAL CELLS (MSCS) AND THEIR PROGENY (I.E., OSTEOBLASTS, ADIPOCYTES, AND RETICULAR CELLS) ARE CONSIDERED AS KEY CELLULAR COMPONENTS OF THE BONE MARROW HAEMOPOIETIC NICHE. MSCS MAY INTERFERE WITH HAEMOPOIETIC AS WELL AS IMMUNE REGULATION. EVIDENCE SUGGESTS THAT BONE MARROW MSCS MAY BE INVOLVED IN IMMUNE-MEDIATED BMFS UNDERLYING PATHOPHYSIOLOGY, HARBORING EITHER NATIVE ABNORMALITIES AND/OR SECONDARY DEFECTS, CAUSED BY EXPOSURE TO ACTIVATED MARROW COMPONENTS. THIS REVIEW SUMMARIZES PREVIOUS AS WELL AS MORE RECENT INFORMATION RELATED TO THE BIOLOGIC/FUNCTIONAL CHARACTERISTICS OF BONE MARROW MSCS IN MYELODYSPLASTIC SYNDROMES, ACQUIRED APLASTIC ANEMIA, AND CHRONIC IDIOPATHIC NEUTROPENIA.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2  1575 20 DNA METHYLATION PATTERNS OF GENES RELATED TO IMMUNE RESPONSE IN THE DIFFERENT CLINICAL FORMS OF ORAL LICHEN PLANUS. BACKGROUND: THE ORAL LICHEN PLANUS IS A CHRONIC INFLAMMATORY DISEASE. ALTHOUGH ITS AETIOLOGY IS NOT WELL UNDERSTOOD, THE ROLE OF T LYMPHOCYTES IN ITS INFLAMMATORY EVENTS IS RECOGNISED. IDENTIFYING THE EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF THIS IMMUNE-MEDIATED CONDITION IS FUNDAMENTAL FOR UNDERSTANDING THE INFLAMMATORY REACTION THAT OCCURS IN THE DISEASE. THE PURPOSE OF THIS WORK WAS TO EVALUATE THE METHYLATION PATTERN OF 21 IMMUNE RESPONSE-RELATED GENES IN THE DIFFERENT CLINICAL FORMS OF ORAL LICHEN PLANUS. METHODS: A CROSS-SECTIONAL STUDY WAS PERFORMED TO ANALYSE THE DNA METHYLATION PATTERNS IN THREE DISTINCT GROUPS OF ORAL LICHEN PLANUS: (I) RETICULAR/PLAQUE LESIONS; (II) EROSIVE LESIONS; (III) NORMAL ORAL MUCOSA (CONTROL GROUP). AFTER DNA EXTRACTION FROM BIOPSIES, THE SAMPLES WERE SUBMITTED TO DIGESTIONS BY METHYLATION-SENSITIVE AND METHYLATION-DEPENDENT ENZYMES AND DOUBLE DIGESTION. THE RELATIVE PERCENTAGE OF METHYLATED DNA FOR EACH GENE WAS PROVIDED USING REAL-TIME POLYMERASE CHAIN REACTION ARRAYS. RESULTS: HYPERMETHYLATION OF THE STAT5A GENE WAS OBSERVED ONLY IN THE CONTROL GROUP (59.0%). A HIGHER HYPERMETHYLATION OF THE ELANE GENE WAS FOUND IN RETICULAR/PLAQUE LESIONS (72.1%) COMPARED TO THE EROSIVE LESIONS (50.0%). CONCLUSION: OUR RESULTS SHOW VARIATIONS IN THE METHYLATION PROFILE OF IMMUNE RESPONSE-RELATED GENES, ACCORDING TO THE CLINICAL TYPE OF ORAL LICHEN PLANUS AFTER COMPARING WITH THE NORMAL ORAL MUCOSA. FURTHER STUDIES ARE NECESSARY TO VALIDATE THESE FINDINGS USING GENE EXPRESSION ANALYSIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
3  3272 32 HEPATOCELLULAR CARCINOMA: AN UPDATE. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON MALIGNANT TUMOR OF MALES IN THE WORLD, WITH AN INCIDENCE OF 1,000,000 NEW CASES A YEAR. IT IS ENDEMIC IN SOUTHEAST ASIA AND SUB-SAHARAN AFRICA. RISK FACTORS INCLUDE CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV), AFLATOXIN B1 UPTAKE, HEMOCHROMATOSIS, AND ALPHA1 -ANTITRIPSIN DEFICIENCY. EPIDEMIOLOGICAL STUDIES PROVIDE EVIDENCE FOR THE ASSOCIATION OF HCC WITH HBV INFECTION. THE INCIDENCE OF HCC IS HIGH IN REGIONS HYPERENDEMIC FOR HBV. CHRONIC CARRIER STATE AND MATERNAL-INFANT TRANSMISSION ARE IMPORTANT FACTORS IN THE DEVELOPMENT OF HCC. EVIDENCE OF DIRECT ONCOGENIC EFFECT OF H BV IS WELL ESTABLISHED, HCCS CONTAIN VIRAL DNA SEQUENCES INTEGRATED INTO HEPATOCYTE DNA THAT ACT AS RANDOM INSERTIONAL MUTAGENS, AND THESE SITES ARE NEAR GENES INVOLVED IN THE CONTROL OF PROLIFERATION AND DIFFERENTIATION. THE MECHANISM OF HEPATITIS C VIRUS IN HEPATOCARCINOGENESIS IS STILL IMPRECISE BUT A HIGH PERCENTAGE OF CASES ARE RELATED TO THIS VIRUS. CHRONIC ALCOHOL CONSUMPTION AND CIRRHOSIS ARE COFACTORS THAT INCREASE THE DEVELOPMENT OF HCC IN PATIENTS WITH CHRONIC VIRAL INFECTION. IN EXPERIMENTAL CARCINOGENESIS A MULTIPOTENTIAL ELEMENT CALLED OVAL CELL PROLIFERATES IN THE EARLY STAGES. THE CELLULAR EVENTS ARE ACCOMPANIED BY INCREASED EXPRESSION OF SEVERAL GROWTH FACTORS THAT ENHANCE THE SURVIVAL OF CARCINOGEN-ACTIVATED CELLS BY SUPPRESSING APOPTOSIS AND INCREASING ELEMENTS ENTERING THE CELL CYCLE. HEPATIC CARCINOGENESIS IS A COMPLEX PROCESS ASSOCIATED WITH ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES THAT RUN THROUGH STEPS OF INITIATION, PROMOTION AND PROGRESSION. ACTIVATION OF ONCOGENES OF THE "RAS" FAMILY AND OTHERS HAS BEEN DETECTED DURING CHEMICALLY-INDUCED HCC IN RODENTS, BUT THERE IS LITTLE EVIDENCE OF SUCH ACTIVATION IN HUMAN TUMORS. THE ROLE OF TUMOR SUPRESSOR GENES SUCH AS RETINOBLASTOMA (RB) AND P53 GENES HAS BEEN DOCUMENTED. AFLATOXIN B1 THAT CONTAMINATES FOODS IN ENDEMIC AREAS HAS A CLEAR ROLE IN HEPATOCARCINOGENESIS. METABOLITES OF THIS TOXIN PROMOTE APURINIC SITES AND G TO T MUTATIONS IN CHROMOSOMAL DNA, THE THIRD BASE OF CODON 249 OF THE P53 GENE IS PREFERENTIALLY TARGETED TO FORM ADUCTS WITH AFLATOXIN B1, AND THIS MUTATION HAS BEEN SPECIFICALLY IDENTIFIED IN HBV INFECTION. HISTOLOGICAL AND CYTOLOGICAL CRITERIA FOR THE DIAGNOSIS OF HCC ARE WELL ESTABLISHED AND ARE BASED IN ARCHITECTURAL AND CYTOLOGICAL CHANGES. AN IMPORTANT ISSUE IS THE DIAGNOSIS OF LIVER "NODULES" DETECTED BY IMAGE, FROM WHICH SMALL BIOPSIES OR ASPIRATION MATERIAL IS OBTAINED. SPECIAL STUDIES SUCH AS RETICULIN, CD34, CYTOKERATIN PROFILE, AND MOC-31 CAN BE VERY USEFUL FOR THE DIFFERENTIAL DIAGNOSIS OF PRIMARY AND METASTATIC TUMORS. TELOMERASE ACTIVITY HAS BEEN FOUND IN HCC AND NEGATIVE IN PERICANCEROUS TISSUE. IT IS MORE PRONOUNCED IN POORLY DIFFERENTIATED TUMORS AND CORRELATES WITH FACTORS OF CLINICAL IMPORTANCE, SUCH AS PROGNOSIS AND RECURRENCES. CELLS OF WELL-DIFFERENTIATED HCC HAVE AN ULTRASTRUCTURAL APPEARANCE SIMILAR TO NORMAL HEPATOCYTES. DURING THE PROCESS OF DEDIFFERENTIATION, THERE IS PROGRESSIVE LOSS OF ORGANIZATION OF INTRACELLULAR ORGANELLES. THE CELL COHESION IS LOST, INTERCELLULAR GAPS WITH MICROVILLI APPEAR, THE SINUSOIDS BECOME CAPILLARIZED, AND REPARATIVE CHANGES ARE SEEN IN THE SPACES OF DISSE. A VARIETY OF INCLUSIONS, SUCH AS MALLORY BODIES, GRANULAR MATERIAL, SECONDARY LYSOSOMES, AND DUBIN-JOHNSON PIGMENT, HAVE BEEN DESCRIBED. FIBROLAMELLAR CARCINOMA HAS A CHARACTERISTIC HISTOLOGICAL PICTURE AND ULTRASTRUCTURALLY ONCOCYTIC FEATURES. NEUROENDOCRINE GRANULES AND COMBINATION OF HCC WITH BILE DUCT CARCINOMA ARE SEEN BY ELECTRON MICROSCOPY.	2001	

4  6619 21 UNDERSTANDING CHRONIC VENOUS DISEASE: A CRITICAL OVERVIEW OF ITS PATHOPHYSIOLOGY AND MEDICAL MANAGEMENT. CHRONIC VENOUS DISEASE (CVD) IS A MULTIFACTORIAL CONDITION AFFECTING AN IMPORTANT PERCENTAGE OF THE GLOBAL POPULATION. IT RANGES FROM MILD CLINICAL SIGNS, SUCH AS TELANGIECTASIAS OR RETICULAR VEINS, TO SEVERE MANIFESTATIONS, SUCH AS VENOUS ULCERATIONS. HOWEVER, VARICOSE VEINS (VVS) ARE THE MOST COMMON MANIFESTATION OF CVD. THE EXPLICIT MECHANISMS OF THE DISEASE ARE NOT WELL-UNDERSTOOD. IT SEEMS THAT GENETICS AND A PLETHORA OF ENVIRONMENTAL AGENTS PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT AND PROGRESSION OF CVD. THE EXPOSURE TO THESE FACTORS LEADS TO ALTERED HEMODYNAMICS OF THE VENOUS SYSTEM, DESCRIBED AS AMBULATORY VENOUS HYPERTENSION, THEREFORE PROMOTING MICROCIRCULATORY CHANGES, INFLAMMATORY RESPONSES, HYPOXIA, VENOUS WALL REMODELING, AND EPIGENETIC VARIATIONS, EVEN WITH IMPORTANT SYSTEMIC IMPLICATIONS. THUS, A PROPER CLINICAL MANAGEMENT OF PATIENTS WITH CVD IS ESSENTIAL TO PREVENT POTENTIAL HARMS OF THE DISEASE, WHICH ALSO ENTAILS A SIGNIFICANT LOSS OF THE QUALITY OF LIFE IN THESE INDIVIDUALS. HENCE, THE AIM OF THE PRESENT REVIEW IS TO COLLECT THE CURRENT KNOWLEDGE OF CVD, INCLUDING ITS EPIDEMIOLOGY, ETIOLOGY, AND RISK FACTORS, BUT EMPHASIZING THE PATHOPHYSIOLOGY AND MEDICAL CARE OF THESE PATIENTS, INCLUDING CLINICAL MANIFESTATIONS, DIAGNOSIS, AND TREATMENTS. FURTHERMORE, FUTURE DIRECTIONS WILL ALSO BE COVERED IN THIS WORK IN ORDER TO PROVIDE POTENTIAL FIELDS TO EXPLORE IN THE CONTEXT OF CVD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5  5455 23 RESCUE OF A PRIMARY MYELOFIBROSIS MODEL BY RETINOID-ANTAGONIST THERAPY. MOLECULAR TARGETING OF THE TWO RECEPTOR INTERACTION DOMAINS OF THE EPIGENETIC REPRESSOR SILENCING MEDIATOR OF RETINOID AND THYROID HORMONE RECEPTORS (SMRT(MRID)) PRODUCED A TRANSPLANTABLE SKELETAL SYNDROME THAT REDUCED RADIAL BONE GROWTH, INCREASED NUMBERS OF BONE-RESORBING PERIOSTEAL OSTEOCLASTS, AND INCREASED BONE FRACTURE RISK. FURTHERMORE, SMRT(MRID) MICE DEVELOP SPONTANEOUS PRIMARY MYELOFIBROSIS, A CHRONIC, USUALLY IDIOPATHIC DISORDER CHARACTERIZED BY PROGRESSIVE BONE MARROW FIBROSIS. FREQUENTLY LINKED TO POLYCYTHEMIA VERA AND CHRONIC MYELOID LEUKEMIA, MYELOFIBROSIS DISPLAYS HIGH PATIENT MORBIDITY AND MORTALITY, AND CURRENT TREATMENT IS MOSTLY PALLIATIVE. TO DECIPHER THE ETIOLOGY OF THIS DISEASE, WE IDENTIFIED THE THROMBOPOIETIN (TPO) GENE AS A TARGET OF THE SMRT-RETINOIC ACID RECEPTOR SIGNALING PATHWAY IN BONE MARROW STROMAL CELLS. CHRONIC INDUCTION OF TPO IN SMRT(MRID) MICE RESULTS IN UP-REGULATION OF TGF-BETA AND PDGF IN MEGAKARYOCYTES, UNCONTROLLED PROLIFERATION OF BONE MARROW RETICULAR CELLS, AND FIBROSIS OF THE MARROW COMPARTMENT. OF THERAPEUTIC RELEVANCE, WE SHOW THAT THIS SYNDROME CAN BE RESCUED BY RETINOID ANTAGONISTS, DEMONSTRATING THAT THE PHYSICAL INTERFACE BETWEEN SMRT AND RETINOIC ACID RECEPTOR CAN BE A POTENTIAL THERAPEUTIC TARGET TO BLOCK PRIMARY MYELOFIBROSIS DISEASE PROGRESSION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6   961 20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7  4442 22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8  4562 24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9  4566 21 MYELOID SOMATIC MUTATION PANEL TESTING IN MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATIVE NEOPLASMS ARE CHARACTERISED BY SOMATIC MUTATIONS IN PATHWAYS THAT REGULATE CELL PROLIFERATION, EPIGENETIC MODIFICATIONS, RNA SPLICING OR DNA REPAIR. ASSESSMENT OF THE MUTATIONAL PROFILE ASSISTS DIAGNOSIS AND CLASSIFICATION, BUT ALSO AIDS ASSESSMENT OF PROGNOSIS, AND MAY GUIDE THE USE OF EMERGING TARGETED THERAPIES. THE MOST PRACTICAL WAY TO PROVIDE INFORMATION ON NUMEROUS GENETIC VARIANTS IS BY USING MASSIVELY PARALLEL SEQUENCING, COMMONLY IN THE FORM OF DISEASE SPECIFIC NEXT GENERATION SEQUENCING (NGS) PANELS. THIS REVIEW SUMMARISES THE DIAGNOSTIC AND PROGNOSTIC VALUE OF SOMATIC MUTATION TESTING IN PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: POLYCYTHAEMIA VERA, ESSENTIAL THROMBOCYTHAEMIA, PRIMARY MYELOFIBROSIS, CHRONIC NEUTROPHILIC LEUKAEMIA, SYSTEMIC MASTOCYTOSIS, AND CHRONIC EOSINOPHILIC LEUKAEMIA. NGS PANEL TESTING IS INCREASING IN ROUTINE PRACTICE AND PROMISES TO IMPROVE THE ACCURACY AND EFFICIENCY OF PATHOLOGICAL DIAGNOSIS AND PROGNOSIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10   962 20 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   255 19 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12   959 22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13   957 25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14  1311 29 DEFINITIONS, BIOLOGY, AND CURRENT THERAPEUTIC LANDSCAPE OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS. MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE HEMATOLOGICAL DISORDERS CHARACTERIZED BY BOTH PROLIFERATIVE AND DYSPLASTIC FEATURES. ACCORDING TO THE 2022 INTERNATIONAL CONSENSUS CLASSIFICATION (ICC), MDS/MPN CONSISTS OF CLONAL MONOCYTOSIS OF UNDETERMINED SIGNIFICANCE (CMUS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML), MDS/MPN WITH SF3B1 MUTATION (MDS/MPN-T-SF3B1), MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS NOT OTHERWISE SPECIFIED (MDS/MPN-RS-T-NOS), AND MDS/MPN-NOS. THESE DISORDERS EXHIBIT A DIVERSE RANGE OF GENETIC ALTERATIONS INVOLVING VARIOUS TRANSCRIPTION FACTORS (E.G., RUNX1), SIGNALING MOLECULES (E.G., NRAS, JAK2), SPLICING FACTORS (E.G., SF3B, SRSF2), AND EPIGENETIC REGULATORS (E.G., TET2, ASXL1, DNMT3A), AS WELL AS SPECIFIC CYTOGENETIC ABNORMALITIES (E.G., 8 TRISOMIES, 7 DELETIONS/MONOSOMIES). CLINICAL STUDIES EXPLORING THERAPEUTIC OPTIONS FOR HIGHER-RISK MDS/MPN OVERLAP SYNDROMES MOSTLY INVOLVE HYPOMETHYLATING AGENTS, BUT OTHER TREATMENTS SUCH AS LENALIDOMIDE AND TARGETED AGENTS SUCH AS JAK INHIBITORS AND INHIBITORS TARGETING PARP, HISTONE DEACETYLASES, AND THE RAS PATHWAY ARE UNDER INVESTIGATION. WHILE THESE TREATMENT MODALITIES CAN PROVIDE PARTIAL DISEASE CONTROL, ALLOGENEIC BONE MARROW TRANSPLANTATION (ALLO-BMT) IS THE ONLY POTENTIALLY CURATIVE OPTION FOR PATIENTS. IMPORTANT PROGNOSTIC FACTORS CORRELATING WITH OUTCOMES AFTER ALLO-BMT INCLUDE COMORBIDITIES, SPLENOMEGALY, KARYOTYPE ALTERATIONS, AND THE BONE MARROW BLASTS PERCENTAGE AT THE TIME OF TRANSPLANTATION. FUTURE RESEARCH IS IMPERATIVE TO OPTIMIZING THERAPEUTIC STRATEGIES AND ENHANCING PATIENT OUTCOMES IN MDS/MPN NEOPLASMS. IN THIS REVIEW, WE SUMMARIZE MDS/MPN DIAGNOSTIC CRITERIA, BIOLOGY, AND CURRENT AND FUTURE TREATMENT OPTIONS, INCLUDING BONE MARROW TRANSPLANTATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15  4485 26 MOLECULAR SIMILARITY BETWEEN MYELODYSPLASTIC FORM OF CHRONIC MYELOMONOCYTIC LEUKEMIA AND REFRACTORY ANEMIA WITH RING SIDEROBLASTS. CHRONIC MYELOMONOCYTIC LEUKEMIA IS SIMILAR TO BUT A SEPARATE ENTITY FROM BOTH MYELOPROLIFERATIVE NEOPLASMS AND MYELODYSPLASTIC SYNDROMES, AND SHOWS EITHER MYELOPROLIFERATIVE OR MYELODYSPLASTIC FEATURES. WE ASK WHETHER THIS DISTINCTION MAY HAVE A MOLECULAR BASIS. WE ESTABLISHED THE GENE EXPRESSION PROFILES OF 39 SAMPLES OF CHRONIC MYELOMONOCYTIC LEUKEMIA (INCLUDING 12 CD34-POSITIVE) AND 32 CD34-POSITIVE SAMPLES OF MYELODYSPLASTIC SYNDROMES BY USING AFFYMETRIX MICROARRAYS, AND STUDIED THE STATUS OF 18 GENES BY SANGER SEQUENCING AND ARRAY-COMPARATIVE GENOMIC HYBRIDIZATION IN 53 SAMPLES. ANALYSIS OF 12 MRNAS FROM CHRONIC MYELOMONOCYTIC LEUKEMIA ESTABLISHED A GENE EXPRESSION SIGNATURE OF 122 PROBE SETS DIFFERENTIALLY EXPRESSED BETWEEN PROLIFERATIVE AND DYSPLASTIC CASES OF CHRONIC MYELOMONOCYTIC LEUKEMIA. AS COMPARED TO PROLIFERATIVE CASES, DYSPLASTIC CASES OVER-EXPRESSED GENES INVOLVED IN RED BLOOD CELL BIOLOGY. WHEN APPLIED TO 32 MYELODYSPLASTIC SYNDROMES, THIS GENE EXPRESSION SIGNATURE WAS ABLE TO DISCRIMINATE REFRACTORY ANEMIAS WITH RING SIDEROBLASTS FROM REFRACTORY ANEMIAS WITH EXCESS OF BLASTS. BY COMPARING MRNAS FROM THESE TWO FORMS OF MYELODYSPLASTIC SYNDROMES WE DERIVED A SECOND GENE EXPRESSION SIGNATURE. THIS SIGNATURE SEPARATED THE MYELODYSPLASTIC AND MYELOPROLIFERATIVE FORMS OF CHRONIC MYELOMONOCYTIC LEUKEMIAS. THESE RESULTS WERE VALIDATED USING TWO INDEPENDENT GENE EXPRESSION DATA SETS. WE FOUND THAT MYELODYSPLASTIC CHRONIC MYELOMONOCYTIC LEUKEMIAS ARE CHARACTERIZED BY MUTATIONS IN TRANSCRIPTION/EPIGENETIC REGULATORS (ASXL1, RUNX1, TET2) AND SPLICING GENES (SRSF2) AND THE ABSENCE OF MUTATIONS IN SIGNALING GENES. MYELODYSPLASTIC CHRONIC MYELOMONOCYTIC LEUKEMIAS AND REFRACTORY ANEMIAS WITH RING SIDEROBLASTS SHARE A COMMON EXPRESSION PROGRAM SUGGESTING THEY ARE PART OF A CONTINUUM, WHICH IS NOT TOTALLY EXPLAINED BY THEIR SIMILAR BUT NOT, HOWEVER, IDENTICAL MUTATION SPECTRUM.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16  5953 27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17  1266 23 CYTOGENETIC AND MOLECULAR ABNORMALITIES IN CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER ASSOCIATED WITH PERIPHERAL BLOOD MONOCYTOSIS AND AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKEMIA. CMML HAS OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. CLONAL CYTOGENETIC CHANGES ARE SEEN IN ~30%, WHEREAS GENE MUTATIONS ARE SEEN IN >90% OF PATIENTS. COMMON CYTOGENETIC ABNORMALITIES INCLUDE; TRISOMY 8, -Y, -7/DEL(7Q), TRISOMY 21 AND DEL(20Q), WITH THE MAYO-FRENCH RISK STRATIFICATION EFFECTIVELY RISK STRATIFYING PATIENTS BASED ON CYTOGENETIC ABNORMALITIES. GENE MUTATIONS FREQUENTLY INVOLVE EPIGENETIC REGULATORS (TET2 ~60%), MODULATORS OF CHROMATIN (ASXL1 ~40%), SPLICEOSOME COMPONENTS (SRSF2 ~50%), TRANSCRIPTION FACTORS (RUNX1 ~15%) AND SIGNAL PATHWAYS (RAS ~30%, CBL ~15%). OF THESE, THUS FAR, ONLY NONSENSE AND FRAMESHIFT ASXL1 MUTATIONS HAVE BEEN SHOWN TO NEGATIVELY IMPACT OVERALL SURVIVAL. THIS HAS RESULTED IN THE DEVELOPMENT OF CONTEMPORARY, MOLECULARLY INTEGRATED (INCLUSIVE OF ASXL1 MUTATIONS) CMML PROGNOSTIC MODELS, INCLUDING MOLECULAR MAYO MODEL AND THE GROUPE FRANCAIS DES MYELODYSPLASIES MODEL. BETTER UNDERSTANDING OF THE PREVALENT GENETIC AND EPIGENETIC DYSREGULATION HAS RESULTED IN EMERGING TARGETED TREATMENT OPTIONS FOR SOME PATIENTS. THE DEVELOPMENT OF AN INTEGRATED (CYTOGENETIC AND MOLECULAR) PROGNOSTIC MODEL ALONG WITH CMML-SPECIFIC RESPONSE ASSESSMENT CRITERIA ARE MUCH NEEDED FUTURE GOALS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18   960 27 CHRONIC MYELOMONOCYTIC LEUKEMIA: 2016 UPDATE ON DIAGNOSIS, RISK STRATIFICATION, AND MANAGEMENT. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. DIAGNOSIS IS BASED ON THE PRESENCE OF PERSISTENT (>3 MONTHS) PERIPHERAL BLOOD MONOCYTOSIS (>1 X 10(9) /L), ALONG WITH BONE MARROW DYSPLASIA. CLONAL CYTOGENETIC ABNORMALITIES OCCUR IN APPROXIMATELY 20-30% OF PATIENTS, WHILE >90% HAVE GENE MUTATIONS. MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT; WITH ONLY ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. TWO MOLECULARLY INTEGRATED, CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE; THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) AND THE MOLECULAR MAYO MODEL (MMM). THE GFM MODEL SEGREGATES PATIENTS INTO 3 GROUPS BASED ON: AGE >65 YEARS, WBC >15 X 10(9) /L, ANEMIA, PLATELETS <100 X 10(9) /L, AND ASXL1 MUTATION STATUS, WITH RESPECTIVE MEDIAN SURVIVALS OF 56 (LOW), 27.4 (INTERMEDIATE), AND 9.2 (HIGH) MONTHS. THE MMM IS BASED ON ASXL1 MUTATIONAL STATUS, ABSOLUTE MONOCYTE COUNT >10 X 10(9) /L, HEMOGLOBIN <10 G/DL, PLATELETS <100 X 109/L AND CIRCULATING IMMATURE MYELOID CELLS. THIS MODEL STRATIFIES PATIENTS INTO FOUR GROUPS; HIGH (>/=3 RISK FACTORS), INTERMEDIATE-2 (2 RISK FACTORS), INTERMEDIATE-1 (1 RISK FACTOR) AND LOW (NO RISK FACTORS), WITH MEDIAN SURVIVALS OF 16, 31, 59, AND 97 MONTHS, RESPECTIVELY. HYPOMETHYLATING AGENTS SUCH AS 5-AZACITIDINE AND DECITABINE ARE COMMONLY USED, WITH OVERALL RESPONSE RATES OF APPROXIMATELY 30-40% AND COMPLETE REMISSION RATES OF APPROXIMATELY 7-17%. ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY POTENTIALLY CURATIVE OPTION, BUT IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY. INDIVIDUALIZED THERAPY, INCLUDING EPIGENETIC MODIFIERS AND SMALL MOLECULE INHIBITORS, ARE EXCITING PROSPECTS. AM. J. HEMATOL. 91:632-642, 2016. (C) 2016 WILEY PERIODICALS, INC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  3872 27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  2277 36 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