1  4753 163 NOVEL THERAPEUTIC ADVANCES IN BETA-THALASSEMIA. THE MAIN CHARACTERISTIC OF THE PATHOPHYSIOLOGY OF BETA-THALASSEMIA IS REDUCED BETA-GLOBIN CHAIN PRODUCTION. THE INEVITABLE IMBALANCE IN THE ALPHA/BETA-GLOBIN RATIO AND ALPHA-GLOBIN ACCUMULATION LEAD TO OXIDATIVE STRESS IN THE ERYTHROID LINEAGE, APOPTOSIS, AND INEFFECTIVE ERYTHROPOIESIS. THE RESULT IS COMPENSATORY HEMATOPOIETIC EXPANSION AND IMPAIRED HEPCIDIN PRODUCTION THAT CAUSES INCREASED INTESTINAL IRON ABSORPTION AND PROGRESSIVE IRON OVERLOAD. CHRONIC HEMOLYSIS AND RED BLOOD CELL TRANSFUSIONS ALSO CONTRIBUTE TO IRON TISSUE DEPOSITION. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS LED TO THE DETECTION OF NEW CURATIVE OR "DISEASE-MODIFYING" THERAPEUTIC OPTIONS. SUBSTANTIAL EVOLVEMENT HAS BEEN MADE IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH CURRENT CLINICAL TRIALS INVESTIGATING NEW CONDITION REGIMENS AS WELL AS DIFFERENT DONORS AND STEM CELL SOURCE OPTIONS. GENE THERAPY HAS ALSO MOVED FORWARD, AND PHASE 2 CLINICAL TRIALS WITH THE USE OF BETA-GLOBIN INSERTION TECHNIQUES HAVE RECENTLY BEEN SUCCESSFULLY COMPLETED LEADING TO APPROVAL FOR USE IN TRANSFUSION-DEPENDENT PATIENTS. GENETIC AND EPIGENETIC MANIPULATION OF THE GAMMA- OR BETA-GLOBIN GENE HAVE ENTERED THE CLINICAL TRIAL SETTING. AGENTS SUCH AS TGF-BETA LIGAND TRAPS AND PYRUVATE KINASE ACTIVATORS, WHICH REDUCE THE INEFFECTIVE ERYTHROPOIESIS, HAVE BEEN TESTED IN CLINICAL TRIALS WITH FAVORABLE RESULTS. ONE TGF-BETA LIGAND TRAP, LUSPATERCEPT, HAS BEEN APPROVED FOR USE IN ADULTS WITH TRANSFUSION-DEPENDENT BETA-THALASSEMIA. THE INDUCTION OF HBF WITH THE PHOSPHODIESTERASE 9 INHIBITOR IMR-687, WHICH INCREASE CYCLIC GUANOSINE MONOPHOSPHATE, IS CURRENTLY BEING TESTED. ANOTHER THERAPEUTIC APPROACH IS TO TARGET THE DYSREGULATION OF IRON HOMEOSTASIS, USING, FOR EXAMPLE, HEPCIDIN AGONISTS (INHIBITORS OF TMPRSS6 AND MINIHEPCIDINS) OR FERROPORTIN INHIBITORS (VIT-2763). THIS REVIEW PROVIDES AN UPDATE ON THE NOVEL THERAPEUTIC OPTIONS THAT ARE PRESENTLY IN DEVELOPMENT AT THE CLINICAL LEVEL IN BETA-THALASSEMIA.	2021	
                                                                                                                                                                                                                        
2    12  84 2017 CLINICAL TRIALS UPDATE IN NEW TREATMENTS OF BETA-THALASSEMIA. THE UNDERLYING BASIS OF BETA-THALASSEMIA PATHOLOGY IS THE DIMINISHED BETA-GLOBIN SYNTHESIS LEADING TO ALPHA-GLOBIN ACCUMULATION AND PREMATURE APOPTOTIC DESTRUCTION OF ERYTHROBLASTS, CAUSING OXIDATIVE STRESS-INDUCED INEFFECTIVE ERYTHROPOIESIS, BONE MARROW HYPERPLASIA, SPLENOMEGALY, AND INCREASED INTESTINAL IRON ABSORPTION WITH PROGRESSIVE IRON OVERLOAD. BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS UNDERLYING THIS DISEASE LED TO THE RECOGNITION OF NEW TARGETS WITH POTENTIAL THERAPEUTIC UTILITY. AGENTS SUCH AS JAK2 INHIBITORS AND TGF-BETA LIGAND TRAPS THAT REDUCE THE INEFFECTIVE ERYTHROPOIESIS PROCESS ARE ALREADY BEING TESTED IN CLINICAL TRIALS WITH PROMISING RESULTS. OTHER AGENTS THAT AIM TO REDUCE OXIDATIVE STRESS (ACTIVATORS OF FOXO3, HRI-EIF2AP, PRX2, HSP70, AND PK ANTI-OXIDANT SYSTEMS AND INHIBITORS OF HO-1) AND TO DECREASE IRON OVERLOAD (HEPCIDIN AGONISTS, ERYTHROFERRONE INHIBITORS AND EXOGENOUS TRANSFERRIN) ARE ALSO UNDER EXPERIMENTAL INVESTIGATION. SIGNIFICANT PROGRESS HAS ALSO BEEN MADE IN THE AREA OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION WITH SEVERAL ONGOING CLINICAL TRIALS EXAMINING NEW CONDITION REGIMENS AS WELL AS DIFFERENT DONOR SELECTION AND STEM CELL SOURCE OPTIONS. GENE THERAPY HAS REACHED A CRITICAL POINT AND PHASE 1 CLINICAL TRIALS HAVE RECENTLY BEEN LAUNCHED TO EXAMINE THE EFFECTIVENESS AND ESPECIALLY LONG TERM SAFETY. EPIGENETIC MANIPULATION AND GENOMIC EDITING OF THE GAMMA- OR BETA-GLOBIN GENE ARE NOVEL AND PROMISING EXPERIMENTAL GENE THERAPY APPROACHES FOR BETA-THALASSEMIA GIVING HOPE FOR CURE FOR THIS CHRONIC DISEASE. THIS REVIEW OUTLINES THE KEY POINTS OF THE MOLECULAR MECHANISMS UNDERLYING BETA-THALASSEMIA IN RELATION TO THE DEVELOPMENT OF NEW THERAPIES AND AN UPDATE IS GIVEN BOTH AT THE PRE-CLINICAL AND CLINICAL LEVEL. AM. J. HEMATOL. 91:1135-1145, 2016. (C) 2016 WILEY PERIODICALS, INC.	2016	
                                                                                                                                                                                                                                                                                                                                                   
3  4686  70 NEW THERAPEUTIC TARGETS IN TRANSFUSION-DEPENDENT AND -INDEPENDENT THALASSEMIA. BETA-THALASSEMIAS ARE CHARACTERIZED BY REDUCED PRODUCTION OF BETA-GLOBIN CHAIN, RESULTING IN ALPHA/BETA-CHAIN UNBALANCE AND PRECIPITATION OF ALPHA-GLOBIN-HEME COMPLEXES AND DETERMINING INEFFECTIVE ERYTHROPOIESIS. INEFFECTIVE ERYTHROPOIESIS, CHRONIC HEMOLYTIC ANEMIA, AND COMPENSATORY HEMATOPOIETIC EXPANSION ARE THE DISEASE HALLMARKS, AND THEY ARE RELATED TO THE SEVERITY OF THE CHAIN UNBALANCE. SEVERAL CLINICAL FORMS OF BETA-THALASSEMIA, INCLUDING THE COINHERITANCE OF BETA-THALASSEMIA WITH HEMOGLOBIN E RESULTING IN HEMOGLOBIN E/BETA-THALASSEMIA, HAVE BEEN DESCRIBED. CLINICALLY, BETA-THALASSEMIAS CAN BE CLASSIFIED AS TRANSFUSION-DEPENDENT THALASSEMIA (TDT) AND NON-TRANSFUSION-DEPENDENT THALASSEMIA (NTDT) ACCORDING TO THE SEVERITY OF THE PHENOTYPE, WHICH IS CAUSED BY A WIDE SPECTRUM OF MUTATIONS IN A HOMOZYGOUS OR COMPOUND HETEROZYGOUS STATE. CURRENT TREATMENT OF TDT CONSISTS OF REGULAR TRANSFUSIONS THAT LEAD TO IRON OVERLOAD, REQUIRING IRON CHELATION TO PREVENT IRON-RELATED ORGAN TOXICITY. NTDT PATIENTS DO NOT REQUIRE TRANSFUSIONS OR ONLY OCCASIONALLY REQUIRE THEM; HOWEVER, THEY DEVELOP IRON OVERLOAD AS WELL BECAUSE OF INCREASED INTESTINAL IRON ABSORPTION CAUSED BY CHRONIC ANEMIA. HEMATOPOIETIC STEM CELL ALLOGENIC TRANSPLANT IS THE ONLY APPROVED CURE FOR BETA-THALASSEMIA; HOWEVER, IT IS STILL LIMITED BY CLINICAL CONDITIONS AND THE AVAILABILITY OF MATCHED DONORS AS WELL AS BY POTENTIAL GRAFT-VERSUS-HOST DISEASE (GVHD). GENE THERAPY COULD AVOID THE GVHD RISK, ALTHOUGH HEMATOPOIETIC STEM CELLS MUST BE GENETICALLY MODIFIED EX VIVO. EPIGENETIC MANIPULATION AND GENOMIC EDITING ARE NOVEL EXPERIMENTAL APPROACHES. AN INCREASED UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT CONTROLS THE DISEASE PROCESS PROMPTED US TO EXPLORE ALTERNATIVE THERAPEUTIC APPROACHES THAT ADDRESS THE UNDERLYING CHAIN UNBALANCE, INEFFECTIVE ERYTHROPOIESIS, AND IRON DYSREGULATION. MOLECULES, SUCH AS JAK2 INHIBITORS AND THE ACTIVIN-RECEPTOR LIGAND TRAP THAT TARGET INEFFECTIVE ERYTHROPOIESIS, ARE ALREADY IN CLINICAL TRIALS WITH PROMISING RESULTS. OTHER AGENTS AIMED TO GENERATE IRON-RESTRICTED ERYTHROPOIESIS ARE ALSO UNDER EXPERIMENTAL EVALUATION.	2017	
                                                
4  3872  40 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	
                                                                                                                              
5   606  32 BEYOND GENETICS--THE EMERGING ROLE OF EPIGENETIC CHANGES IN HEMATOPOIETIC MALIGNANCIES. THE TERM EPIGENETIC REFERS TO A HERITABLE CHANGE IN GENE EXPRESSION THAT IS MEDIATED BY MECHANISMS OTHER THAN ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. DNA METHYLATION AT CYTOSINE BASES THAT ARE LOCATED 5' TO GUANOSINE WITHIN A CPG DINUCLEOTIDE IS THE MAIN EPIGENETIC MODIFICATION IN HUMANS. PATTERNS OF DNA METHYLATION ARE PROFOUNDLY DERANGED IN HUMAN CANCER AND COMPRISE GENOME-WIDE LOSSES AS WELL AS REGIONAL GAINS IN DNA METHYLATION. HYPERMETHYLATION OF CPG ISLANDS WITHIN GENE PROMOTER REGIONS IS ASSOCIATED WITH TRANSCRIPTIONAL INACTIVATION AND REPRESENTS, IN ADDITION TO GENETIC ABERRATIONS, AN IMPORTANT MECHANISM OF GENE SILENCING IN THE PATHOGENESIS OF HEMATOPOIETIC MALIGNANCIES. THIS EPIGENETIC PHENOMENON ACTS AS AN ALTERNATIVE TO MUTATIONS AND DELETIONS TO DISRUPT TUMOR SUPPRESSOR GENE FUNCTION. A LARGE NUMBER OF GENES INVOLVING FUNDAMENTAL CELLULAR PATHWAYS MAY BE AFFECTED IN VIRTUALLY ALL TYPES OF HUMAN CANCER BY ABERRANT CPG ISLAND METHYLATION IN ASSOCIATION WITH TRANSCRIPTIONAL SILENCING. ALTERED METHYLATION PATTERNS CAN BE USED AS BIOMARKERS FOR CANCER DETECTION, ASSESSMENT OF PROGNOSIS, AND PREDICTION OF RESPONSE TO ANTITUMOR TREATMENT. FURTHERMORE, CLINICAL TRIALS USING EPIGENETICALLY TARGETED THERAPIES HAVE YIELDED PROMISING RESULTS FOR ACUTE AND CHRONIC LEUKEMIAS AS WELL AS FOR MYELODYSPLASTIC SYNDROMES. THE EXPLORATION OF OUR GROWING KNOWLEDGE ABOUT EPIGENETIC ABERRATIONS MAY HELP DEVELOP NOVEL STRATEGIES FOR THE DIAGNOSIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES IN THE FUTURE.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6   957  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7  3871  23 JUVENILE MYELOMONOCYTIC LEUKEMIA - A BONA FIDE RASOPATHY SYNDROME. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROME WITH SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS, AGGRESSIVE FEATURES, AND POOR OUTCOMES. IN >90% OF CASES JMML IS DRIVEN BY GERMLINE OR SOMATIC MUTATIONS INVOLVING THE CANONICAL RAS PATHWAY (PTPN11, NRAS, CBL, KRAS AND NF1), WITH SOMATIC MUTATIONS/ALTERATIONS IN RAS PATHWAY GENES (SECOND HIT), SETBP1, ASXL1 AND JAK3 RESULTING IN DISEASE PROGRESSION. WHILE SPONTANEOUS REGRESSION HAS BEEN SEEN IN GERMLINE PTPN11 AND CBL MUTANT JMML, IN MOST PATIENTS, ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY CURATIVE MODALITY. JMML SHARES SEVERAL PHENOTYPIC FEATURES WITH ITS ADULT COUNTERPART PROLIFERATIVE, CHRONIC MYELOMONOCYTIC LEUKEMIA (PCMML). PCMML LARGELY OCCURS DUE TO RAS PATHWAY MUTATIONS THAT OCCUR IN THE CONTEXT OF AGE RELATED CLONAL HEMATOPOIESIS (TET2, SRSF2, ASXL1), WHILE JMML IS A BONA FIDE RASOPATHY, WITH ADDITIONAL SOMATIC MUTATIONS, INCLUDING IN EPIGENETIC REGULATORS GENES RESULTING IN DISEASE PROGRESSION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8  4562  34 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  1242  42 CURRENT AND NOVEL THERAPEUTIC APPROACHES IN MYELODYSPLASTIC SYNDROMES. MYELODYSPLASTIC SYNDROMES (MDS) ARE A HETEROGENEOUS GROUP OF HEMATOLOGIC NEOPLASMS WITH AN ANNUAL INCIDENCE OF 4.1 CASES PER 100,000 AMERICANS. PATIENTS WITH MDS SUFFER FROM CHRONIC CYTOPENIAS THAT MAY LEAD TO RECURRENT TRANSFUSIONS, INFECTIONS, AND INCREASED RISK FOR BLEEDING. THEY ARE ALSO AT RISK FOR PROGRESSION TO ACUTE MYELOID LEUKEMIA. ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IS THE ONLY POTENTIALLY CURATIVE TREATMENT FOR MDS, ALTHOUGH 3 DRUGS HAVE BEEN APPROVED BY THE US FOOD AND DRUG ADMINISTRATION FOR ITS TREATMENT: LENALIDOMIDE, 5-AZACITIDINE, AND DECITABINE. THESE THERAPIES CAN BE EFFECTIVE IN THE RELIEF OF CYTOPENIAS, ACHIEVEMENT OF CYTOGENETIC REMISSIONS, AND REDUCTION IN BONE MARROW BLASTS. 5-AZACITIDINE HAS ALSO BEEN SHOWN TO IMPROVE OVERALL SURVIVAL. HOWEVER, THERE REMAIN MANY UNMET NEEDS IN THE TREATMENT OF MDS. BREAKTHROUGHS IN OUR UNDERSTANDING OF THE COMPLEX PATHOGENESIS OF MDS THROUGH EPIGENETIC, GENETIC, IMMUNOLOGIC, AND OTHER BIOLOGICAL MECHANISMS HAVE ALLOWED US TO DEVELOP NEW THERAPEUTIC STRATEGIES THAT CAN LEAD TO IMPROVEMENTS IN OUTCOMES IN MDS. IN THIS REVIEW, WE AIM TO PROVIDE AN OVERVIEW OF THE EVOLUTION IN CLASSIFCATION AND RISK STRATIFCATION IN MDS AND TO ILLUSTRATE HOW WE CAN USE THIS TO GUIDE US IN TAILORING THERAPEUTIC CHOICES IN THIS DISEASE. RESPONSES AND OUTCOMES RELATED TO COM MONLY USED MDS THERAPIES WILL BE DISCUSSED TOGETHER WITH NOVEL THERAPIES THAT HAVE EVOLVED WITH THE IMPROVED UNDERSTANDING OF MDS PATHOPHYSIOLOGY.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10  2277  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11   958  35 CHRONIC MYELOMONOCYTIC LEUKEMIA - A REVIEW. INTRODUCTION: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL MYELOID NEOPLASM, DENOTED BY OVERLAPPING MYELODYSPLASTIC AND MYELOPROLIFERATIVE FEATURES, WITH POOR OVERALL SURVIVAL AND HIGH TRANSFORMATION RATE TO ACUTE MYELOID LEUKEMIA. AREAS COVERED: THIS REVIEW, FOLLOWING A THOROUGH MEDLINE SEARCH OF PERTINENT PUBLISHED LITERATURE, DISCUSSES THE DIAGNOSTIC CRITERIA, THE PATHOGENESIS, AND THE COMPLEX GENETIC LANDSCAPE OF THE DISEASE. PROGNOSTICATION, RESPONSE CRITERIA, THERAPEUTIC MANAGEMENT OF PATIENTS, EFFICACY OF ESTABLISHED AND NOVEL TREATMENT MODALITIES ARE THOROUGHLY REVIEWED. EXPERT OPINION: CYTOGENETIC ABNORMALITIES AND MUTATIONS IN GENES INVOLVED IN EPIGENETIC AND TRANSCRIPTIONAL REGULATION, AND CELL-SIGNALING ARE ABUNDANT IN CMML AND IMPLICATED IN ITS COMPLEX PATHOGENESIS. AS PRESENCE OF THESE MUTATIONS CARRY A PROGNOSTIC IMPACT, THEY ARE INCREASINGLY INCORPORATED IN RISK-STRATIFICATION SCHEMES. NOVEL RESPONSE CRITERIA HAVE BEEN PROPOSED, CONSIDERING THE UNIQUE FEATURES OF THE DISEASE. ALTHOUGH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION REMAINS THE ONLY TREATMENT WITH CURATIVE INTENT, IT IS RESERVED FOR A MINORITY OF PATIENTS; THEREFORE, THERE IS AN UNMET NEED FOR OPTIMIZING TREATMENT MODALITIES, SUCH AS HYPOMETHYLATING AGENTS, AND INTRODUCING NOVEL AGENTS, WHICH COULD SUBSTANTIALLY IMPROVE SURVIVAL AND QUALITY OF LIFE OF CMML PATIENTS. CLINICAL TRIALS DEDICATED SPECIFICALLY TO CMML ARE NEEDED TO EXPLORE THE EFFICACY AND SAFETY OF NOVEL TREATMENT MODALITIES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12  5284  38 PROPOSALS FOR CLINICAL TRIALS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOLOGIC MALIGNANCY OF MOSTLY OLDER INDIVIDUALS THAT EXHIBITS BOTH MYELODYSPLASTIC AND MYELOPROLIFERATIVE FEATURES. CMML PRESENTATION AND OUTCOME ARE VARIABLE, REFLECTING GENETIC AND CLINICAL HETEROGENEITY. HYPOMETHYLATING AGENTS ARE THE MAINSTAY OF THERAPY BUT INDUCE COMPLETE REMISSIONS IN LESS THAN 20% OF PATIENTS AND DO NOT PROLONG SURVIVAL COMPARED TO HYDROXYUREA. ALLOGENEIC STEM CELL TRANSPLANT (ASCT) IS POTENTIALLY CURATIVE, BUT FEW PATIENTS QUALIFY DUE TO ADVANCED AGE AND/OR COMORBIDITIES. WORK OF THE PAST SEVERAL YEARS HAS IDENTIFIED KEY MOLECULAR PATHWAYS THAT DRIVE DISEASE PROLIFERATION AND TRANSFORMATION TO ACUTE LEUKEMIA, INCLUDING JAK/STAT AND MAPK SIGNALING AND EPIGENETIC DYSREGULATION. THERE IS INCREASINGLY COMPELLING EVIDENCE THAT INFLAMMATION IS A MAJOR DRIVER OF CMML PROGRESSION. THUS FAR HOWEVER, THIS MECHANISTIC KNOWLEDGE HAS NOT YET BEEN TRANSLATED INTO IMPROVED OUTCOMES, SUGGESTING THAT FUNDAMENTALLY NEW APPROACHES ARE REQUIRED. IN THIS REVIEW, WE DISCUSS THE DISEASE COURSE, NEW CLASSIFICATIONS, AND CURRENT TREATMENT LANDSCAPE OF CMML. WE REVIEW ONGOING CLINICAL STUDIES AND DISCUSS OPTIONS FOR RATIONALLY BASED FUTURE CLINICAL TRIALS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
13   961  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14   962  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15  4681  31 NEW OPTIONS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROME. MYELODYSPLASTIC SYNDROME (MDS) IS A HETEROGENEOUS GROUP OF PROGRESSIVE CHRONIC HEMATOPOIETIC DISORDERS, USUALLY PRESENTING AS REFRACTORY ANEMIA OR CYTOPENIA, WITH AN APPROXIMATELY 25% RISK OF PROGRESSION TOWARD ACUTE MYELOID LEUKAEIMA (AML), AND NO PROVEN CURATIVE TREATMENT. NOVEL BIOLOGICAL TREATMENT STRATEGIES TARGETING BOTH THE MALIGNANT BLOOD CELL AND ITS MICROENVIRONMENT CAN OVERCOME RESISTANCE TO CURRENT THERAPIES, AND REPRESENT A PROMISING TREATMENT PARADIGM FOR IMPROVING PATIENT OUTCOME. MANY OF THESE AGENTS HAVE MULTIPLE BIOLOGIC ACTIVITIES. THE OBJECTIVE OF THIS ARTICLE IS TO PRESENT A COMPARATIVE REVIEW OF CLASSIFICATION SYSTEMS IN MDS AND TO DISCUSS THE EVOLVING TRENDS IN THE TREATMENT OF MDS (IMMUNOSUPPRESIVE THERAPY, IMMUNOMODULATORY DRUGS, ARSENIC TRIOXIDE, PROTEASOME INHIBITORS, EPIGENETIC THERAPY).	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16  4565  23 MYELOID MALIGNANCIES: MUTATIONS, MODELS AND MANAGEMENT. MYELOID MALIGNANT DISEASES COMPRISE CHRONIC (INCLUDING MYELODYSPLASTIC SYNDROMES, MYELOPROLIFERATIVE NEOPLASMS AND CHRONIC MYELOMONOCYTIC LEUKEMIA) AND ACUTE (ACUTE MYELOID LEUKEMIA) STAGES. THEY ARE CLONAL DISEASES ARISING IN HEMATOPOIETIC STEM OR PROGENITOR CELLS. MUTATIONS RESPONSIBLE FOR THESE DISEASES OCCUR IN SEVERAL GENES WHOSE ENCODED PROTEINS BELONG PRINCIPALLY TO FIVE CLASSES: SIGNALING PATHWAYS PROTEINS (E.G. CBL, FLT3, JAK2, RAS), TRANSCRIPTION FACTORS (E.G. CEBPA, ETV6, RUNX1), EPIGENETIC REGULATORS (E.G. ASXL1, DNMT3A, EZH2, IDH1, IDH2, SUZ12, TET2, UTX), TUMOR SUPPRESSORS (E.G. TP53), AND COMPONENTS OF THE SPLICEOSOME (E.G. SF3B1, SRSF2). LARGE-SCALE SEQUENCING EFFORTS WILL SOON LEAD TO THE ESTABLISHMENT OF A COMPREHENSIVE REPERTOIRE OF THESE MUTATIONS, ALLOWING FOR A BETTER DEFINITION AND CLASSIFICATION OF MYELOID MALIGNANCIES, THE IDENTIFICATION OF NEW PROGNOSTIC MARKERS AND THERAPEUTIC TARGETS, AND THE DEVELOPMENT OF NOVEL THERAPIES. GIVEN THE IMPORTANCE OF EPIGENETIC DEREGULATION IN MYELOID DISEASES, THE USE OF DRUGS TARGETING EPIGENETIC REGULATORS APPEARS AS A MOST PROMISING THERAPEUTIC APPROACH.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  6857  48 [NOVEL CONVENTIONAL THERAPIES IN ONCO-HEMATHOLOGY]. CYTOGENETIC, MOLECULAR AND PHENOTYPING FEATURES OF MALIGNANT HEMATOLOGIC DISEASES SUCCEEDED IN IMPROVING THEIR MANAGEMENT BY A MORE ACCURATE STRATIFICATION OF PATIENTS ACCORDING TO SEVERAL GROUPS OF RISK AND BY PROVIDING A RATIONAL FOR TARGETED THERAPY. THREE MAJOR TYPES OF TREATMENT (EXCLUDING CELLULAR THERAPY) ARE CURRENTLY AVAILABLE IN ONCO-HEMATOLOGY: CONVENTIONAL CHEMOTHERAPY, SMALL MOLECULES FOR TARGETED THERAPY AND MONOCLONAL ANTIBODIES. CONVENTIONAL CHEMOTHERAPY WITH OPTIMIZATION OF DOSES AND MULTIDRUG-BASED REGIMENS ALLOWED TO SUBSTANTIALLY IMPROVE SURVIVAL OF PATIENTS AND KEEPS A PLACE OF CHOICE IN TREATMENT OF THESE DISEASES. TARGETED TREATMENTS CAME FROM THE CYTOGENETIC AND MOLECULAR CHARACTERIZATION OF HEMOPATHIES. THUS, THE KINASE BCR-ABL, AS A RESULT OF THE TRANSLOCATION T(9;22)(Q34;Q11), HAS BEEN SUCCESSFULLY TARGETED BY TYROSINE KINASE INHIBITORS (TKI) IN CHRONIC MYELOID LEUKEMIA AND PH+ ACUTE LYMPHOBLASTIC LEUKEMIA. MOLECULAR ABNORMALITIES LIKE INTERNAL-TANDEM DUPLICATION/POINT ACTIVATING MUTATIONS IN FLT3 IN SOME ACUTE MYELOBLASTIC LEUKEMIA OR EPIGENETIC DYSREGULATIONS IN SOME BLOOD MALIGNANCIES CAN ALSO BE TARGETED BY SMALL MOLECULES. HEMATOPOIETIC MALIGNANT CELLS ARE PHENOTYPICALLY CHARACTERIZED BY EXPRESSION OF CLUSTER OF DIFFERENTIATION (CD) ON THEIR SURFACE. THESE CD ARE DETECTED BY FLOW CYTOMETRY USING SPECIFIC ANTIBODIES. MONOCLONAL ANTIBODIES TARGETING DIFFERENT CD HAVE BEEN DEVELOPED FOR TREATMENT. RITUXIMAB, AN ANTI-CD20 ANTIBODY, WAS THE FIRST MONOCLONAL ANTIBODY SUCCESSFULLY DEVELOPED FOR TREATMENT OF MALIGNANT HEMATOLOGIC DISEASES. SINCE RITUXIMAB, MANY OTHER MONOCLONAL ANTIBODIES ARE BEING DEVELOPED. TRENDS IN MALIGNANT HEMATOLOGIC DISEASES PRESENTED HERE WILL INCLUDE TREATMENTS, WHICH HAVE AT LEAST ENTERED PHASE I/II CLINICAL TRIALS IN ADULT OR CHILDHOOD LEUKEMIA. THEY INCLUDE SOME NOVEL DRUGS OF CONVENTIONAL CHEMOTHERAPY LIKE SECOND-GENERATION NUCLEOSIDE ANALOGUES. WE WILL GIVE AN OVERVIEW OF THE SMALL MOLECULES TARGETING THE DIFFERENT CELLULAR PATHWAYS AND WE WILL HIGHLIGHT THOSE APPEARING AS THE MOST PROMISING LIKE NOVEL TKIS. THE LARGE FIELD OF MONOCLONAL ANTIBODIES WILL BE ALSO APPROACHED FOCUSING ON ANTIBODIES DEVELOPED IN LEUKEMIAS.	2011	

18  4557  16 MUTATIONS IN ASXL1 ARE ASSOCIATED WITH POOR PROGNOSIS ACROSS THE SPECTRUM OF MALIGNANT MYELOID DISEASES. THE ASXL1 GENE IS ONE OF THE MOST FREQUENTLY MUTATED GENES IN MALIGNANT MYELOID DISEASES. THE ASXL1 PROTEIN BELONGS TO PROTEIN COMPLEXES INVOLVED IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. ASXL1 MUTATIONS ARE FOUND IN MYELOPROLIFERATIVE NEOPLASMS (MPN), MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ACUTE MYELOID LEUKEMIA (AML). THEY ARE GENERALLY ASSOCIATED WITH SIGNS OF AGGRESSIVENESS AND POOR CLINICAL OUTCOME. BECAUSE OF THIS, A SYSTEMATIC DETERMINATION OF ASXL1 MUTATIONAL STATUS IN MYELOID MALIGNANCIES SHOULD HELP IN PROGNOSIS ASSESSMENT.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19  4436  25 MOLECULAR EVOLUTION OF CHRONIC MYELOID LEUKAEMIA. CHRONIC MYELOID LEUKAEMIA (CML) IS A CLONAL DISORDER OF THE PLURIPOTENT HAEMATOPOIETIC STEM CELL. THE TYPICAL TRIPHASIC COURSE OF CML STARTS WITH THE PREMALIGNANT CHRONIC PHASE INITIATED BY BCR-ABL HYBRID ONCOGENE FORMATION. SECONDARY GENETIC AND EPIGENETIC ABERRATIONS ACCOMPANY THE PROGRESSION TO THE ACCELERATED PHASE AND FATAL BLASTIC CRISIS. PROPERLY TIMED BONE MARROW TRANSPLANTATION IN ELIGIBLE PATIENTS CAN RESULT IN DURABLE REMISSIONS OR CURE. BOTH OF THESE STATES ARE OFTEN ACCOMPANIED BY A LONG-TERM PERSISTENCE OF QUIESCENT LEUKAEMIC CELLS. ACCORDINGLY, A "FUNCTIONAL CURE" (I.E. TUMOUR DORMANCY INDUCTION), RATHER THAN COMPLETE ERADICATION OF THE MALIGNANT CELLS, IS AN ADEQUATE THERAPEUTICAL GOAL. THE LEVEL OF THE RESIDUAL BCR-ABL-POSITIVE CLONES SHOULD BE MONITORED AND SALVAGE TREATMENT INITIATED WHENEVER THESE QUIESCENT LEUKAEMIC CELLS EXIT THEIR DORMANT STATE.	2001	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20   952  29 CHRONIC MYELOID LEUKEMIA STEM CELL BIOLOGY. LEUKEMIA PROGRESSION AND RELAPSE IS FUELED BY LEUKEMIA STEM CELLS (LSC) THAT ARE RESISTANT TO CURRENT TREATMENTS. IN THE PROGRESSION OF CHRONIC MYELOID LEUKEMIA (CML), BLAST CRISIS PROGENITORS ARE CAPABLE OF ADOPTING MORE PRIMITIVE BUT DEREGULATED STEM CELL FEATURES WITH ACQUIRED RESISTANCE TO TARGETED THERAPIES. THIS IN TURN PROMOTES LSC BEHAVIOR CHARACTERIZED BY ABERRANT SELF-RENEWAL, DIFFERENTIATION, AND SURVIVAL CAPACITY. MULTIPLE REPORTS SUGGEST THAT CELL CYCLE ALTERATIONS, ACTIVATION OF CRITICAL SIGNALING PATHWAYS, ABERRANT MICROENVIRONMENTAL CUES FROM THE HEMATOPOIETIC NICHE, AND ABERRANT EPIGENETIC EVENTS AND DEREGULATION OF RNA PROCESSING MAY FACILITATE THE ENHANCED SURVIVAL AND MALIGNANT TRANSFORMATION OF CML PROGENITORS. HERE WE REVIEW THE MOLECULAR EVOLUTION OF CML LSC THAT PROMOTES CML PROGRESSION AND RELAPSE. RECENT ADVANCES IN THESE AREAS HAVE IDENTIFIED NOVEL TARGETS THAT REPRESENT IMPORTANT AVENUES FOR FUTURE THERAPEUTIC APPROACHES AIMED AT SELECTIVELY ERADICATING THE LSC POPULATION WHILE SPARING NORMAL HEMATOPOIETIC PROGENITORS IN PATIENTS SUFFERING FROM CHRONIC MYELOID MALIGNANCIES.	2012