1  4485 131 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2  1621  38 DNA METHYLTRANSFERASES AS TARGETS FOR CANCER THERAPY. METHYLATION OF DNA AT 5-POSITION OF CYTOSINE, CATALYZED BY DNA METHYLTRANSFERASES, IS THE PREDOMINANT EPIGENETIC MODIFICATION IN MAMMALS. ABERRATIONS IN METHYLATION PLAY A CAUSAL ROLE IN A VARIETY OF DISEASES, INCLUDING CANCER. RECENT STUDIES HAVE ESTABLISHED THAT LIKE MUTATION, METHYLATION-MEDIATED GENE SILENCING OFTEN LEADS TO TUMORIGENESIS. PARADOXICALLY, GENOME-WIDE DNA HYPOMETHYLATION MAY ALSO PLAY A CAUSAL ROLE IN CARCINOGENESIS BY INDUCING CHROMOSOMAL INSTABILITY AND SPURIOUS GENE EXPRESSION. SINCE METHYLATION DOES NOT ALTER DNA BASE SEQUENCE, MUCH ATTENTION HAS BEEN FOCUSED RECENTLY ON DEVELOPING SMALL MOLECULE INHIBITORS OF DNA METHYLTRANSFERASES THAT CAN POTENTIALLY BE USED AS ANTICANCER AGENTS. VIDAZA (5-AZACYTIDINE), MARKETED BY PHARMION (BOULDER, CO, USA), WAS THE FIRST DNA METHYLTRANSFERASE INHIBITOR APPROVED BY THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) FOR CHEMOTHERAPY AGAINST MYELODYSPLASTIC SYNDROME (MDS), A HETEROGENEOUS BONE MARROW DISORDER. RECENTLY MGI PHARMA INC. (BLOOMINGTON, MN, USA) GOT FDA APPROVAL TO MARKET DACOGEN (5-AZA-2'-DEOXYCYTIDINE, OR DECITABINE) FOR TREATING MDS PATIENTS. THESE DRUGS WERE USED EARLIER AGAINST CERTAIN ANEMIAS TO INDUCE EXPRESSION OF FETAL GLOBIN GENES. INTEREST IN CLINICAL TRIALS OF THESE DRUGS AS ANTICANCER AGENTS HAS BEEN RENEWED ONLY RECENTLY BECAUSE OF REVERSAL OF METHYLATION-MEDIATED SILENCING OF CRITICAL GENES IN CANCER. CLINICAL TRIALS HAVE SHOWN THAT BOTH DRUGS HAVE THERAPEUTIC POTENTIAL AGAINST LEUKEMIA SUCH AS MDS, ACUTE MYELOID LEUKEMIA, CHRONIC MYELOGENOUS LEUKEMIA AND CHRONIC MYELOMONOCYTIC LEUKEMIA. IN CONTRAST, THEIR EFFECTIVENESS WITH SOLID TUMORS APPEARS TO BE LESS PROMISING, WHICH CHALLENGES RESEARCHERS TO DEVELOP INHIBITORS WITH MORE EFFICACY AND LESS TOXICITY. THE MAJOR HINDRANCE OF THEIR USAGE AS ANTICANCER AGENTS IS THEIR INSTABILITY IN VIVO AS WELL AS THE TOXICITY SECONDARY TO THEIR EXCESSIVE INCORPORATION INTO DNA, WHICH CAUSES CELL CYCLE ARREST. GENE EXPRESSION PROFILING IN CANCER CELLS REVEALED THAT ANTINEOPLASTIC PROPERTY OF THESE DRUGS IS MEDIATED THROUGH BOTH METHYLATION-DEPENDENT AND -INDEPENDENT PATHWAYS. RECENTLY, WE HAVE SHOWN THAT TREATMENT OF CANCER CELLS WITH THESE CYTIDINE ANALOGUES ALSO INDUCES PROTEASOMAL DEGRADATION OF DNA METHYLTRANSFERASE 1, THE UBIQUITOUSLY EXPRESSED ENZYME UPREGULATED IN ALMOST ALL CANCER CELLS. DEVELOPMENT OF RELATED STABLE DRUGS THAT CAN FACILITATE GENE ACTIVATION IN CANCER CELLS BY ENHANCING DEGRADATION OF DNA METHYLTRANSFERASES WITHOUT BEING INCORPORATED INTO DNA WOULD BE IDEAL FOR CHEMOTHERAPY. IN THIS MONOGRAPH WE REVIEW HISTORICAL PERSPECTIVE AND RECENT ADVANCES ON THE MOLECULAR MECHANISMS OF ACTION AND CLINICAL APPLICATIONS OF THESE DNA HYPOMETHYLATING AGENTS.	2007	

3  6780  29 [BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM ACCOMPANIED BY CHRONIC MYELOMONOCYTIC LEUKEMIA SUCCESSFULLY TREATED WITH AZACITIDINE]. BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN) IS A RARE DISEASE THAT DEVELOPS WITH A SKIN LESION AND IS OFTEN ACCOMPANIED BY LEUKEMIC TRANSFORMATION. THE NORMAL COUNTERPARTS OF BPDCN TUMOR CELLS ARE PROGENITORS OF PLASMACYTOID DENDRITIC CELLS, WHEREAS THE ORIGINS ARE THOUGHT TO BE HEMATOPOIETIC STEM CELLS. APPROXIMATELY 10%-20% OF BPDCN PATIENTS DEVELOP OTHER HEMATOLOGIC MALIGNANCIES, INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). MUTATIONS IN EPIGENETIC REGULATORS ARE FREQUENTLY OBSERVED IN BOTH BPDCN AND CMML TUMORS. AZACITIDINE, A DRUG THAT TARGETS EPIGENETIC DYSREGULATION, IS KNOWN TO BE AN EFFECTIVE TREATMENT FOR CMML. HOWEVER, IT HAS BEEN USED IN FEW BPDCN PATIENTS. HERE, WE REPORT A BPDCN PATIENT WITH SKIN LESIONS, BONE MARROW INFILTRATION, AND LYMPHADENOPATHY. CMML ALSO DEVELOPED DURING THE COURSE OF BPDCN. AZACITIDINE HAD POSITIVE EFFECTS ON CMML; HOWEVER, BPDCN AGGRESSIVELY RELAPSED DURING TREATMENT. TWO TET2 MUTATIONS WERE FOUND IN BOTH BPDCN AND CMML TUMORS; ONE OF WHICH WAS COMMONLY IDENTIFIED IN BOTH TUMORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4  4562  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5  4557  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6   961  34 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  5911  30 TARGETED NEXT-GENERATION SEQUENCING IN MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA AIDS DIAGNOSIS IN CHALLENGING CASES AND IDENTIFIES FREQUENT SPLICEOSOME MUTATIONS IN TRANSFORMED ACUTE MYELOID LEUKEMIA. OBJECTIVES: OPTIMAL INTEGRATION OF NEXT-GENERATION SEQUENCING (NGS) INTO CLINICAL PRACTICE IN HEMATOLOGIC MALIGNANCIES REMAINS UNCLEAR. WE EVALUATE THE UTILITY OF NGS IN MYELOID MALIGNANCIES. METHODS: A 42-GENE PANEL WAS USED TO SEQUENCE 109 CASES OF MYELODYSPLASTIC SYNDROME (MDS, N = 38), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML, N = 14), MYELOPROLIFERATIVE NEOPLASM (MPN, N = 24), AND MDS AND/OR MPN TRANSFORMED TO ACUTE MYELOID LEUKEMIA (AML, N = 33). RESULTS: AT LEAST ONE PATHOGENIC MUTATION WAS IDENTIFIED IN 74% OF CASES OF MDS, 100% OF CMMLS, AND 96% OF MPNS. IN CONTRAST, ONLY 47% OF CASES OF MDS (18/38) AND 7% (1/14) OF CMMLS EXHIBITED ABNORMAL CYTOGENETICS. IN DIAGNOSTICALLY DIFFICULT CASES OF MDS OR CMML WITH NORMAL CYTOGENETICS, NGS IDENTIFIED A PATHOGENIC MUTATION AND WAS CRITICAL IN ESTABLISHING THE CORRECT DIAGNOSIS. SPLICEOSOMAL GENES AND EPIGENETIC MODIFIERS WERE FREQUENTLY MUTATED. SPLICEOSOME MUTATIONS WERE ALSO FREQUENTLY DETECTED IN AML ARISING FROM MDS, CMML, OR MPN (39%) COMPARED WITH THE REPORTED RATE IN DE NOVO AML (7%-14%). CONCLUSIONS: IN DIFFICULT CASES OF MDS OR MPN, NGS FACILITATES DIAGNOSIS BY DETECTION OF GENE MUTATIONS TO CONFIRM CLONALITY, AND AMLS EVOLVING FROM MDS OR MPN CARRY FREQUENT MUTATIONS IN SPLICEOSOMAL GENES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8   959  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9  4565  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10  4442  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11  2277  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12  2760  35 EXPRESSION OF PD-L1, PD-L2, PD-1 AND CTLA4 IN MYELODYSPLASTIC SYNDROMES IS ENHANCED BY TREATMENT WITH HYPOMETHYLATING AGENTS. BLOCKADE OF IMMUNE CHECKPOINTS IS EMERGING AS A NEW FORM OF ANTICANCER THERAPY. WE STUDIED THE EXPRESSION OF PROGRAMMED DEATH LIGAND 1 (PD-L1), PD-L2, PROGRAMMED DEATH 1 (PD-1) AND CYTOTOXIC T LYMPHOCYTE-ASSOCIATED ANTIGEN 4 (CTLA4) MRNA IN CD34+ CELLS FROM MYELODYSPLASTIC SYNDROME (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ACUTE MYELOID LEUKEMIA (AML) PATIENTS (N=124). ABERRANT UPREGULATION (?2-FOLD) WAS OBSERVED IN 34, 14, 15 AND 8% OF THE PATIENTS. INCREASED EXPRESSION OF THESE FOUR GENES WAS ALSO OBSERVED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMNCS) (N=61). THE RELATIVE EXPRESSION OF PD-L1 FROM PBMNC WAS SIGNIFICANTLY HIGHER IN MDS (P=0.018) AND CMML (P=0.0128) COMPARED WITH AML. BY IMMUNOHISTOCHEMICAL ANALYSIS, PD-L1 PROTEIN EXPRESSION WAS OBSERVED IN MDS CD34+ CELLS, WHEREAS STROMA/NON-BLAST CELLULAR COMPARTMENT WAS POSITIVE FOR PD-1. IN A COHORT OF PATIENTS TREATED WITH EPIGENETIC THERAPY, PD-L1, PD-L2, PD-1 AND CTLA4 EXPRESSION WAS UPREGULATED. PATIENTS RESISTANT TO THERAPY HAD RELATIVE HIGHER INCREMENTS IN GENE EXPRESSION COMPARED WITH PATIENTS WHO ACHIEVED RESPONSE. TREATMENT OF LEUKEMIA CELLS WITH DECITABINE RESULTED IN A DOSE-DEPENDENT UPREGULATION OF ABOVE GENES. EXPOSURE TO DECITABINE RESULTED IN PARTIAL DEMETHYLATION OF PD-1 IN LEUKEMIA CELL LINES AND HUMAN SAMPLES. THIS STUDY SUGGESTS THAT PD-1 SIGNALING MAY BE INVOLVED IN MDS PATHOGENESIS AND RESISTANCE MECHANISMS TO HYPOMETHYLATING AGENTS. BLOCKADE OF THIS PATHWAY CAN BE A POTENTIAL THERAPY IN MDS AND AML.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13  5478  30 RESULTS OF A RANDOMIZED STUDY OF 3 SCHEDULES OF LOW-DOSE DECITABINE IN HIGHER-RISK MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA. EPIGENETIC THERAPY WITH HYPOMETHYLATING DRUGS IS NOW THE STANDARD OF CARE IN MYELODYSPLASTIC SYNDROME (MDS). RESPONSE RATES REMAIN LOW, AND MECHANISM-BASED DOSE OPTIMIZATION HAS NOT BEEN REPORTED. WE INVESTIGATED THE CLINICAL AND PHARMACODYNAMIC RESULTS OF DIFFERENT DOSE SCHEDULES OF DECITABINE. ADULTS WITH ADVANCED MDS OR CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) WERE RANDOMIZED TO 1 OF 3 DECITABINE SCHEDULES: (1) 20 MG/M2 INTRAVENOUSLY DAILY FOR 5 DAYS; (2) 20 MG/M2 SUBCUTANEOUSLY DAILY FOR 5 DAYS; AND (3) 10 MG/M2 INTRAVENOUSLY DAILY FOR 10 DAYS. RANDOMIZATION FOLLOWED A BAYESIAN ADAPTIVE DESIGN. NINETY-FIVE PATIENTS WERE TREATED (77 WITH MDS, AND 18 WITH CMML). OVERALL, 32 PATIENTS (34%) ACHIEVED A COMPLETE RESPONSE (CR), AND 69 (73%) HAD AN OBJECTIVE RESPONSE BY THE NEW MODIFIED INTERNATIONAL WORKING GROUP CRITERIA. THE 5-DAY INTRAVENOUS SCHEDULE, WHICH HAD THE HIGHEST DOSE-INTENSITY, WAS SELECTED AS OPTIMAL; THE CR RATE IN THAT ARM WAS 39%, COMPARED WITH 21% IN THE 5-DAY SUBCUTANEOUS ARM AND 24% IN THE 10-DAY INTRAVENOUS ARM (P < .05). THE HIGH DOSE-INTENSITY ARM WAS ALSO SUPERIOR AT INDUCING HYPOMETHYLATION AT DAY 5 AND AT ACTIVATING P15 EXPRESSION AT DAYS 12 OR 28 AFTER THERAPY. WE CONCLUDE THAT A LOW-DOSE, DOSE-INTENSITY SCHEDULE OF DECITABINE OPTIMIZES EPIGENETIC MODULATION AND CLINICAL RESPONSES IN MDS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14  4555  35 MUTATIONAL SPECTRUM ANALYSIS OF CHRONIC MYELOMONOCYTIC LEUKEMIA INCLUDES GENES ASSOCIATED WITH EPIGENETIC REGULATION: UTX, EZH2, AND DNMT3A. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), A MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM, IS CHARACTERIZED BY MONOCYTIC PROLIFERATION, DYSPLASIA, AND PROGRESSION TO ACUTE MYELOID LEUKEMIA. CMML HAS BEEN ASSOCIATED WITH SOMATIC MUTATIONS IN DIVERSE RECENTLY IDENTIFIED GENES. WE ANALYZED 72 WELL-CHARACTERIZED PATIENTS WITH CMML (N = 52) AND CMML-DERIVED ACUTE MYELOID LEUKEMIA (N = 20) FOR RECURRENT CHROMOSOMAL ABNORMALITIES WITH THE USE OF ROUTINE CYTOGENETICS AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAYS ALONG WITH COMPREHENSIVE MUTATIONAL SCREENING. CYTOGENETIC ABERRATIONS WERE PRESENT IN 46% OF CASES, WHEREAS SINGLE NUCLEOTIDE POLYMORPHISM ARRAY INCREASED THE DIAGNOSTIC YIELD TO 60%. AT LEAST 1 MUTATION WAS FOUND IN 86% OF ALL CASES; NOVEL UTX, DNMT3A, AND EZH2 MUTATIONS WERE FOUND IN 8%, 10%, AND 5.5% OF PATIENTS, RESPECTIVELY. TET2 MUTATIONS WERE PRESENT IN 49%, ASXL1 IN 43%, CBL IN 14%, IDH1/2 IN 4%, KRAS IN 7%, NRAS IN 4%, AND JAK2 V617F IN 1% OF PATIENTS. VARIOUS MUTANT GENOTYPE COMBINATIONS WERE OBSERVED, INDICATING MOLECULAR HETEROGENEITY IN CMML. OUR RESULTS SUGGEST THAT MOLECULAR DEFECTS AFFECTING DISTINCT PATHWAYS CAN LEAD TO SIMILAR CLINICAL PHENOTYPES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15   962  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  5979  34 TET2 MUTATIONS ARE ASSOCIATED WITH SPECIFIC 5-METHYLCYTOSINE AND 5-HYDROXYMETHYLCYTOSINE PROFILES IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) HAS RECENTLY BEEN ASSOCIATED WITH A HIGH INCIDENCE OF DIVERSE MUTATIONS IN GENES SUCH AS TET2 OR EZH2 THAT ARE IMPLICATED IN EPIGENETIC MECHANISMS. WE HAVE PERFORMED GENOME-WIDE DNA METHYLATION ARRAYS AND MUTATIONAL ANALYSIS OF TET2, IDH1, IDH2, EZH2 AND JAK2 IN A GROUP OF 24 PATIENTS WITH CMML. 249 GENES WERE DIFFERENTIALLY METHYLATED BETWEEN CMML PATIENTS AND CONTROLS. USING INGENUITY PATHWAY ANALYSIS, WE IDENTIFIED ENRICHMENT IN A GENE NETWORK CENTERED AROUND PLC, JNK AND ERK SUGGESTING THAT THESE PATHWAYS, WHOSE DEREGULATION HAS BEEN RECENTLY DESCRIBED IN CMML, ARE AFFECTED BY EPIGENETIC MECHANISMS. MUTATIONS OF TET2, JAK2 AND EZH2 WERE FOUND IN 15 PATIENTS (65%), 4 PATIENTS (17%) AND 1 PATIENT (4%) RESPECTIVELY WHILE NO MUTATIONS IN THE IDH1 AND IDH2 GENES WERE IDENTIFIED. INTERESTINGLY, PATIENTS WITH WILD TYPE TET2 CLUSTERED SEPARATELY FROM PATIENTS WITH TET2 MUTATIONS, SHOWED A HIGHER DEGREE OF HYPERMETHYLATION AND WERE ASSOCIATED WITH HIGHER RISK KARYOTYPES. OUR RESULTS DEMONSTRATE THE PRESENCE OF ABERRANT DNA METHYLATION IN CMML AND IDENTIFIES TET2 MUTANT CMML AS A BIOLOGICALLY DISTINCT DISEASE SUBTYPE WITH A DIFFERENT EPIGENETIC PROFILE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17  1184  22 COOPERATIVE EPIGENETIC REMODELING BY TET2 LOSS AND NRAS MUTATION DRIVES MYELOID TRANSFORMATION AND MEK INHIBITOR SENSITIVITY. MUTATIONS IN EPIGENETIC MODIFIERS AND SIGNALING FACTORS OFTEN CO-OCCUR IN MYELOID MALIGNANCIES, INCLUDING TET2 AND NRAS MUTATIONS. CONCURRENT TET2 LOSS AND NRAS(G12D) EXPRESSION IN HEMATOPOIETIC CELLS INDUCED MYELOID TRANSFORMATION, WITH A FULLY PENETRANT, LETHAL CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), WHICH WAS SERIALLY TRANSPLANTABLE. TET2 LOSS AND NRAS MUTATION COOPERATIVELY LED TO DECREASE IN NEGATIVE REGULATORS OF MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) ACTIVATION, INCLUDING SPRY2, THEREBY CAUSING SYNERGISTIC ACTIVATION OF MAPK SIGNALING BY EPIGENETIC SILENCING. TET2/NRAS DOUBLE-MUTANT LEUKEMIA SHOWED PREFERENTIAL SENSITIVITY TO MAPK KINASE (MEK) INHIBITION IN BOTH MOUSE MODEL AND PATIENT SAMPLES. THESE DATA PROVIDE INSIGHTS INTO HOW EPIGENETIC AND SIGNALING MUTATIONS COOPERATE IN MYELOID TRANSFORMATION AND PROVIDE A RATIONALE FOR MECHANISM-BASED THERAPY IN CMML PATIENTS WITH THESE HIGH-RISK GENETIC LESIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18  6574  24 TREATMENT OF CHRONIC MYELOMONOCYTIC LEUKEMIA WITH 5-AZACYTIDINE: CASE REPORTS. EPIGENETIC THERAPY WITH HYPOMETHYLATING AGENT (5-AZACYTIDINE; AZA) IS COMMON IN THE MANAGEMENT OF SPECIFIC SUBTYPES OF MYELODYSPLASTIC SYNDROME (MDS), BUT THERE ARE ONLY FEW STUDIES IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) PATIENTS. IN THIS PAPER OUR EXPERIENCE WITH 3 CMML PATIENTS TREATED WITH AZA IS DESCRIBED. IN ONE PATIENT TRANSFUSION INDEPENDENCY WAS OBSERVED AFTER 4 TREATMENT CYCLES; IN ONE CASE A PARTIAL RESPONSE WAS RECORDED, BUT A PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML) AFTER 13 AZA CYCLES HAS APPEARED. IN ONE PATIENT, AZA IN REDUCED DOSAGE WAS ADMINISTERED AS A BRIDGING TREATMENT BEFORE ALLOGENEIC STEM CELL TRANSPLANTATION (ASCT), BUT IN THE CONTROL BONE MARROW ASPIRATE (BEFORE ASCT) A PROGRESSION TO AML WAS RECORDED. FUTURE STUDIES ARE MANDATORY FOR EVALUATION OF NEW MOLECULAR AND CLINICAL FEATURES WHICH COULD PREDICT THE EFFICIENCY OF HYPOMETHYLATING AGENTS IN CMML THERAPY WITH RESPECT TO OVERALL SURVIVAL, EVENT-FREE SURVIVAL, QUALITY-ADJUSTED LIFE YEAR, AND PHARMACOECONOMY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  4748  36 NOVEL MUTATIONS AND THEIR FUNCTIONAL AND CLINICAL RELEVANCE IN MYELOPROLIFERATIVE NEOPLASMS: JAK2, MPL, TET2, ASXL1, CBL, IDH AND IKZF1. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ORIGINATE FROM GENETICALLY TRANSFORMED HEMATOPOIETIC STEM CELLS THAT RETAIN THE CAPACITY FOR MULTILINEAGE DIFFERENTIATION AND EFFECTIVE MYELOPOIESIS. BEGINNING IN EARLY 2005, A NUMBER OF NOVEL MUTATIONS INVOLVING JANUS KINASE 2 (JAK2), MYELOPROLIFERATIVE LEUKEMIA VIRUS (MPL), TET ONCOGENE FAMILY MEMBER 2 (TET2), ADDITIONAL SEX COMBS-LIKE 1 (ASXL1), CASITAS B-LINEAGE LYMPHOMA PROTO-ONCOGENE (CBL), ISOCITRATE DEHYDROGENASE (IDH) AND IKAROS FAMILY ZINC FINGER 1 (IKZF1) HAVE BEEN DESCRIBED IN BCR-ABL1-NEGATIVE MPNS. HOWEVER, NONE OF THESE MUTATIONS WERE MPN SPECIFIC, DISPLAYED MUTUAL EXCLUSIVITY OR COULD BE TRACED BACK TO A COMMON ANCESTRAL CLONE. JAK2 AND MPL MUTATIONS APPEAR TO EXERT A PHENOTYPE-MODIFYING EFFECT AND ARE DISTINCTLY ASSOCIATED WITH POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA AND PRIMARY MYELOFIBROSIS; THE CORRESPONDING MUTATIONAL FREQUENCIES ARE APPROXIMATELY 99, 55 AND 65% FOR JAK2 AND 0, 3 AND 10% FOR MPL MUTATIONS. THE INCIDENCE OF TET2, ASXL1, CBL, IDH OR IKZF1 MUTATIONS IN THESE DISORDERS RANGES FROM 0 TO 17%; THESE LATTER MUTATIONS ARE MORE COMMON IN CHRONIC (TET2, ASXL1, CBL) OR JUVENILE (CBL) MYELOMONOCYTIC LEUKEMIAS, MASTOCYTOSIS (TET2), MYELODYSPLASTIC SYNDROMES (TET2, ASXL1) AND SECONDARY ACUTE MYELOID LEUKEMIA, INCLUDING BLAST-PHASE MPN (IDH, ASXL1, IKZF1). THE FUNCTIONAL CONSEQUENCES OF MPN-ASSOCIATED MUTATIONS INCLUDE UNREGULATED JAK-STAT (JANUS KINASE/SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION) SIGNALING, EPIGENETIC MODULATION OF TRANSCRIPTION AND ABNORMAL ACCUMULATION OF ONCOPROTEINS. HOWEVER, IT IS NOT CLEAR AS TO WHETHER AND HOW THESE ABNORMALITIES CONTRIBUTE TO DISEASE INITIATION, CLONAL EVOLUTION OR BLASTIC TRANSFORMATION.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  1266  33 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