1   913 96 CHRONIC FLT3-ITD SIGNALING IN ACUTE MYELOID LEUKEMIA IS CONNECTED TO A SPECIFIC CHROMATIN SIGNATURE. ACUTE MYELOID LEUKEMIA (AML) IS CHARACTERIZED BY RECURRENT MUTATIONS THAT AFFECT THE EPIGENETIC REGULATORY MACHINERY AND SIGNALING MOLECULES, LEADING TO A BLOCK IN HEMATOPOIETIC DIFFERENTIATION. CONSTITUTIVE SIGNALING FROM MUTATED GROWTH FACTOR RECEPTORS IS A MAJOR DRIVER OF LEUKEMIC GROWTH, BUT HOW ABERRANT SIGNALING AFFECTS THE EPIGENOME IN AML IS LESS UNDERSTOOD. FURTHERMORE, AML CELLS UNDERGO EXTENSIVE CLONAL EVOLUTION, AND THE MUTATIONS IN SIGNALING GENES ARE OFTEN SECONDARY EVENTS. TO ELUCIDATE HOW CHRONIC GROWTH FACTOR SIGNALING ALTERS THE TRANSCRIPTIONAL NETWORK IN AML, WE PERFORMED A SYSTEM-WIDE MULTI-OMICS STUDY OF PRIMARY CELLS FROM PATIENTS SUFFERING FROM AML WITH INTERNAL TANDEM DUPLICATIONS IN THE FLT3 TRANSMEMBRANE DOMAIN (FLT3-ITD). THIS STRATEGY REVEALED COOPERATION BETWEEN THE MAP KINASE (MAPK) INDUCIBLE TRANSCRIPTION FACTOR AP-1 AND RUNX1 AS A MAJOR DRIVER OF A COMMON, FLT3-ITD-SPECIFIC GENE EXPRESSION AND CHROMATIN SIGNATURE, DEMONSTRATING A MAJOR IMPACT OF MAPK SIGNALING PATHWAYS IN SHAPING THE EPIGENOME OF FLT3-ITD AML.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  5589 27 ROLE OF SIRT1 IN THE GROWTH AND REGULATION OF NORMAL HEMATOPOIETIC AND LEUKEMIA STEM CELLS. PURPOSE OF REVIEW: RECENT STUDIES HAVE ENHANCED OUR UNDERSTANDING OF THE ROLE OF THE SIRT1 DEACETYLASE IN REGULATION OF NORMAL HEMATOPOIETIC STEM CELLS (HSCS) AND LEUKEMIA STEM CELLS (LSCS), AND ITS IMPORTANCE IN REGULATING AUTOPHAGY AND EPIGENETIC REPROGRAMMING IN RESPONSE TO METABOLIC ALTERATIONS. RECENT FINDINGS: STUDIES EMPLOYING CONDITIONAL DELETION MOUSE MODELS INDICATE AN IMPORTANT ROLE OF SIRT1 IN MAINTENANCE OF ADULT HSCS UNDER CONDITIONS OF STRESS. SIRT1 IS SIGNIFICANTLY OVEREXPRESSED IN LSC POPULATIONS FROM ACUTE MYELOID LEUKEMIA (AML) PATIENTS WITH THE FLT3-ITD MUTATION, AND MAINTAINS THEIR SURVIVAL, GROWTH AND DRUG RESISTANCE, AS PREVIOUSLY DESCRIBED FOR CHRONIC MYELOGENOUS LEUKEMIA (CML). SIRT1 CAN ALSO ENHANCE LEUKEMIA EVOLUTION AND DRUG RESISTANCE BY PROMOTING GENETIC INSTABILITY. RECENT STUDIES INDICATE AN IMPORTANT ROLE OF SIRT1 IN REGULATING AUTOPHAGY IN RESPONSE TO OXIDATIVE STRESS AND NUTRIENT REQUIREMENTS, AND HAVE ELUCIDATED COMPLEX MECHANISMS BY WHICH SIRT1 REGULATES EPIGENETIC REPROGRAMMING OF STEM CELLS. SUMMARY: SIRT1 INHIBITION HOLDS PROMISE AS A NOVEL APPROACH FOR ABLATION OF LSCS IN CHRONIC PHASE CML OR FLT3-ITD-ASSOCIATED AML. ADDITIONAL STUDIES TO UNDERSTAND THE ROLE OF SIRT1 IN LINKING METABOLIC ALTERATIONS TO GENOMIC STABILITY, AUTOPHAGY AND EPIGENETIC REPROGRAMMING OF STEM CELLS ARE WARRANTED.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3  2237 27 EPIGENETIC MODIFIERS IN MYELOID MALIGNANCIES: THE ROLE OF HISTONE DEACETYLASE INHIBITORS. MYELOID HEMATOLOGICAL MALIGNANCIES ARE CLONAL BONE MARROW NEOPLASMS, COMPRISING OF ACUTE MYELOID LEUKEMIA (AML), THE MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), THE MYELOPROLIFERATIVE NEOPLASMS (MPN) AND SYSTEMIC MASTOCYTOSIS (SM). THE FIELD OF EPIGENETIC REGULATION OF NORMAL AND MALIGNANT HEMATOPOIESIS IS RAPIDLY GROWING. IN RECENT YEARS, HETEROZYGOUS SOMATIC MUTATIONS IN GENES ENCODING EPIGENETIC REGULATORS HAVE BEEN FOUND IN ALL SUBTYPES OF MYELOID MALIGNANCIES, SUPPORTING THE RATIONALE FOR TREATMENT WITH EPIGENETIC MODIFIERS. HISTONE DEACETYLASE INHIBITORS (HDACI) ARE EPIGENETIC MODIFIERS THAT, IN VITRO, HAVE BEEN SHOWN TO INDUCE GROWTH ARREST, APOPTOTIC OR AUTOPHAGIC CELL DEATH, AND TERMINAL DIFFERENTIATION OF MYELOID TUMOR CELLS. THESE EFFECTS WERE OBSERVED BOTH AT THE BULK TUMOR LEVEL AND IN THE MOST IMMATURE CD34(+)38(-) CELL COMPARTMENTS CONTAINING THE LEUKEMIC STEM CELLS. THUS, THERE IS A STRONG RATIONALE SUPPORTING HDACI THERAPY IN MYELOID MALIGNANCIES. HOWEVER, DESPITE INITIAL PROMISING RESULTS IN PHASE I TRIALS, HDACI IN MONOTHERAPY AS WELL AS IN COMBINATION WITH OTHER DRUGS, HAVE FAILED TO IMPROVE RESPONSES OR SURVIVAL. THIS REVIEW PROVIDES AN OVERVIEW OF THE RATIONALE FOR HDACI IN MYELOID MALIGNANCIES, CLINICAL RESULTS AND SPECULATIONS ON WHY CLINICAL TRIALS HAVE THUS FAR NOT MET THE EXPECTATIONS, AND HOW THIS MAY BE IMPROVED IN THE FUTURE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4  1046 22 CLINICAL DEVELOPMENT OF DECITABINE AS A PROTOTYPE FOR AN EPIGENETIC DRUG PROGRAM. THIS REVIEW HIGHLIGHTS DECITABINE AS A PROTOTYPE EPIGENETIC MODIFYING DRUG TO SHOW HOW THE CLINICAL DEVELOPMENT OF EPIGENETIC AGENTS DIFFERS FROM THAT OF TRADITIONAL CYTOTOXIC CHEMOTHERAPIES. DECITABINE, A CYTOSINE ANALOGUE, IS CYTOTOXIC AT HIGH DOSES BUT HAS SELECTIVE DNA DEMETHYLATING ACTIVITY AT LOW DOSES. THE FOCUS OF CURRENT DECITABINE INVESTIGATIONS IS TWOFOLD: TO ELUCIDATE ALL OF THE MECHANISMS OF ACTION AND TO DETERMINE THE OPTIMAL DOSE, SCHEDULE, AND CONCOMITANT THERAPIES. NEW PHASE I TRIALS HAVE IDENTIFIED A "BIOLOGICALLY EFFECTIVE DOSE," WHICH IS 1 TO 2 LOGS LOWER THAN THE CYTOTOXIC DOSE. A CLINICAL DEVELOPMENT PROGRAM WITH LOW-DOSE DECITABINE IN MALIGNANT DISEASES IS FOCUSED ON MYELODYSPLASTIC SYNDROME (MDS), ACUTE MYELOGENOUS LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). A PHASE III TRIAL IN MDS SHOWED OBJECTIVE RESPONSES (COMPLETE [CR] PLUS PARTIAL [PR] REMISSION) AND LONGER MEDIAN TIME TO PROGRESSION TO AML OR DEATH WITH DECITABINE THAN WITH SUPPORTIVE CARE ALONE. THE OPTIMAL USE OF DECITABINE MAY BE IN COMBINATION WITH OTHER AGENTS THAT PROMOTE GENE EXPRESSION, NAMELY, HISTONE DEACETYLASE (HDAC) INHIBITORS. OPTIMIZED DECITABINE DOSES AND COMBINATIONS WITH OTHER EPIGENETIC THERAPIES THAT CAN BE USED AT MINIMALLY TOXIC DOSES PROVIDE POTENTIALLY SAFER THERAPEUTIC OPTIONS AND INTRODUCE NOVEL COMBINATION THERAPIES.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  1882 20 EMERGING TREATMENTS IN ACUTE MYELOID LEUKAEMIA. ACUTE MYELOID LEUKAEMIA (AML) IS THE MOST COMMON FORM OF LEUKAEMIA IN YOUNG ADULTS. ALTHOUGH 75-85% OF PATIENTS WILL ACHIEVE COMPLETE REMISSION AFTER INDUCTION CHEMOTHERAPY, THE LONG-TERM SURVIVAL IS STILL < 50% AT 5 YEARS. CHEMOTHERAPY HAS INCREASED IN INTENSITY IN RECENT YEARS AND IS PERCEIVED TO HAVE REACHED THE LIMIT OF TOXICITY. ALLOGENEIC BONE MARROW TRANSPLANTATION, WHICH IS UNDOUBTEDLY THE MOST EFFECTIVE WAY TO PREVENT RELAPSE, MAY NOT ADD SUBSTANTIAL SURVIVAL BENEFITS. SEVERAL NEW PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF AML ARE NOW BECOMING AVAILABLE, WITH VARIOUS MOLECULAR TARGETS IDENTIFIED, INCLUDING THE FARNESYLATION OF RAS FAMILY PROTEINS AND TYROSINE KINASES INVOLVED IN SIGNAL TRANSDUCTION AND EPIGENETIC METHYLATION. MORE SELECTIVE DELIVERY OF CHEMOTHERAPEUTIC AGENTS IS ALSO FEASIBLE USING HUMANISED MONOCLONAL ANTIBODIES, WITH THE INTRIGUING POSSIBILITY OF INCREASING TREATMENT DELIVERY WITHOUT INCREASING THE TOXICITY. HOWEVER, DESPITE THE PROGRESS IN THE RATIONAL DESIGN OF DRUGS IN DISORDERS SUCH AS CHRONIC MYELOID LEUKAEMIA, AML LACKS A SINGLE SPECIFIC PATHOGNOMIC GENETIC EVENT TO ACT AS A DRUG TARGET. THIS REVIEW DISCUSSES THE DRUGS PRESENTLY UNDER INVESTIGATION IN PHASE II OR PHASE III TRIALS IN AML.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  4660 33 NEW APPROACHES TO THE TREATMENT OF MYELODYSPLASIA. THE THERAPEUTIC DILEMMA THAT CONFRONTS THE MANAGEMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) IS ILLUSTRATED BY THE ABSENCE OF A FOOD AND DRUG ADMINISTRATION-APPROVED AGENT WITH AN INDICATION FOR THIS DISEASE. CLINICAL HETEROGENEITY AND INADEQUATE UNDERSTANDING OF THE DISEASE PATHOBIOLOGY HAVE LIMITED PROGRESS IN THE DEVELOPMENT OF NOVEL THERAPEUTICS. PRECLINICAL INVESTIGATIONS INDICATE THAT RECIPROCAL INTERACTION BETWEEN THE MALIGNANT CLONE AND THE MICROENVIRONMENT SERVE TO CREATE A HOSTILE MILIEU THAT REINFORCES INEFFECTIVE BLOOD CELL PRODUCTION. INEFFECTIVE HEMATOPOIESIS, THE HALLMARK OF MDS, ARISES FROM IMPAIRED PROGENITOR RESPONSIVENESS TO NORMAL TROPHIC SIGNALS AND EXCESS LOCAL GENERATION OF INHIBITORY CYTOKINES, WHICH PROMOTE ACCELERATED APOPTOTIC LOSS OF PROGENITORS AND THEIR PROGENY. EVIDENCE TO SUPPORT THIS MODEL DERIVES FROM CYTOKINE NEUTRALIZATION STUDIES AND THE DIRECT RELATIONSHIP BETWEEN PLASMA TUMOR NECROSIS FACTOR-ALPHA CONCENTRATION AND DNA OXIDATION AND GLUTATHIONE DEPLETION IN MALIGNANT CD34+ PROGENITORS. RECENT INVESTIGATIONS INDICATE THAT ANGIOGENIC MOLECULES GENERATED BY MALIGNANT MYELOMONOCYTIC PRECURSORS REPRESENT INTEGRAL DIFFUSABLE SIGNALS THAT REINFORCE LEUKEMIA PROGENITOR SELF-RENEWAL WHILE PROMOTING THE GENERATION OF PROAPOPTOTIC CYTOKINES AND MEDULLARY ANGIOGENIC RESPONSE. THE POTENTIAL FOR LEUKEMIA EVOLUTION IS COMPOUNDED BY EPIGENETIC EVENTS INCLUDING METHYLATION SILENCING OF THE P15 PROTO-ONCOGENE OR ACTIVATING RAS POINT MUTATIONS. DELINEATION OF SUCH BIOLOGIC FEATURES THAT ARE CENTRAL TO THE PATHOBIOLOGY OF MDS PROVIDES A RELIABLE FRAMEWORK FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. ANTIANGIOGENIC AGENTS IN CLINICAL TESTING INCLUDE VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) RECEPTOR TYROSINE KINASE INHIBITORS, THALIDOMIDE AND RELATED ANALOGUES, AND THE RECOMBINANT VEGF NEUTRALIZING ANTIBODY, BEVACIZUMAB. AGENTS WHOSE ACTIONS MAY RESTORE DIFFERENTIATION PROGRAMS, SUCH AS THE DNA METHYLTRANSFERASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS, OFFER THE PROSPECT TO PROMOTE EFFECTIVE HEMATOPOIESIS WHILE IMPACTING THE POTENTIAL FOR LEUKEMIA EVOLUTION. RAS FARNESYL TRANSFERASE INHIBITORS HAVE SHOWN ENCOURAGING PRELIMINARY RESULTS IN ACUTE MYELOID LEUKEMIA AND ARE CURRENTLY UNDER INVESTIGATION IN ADVANCED MDS AND CHRONIC MYELOMONOCYTIC LEUKEMIA. ARSENIC TRIOXIDE (ATO) INTERACTS WITH A SPECTRUM OF BIOLOGIC TARGETS THAT MAY BE UNIQUELY SUITED TO MDS. ATO IS A POTENT INDUCER OF APOPTOSIS IN THIOL-DEPLETED MALIGNANT PROGENITORS AND NEOVASCULAR ENDOTHELIUM, WHILE PROMOTING DIFFERENTIATION THROUGH HISTONE ACETYLATION AND INACTIVATION OF TRANSCRIPTIONAL COREPRESSORS. THE IDENTIFICATION OF RELEVANT BIOLOGIC TARGETS IN MDS HAS RAISED EXPECTATIONS FOR THE DEVELOPMENT OF DISEASE-SPECIFIC THERAPIES FOR MDS IN THE YEARS THAT FOLLOW.	2002	

7  1674 34 DRIVER MUTATIONS IN LEUKEMIA PROMOTE DISEASE PATHOGENESIS THROUGH A COMBINATION OF CELL-AUTONOMOUS AND NICHE MODULATION. STUDIES OF PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) HAVE LED TO THE IDENTIFICATION OF MUTATIONS THAT AFFECT DIFFERENT CELLULAR PATHWAYS. SOME OF THESE HAVE BEEN CLASSIFIED AS PRELEUKEMIC, AND A STEPWISE EVOLUTION PROGRAM WHEREBY CELLS ACQUIRE ADDITIONAL MUTATIONS HAS BEEN PROPOSED IN THE DEVELOPMENT OF AML. HOW THE TIMING OF ACQUISITION OF THESE MUTATIONS AND THEIR IMPACT ON TRANSFORMATION AND THE BONE MARROW (BM) MICROENVIRONMENT OCCURS HAS ONLY RECENTLY BEGUN TO BE INVESTIGATED. WE SHOW THAT CONSTITUTIVE AND EARLY LOSS OF THE EPIGENETIC REGULATOR, TET2, WHEN COMBINED WITH CONSTITUTIVE ACTIVATION OF FLT3, RESULTS IN TRANSFORMATION OF CHRONIC MYELOMONOCYTIC LEUKEMIA-LIKE OR MYELOPROLIFERATIVE NEOPLASM-LIKE PHENOTYPE TO AML, WHICH IS MORE PRONOUNCED IN DOUBLE-MUTANT MICE RELATIVE TO MICE CARRYING MUTATIONS IN SINGLE GENES. FURTHERMORE, WE SHOW THAT IN PRELEUKEMIC AND LEUKEMIC MICE THERE ARE ALTERATIONS IN THE BM NICHE AND SECRETED CYTOKINES, WHICH CREATES A PERMISSIVE ENVIRONMENT FOR THE GROWTH OF MUTATION-BEARING CELLS RELATIVE TO NORMAL CELLS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
8  3702 25 INFLAMMATORY SIGNALING PATHWAYS IN PRELEUKEMIC AND LEUKEMIC STEM CELLS. HEMATOPOIETIC STEM CELLS (HSCS) ARE A RARE SUBSET OF BONE MARROW CELLS THAT USUALLY EXIST IN A QUIESCENT STATE, ONLY ENTERING THE CELL CYCLE TO REPLENISH THE BLOOD COMPARTMENT, THEREBY LIMITING THE POTENTIAL FOR ERRORS IN REPLICATION. INFLAMMATORY SIGNALS THAT ARE RELEASED IN RESPONSE TO ENVIRONMENTAL STRESSORS, SUCH AS INFECTION, TRIGGER ACTIVE CYCLING OF HSCS. THESE INFLAMMATORY SIGNALS CAN ALSO DIRECTLY INDUCE HSCS TO RELEASE CYTOKINES INTO THE BONE MARROW ENVIRONMENT, PROMOTING MYELOID DIFFERENTIATION. AFTER STRESS MYELOPOIESIS IS TRIGGERED, HSCS REQUIRE INTRACELLULAR SIGNALING PROGRAMS TO DEACTIVATE THIS RESPONSE AND RETURN TO STEADY STATE. PROLONGED OR EXCESSIVE EXPOSURE TO INFLAMMATORY CYTOKINES, SUCH AS IN PROLONGED INFECTION OR IN CHRONIC RHEUMATOLOGIC CONDITIONS, CAN LEAD TO CONTINUED HSC CYCLING AND EVENTUAL HSC LOSS. THIS PROMOTES BONE MARROW FAILURE, AND CAN PRECIPITATE PRELEUKEMIC STATES OR LEUKEMIA THROUGH THE ACQUISITION OF GENETIC AND EPIGENETIC CHANGES IN HSCS. THIS CAN OCCUR THROUGH THE INITIATION OF CLONAL HEMATOPOIESIS, FOLLOWED BY THE EMERGENCE PRELEUKEMIC STEM CELLS (PRE-LSCS). IN THIS REVIEW, WE DESCRIBE THE ROLES OF MULTIPLE INFLAMMATORY SIGNALING PATHWAYS IN THE GENERATION OF PRE-LSCS AND IN PROGRESSION TO MYELODYSPLASTIC SYNDROME (MDS), MYELOPROLIFERATIVE NEOPLASMS, AND ACUTE MYELOID LEUKEMIA (AML). IN AML, ACTIVATION OF SOME INFLAMMATORY SIGNALING PATHWAYS CAN PROMOTE THE CYCLING AND DIFFERENTIATION OF LSCS, AND THIS CAN BE EXPLOITED THERAPEUTICALLY. WE ALSO DISCUSS THE THERAPEUTIC POTENTIAL OF MODULATING INFLAMMATORY SIGNALING FOR THE TREATMENT OF MYELOID MALIGNANCIES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
9  2259 20 EPIGENETIC PRIMING IN DRUG ADDICTION. DRUG ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER THAT IS CHARACTERIZED BY COMPULSIVE DRUG SEEKING AND CONTINUED USE DESPITE NEGATIVE OUTCOMES. CURRENT PHARMACOLOGICAL THERAPIES TARGET NEURONAL RECEPTORS OR TRANSPORTERS UPON WHICH DRUGS OF ABUSE ACT INITIALLY, YET THESE TREATMENTS REMAIN INEFFECTIVE FOR MOST INDIVIDUALS AND DO NOT PREVENT DISEASE RELAPSE AFTER ABSTINENCE. DRUGS OF ABUSE, IN ADDITION TO THEIR ACUTE EFFECTS, CAUSE PERSISTENT PLASTICITY AFTER REPEATED USE, INVOLVING DYSREGULATED GENE EXPRESSION IN THE BRAIN'S REWARD REGIONS, WHICH ARE THOUGHT TO MEDIATE THE PERSISTENT BEHAVIORAL ABNORMALITIES THAT CHARACTERIZE ADDICTION. EMERGING EVIDENCE IMPLICATES EPIGENETIC PRIMING AS A KEY MECHANISM THAT UNDERLIES THE LONG-LASTING ALTERATIONS IN NEURONAL GENE REGULATION, WHICH CAN REMAIN LATENT UNTIL TRIGGERED BY RE-EXPOSURE TO DRUG-ASSOCIATED STIMULI OR THE DRUG ITSELF. THUS, TO EFFECTIVELY TREAT DRUG ADDICTION, WE MUST IDENTIFY THE PRECISE EPIGENETIC MECHANISMS THAT ESTABLISH AND PRESERVE THE DRUG-INDUCED PATHOLOGY OF THE BRAIN REWARD CIRCUITRY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  2582 32 EPIGENETICS OF MYELODYSPLASTIC SYNDROMES. MYELODYSPLASTIC SYNDROMES (MDS) ARE CLONAL DISEASES OF THE ELDERLY CHARACTERIZED BY CHRONIC CYTOPENIAS, DYSPLASIA AND A VARIABLE RISK OF PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML). ABERRANT METHYLATION OF TUMOR-SUPPRESSOR GENE PROMOTERS HAS BEEN ESTABLISHED FOR MANY YEARS AND RECENTLY TRACKED TO THE MOST IMMATURE CELLS OF MDS, SUGGESTING THAT THESE ALTERATIONS ARE DRIVERS OF MDS PATHOGENESIS. IN RECENT YEARS, RECURRENT SOMATIC MUTATIONS IN GENES ENCODING PROTEINS INVOLVED IN DNA METHYLATION AND DEMETHYLATION AND IN COVALENT HISTONE MODIFICATIONS HAVE BEEN REPORTED IN MYELOID MALIGNANCIES, INCLUDING MDS. WHOLE-GENOME EPIGENETIC PROFILES OF MDS ARE ALSO EMERGING. IN PARALLEL WITH THESE ADVANCES IN THE MOLECULAR PATHOGENESIS OF MDS, CLINICAL TRIALS HAVE ESTABLISHED HYPOMETHYLATING AGENTS (HMAS) AS THE MAINSTAY OF THERAPY IN THE ADVANCED FORMS OF THE DISEASE. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF THE MOLECULAR MACHINERY INVOLVED IN EPIGENETIC REGULATION, DISCUSS HOW EPIGENETIC ALTERATIONS ARISE IN MDS AND CONTRIBUTE TO ITS PATHOGENESIS AND THEN DISCUSS THE MODE OF ACTION OF HMAS IN MDS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11  5499 20 REVIEW: RECENT CLINICAL TRIALS IN EPIGENETIC THERAPY. EPIGENETIC FACTORS SUCH AS DNA METHYLATION AND HISTONE DEACETYLATION ARE KNOWN TO CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF CELLS BY SILENCING CRITICAL GENES. DRUGS THAT INHIBIT DNA METHYLTRANSFERASES OR HISTONE DEACETYLASES WERE SHOWN TO HAVE THE POTENTIAL TO REACTIVATE SILENCED GENES AND INDUCE DIFFERENTIATION OR APOPTOSIS OF MALIGNANT CELLS. THE MOST INTENSIVELY STUDIED CLASS OF SUCH AGENTS IS DNA METHYLTRANSFERASE INHIBITORS, INCLUDING 5-AZACYTIDINE (AZACITIDINE) AND 5-AZA-2'-DEOXYCYTIDINE (DECITABINE). IN 2004, AZACITIDINE WAS APPROVED FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME ON THE BASIS OF PHASE II AND III STUDIES THAT SHOWED A RESPONSE RATE (COMPLETE AND PARTIAL RESPONSES) OF 15%. AZACITIDINE IS ALSO BEING EVALUATED IN CLINICAL TRIALS FOR OTHER MALIGNANT DISEASES. DECITABINE HAS RESPONSE RATES OF 17-49% IN MYELODYSPLASTIC SYNDROME IN MULTIPLE PHASE II AND III STUDIES AND ALSO ACTIVITY IN ACUTE AND CHRONIC MYELOGENOUS LEUKEMIA. HISTONE DEACETYLASE INHIBITORS BELONG TO ANOTHER CLASS OF EPIGENETIC MODIFYING AGENTS THAT INCLUDE DEPSIPEPTIDE, BUTYRATE DERIVATIVES, SUBEROYLANILIDE HYDROXAMIC ACID AND VALPROIC ACID. NO AGENT IN THIS CLASS HAS BEEN STUDIED IN A PHASE III TRIAL, BUT SEVERAL AGENTS HAVE BEEN OR ARE BEING STUDIED IN PHASE II TRIALS. FURTHER RESEARCH IS NEEDED TO DETERMINE THE APPROPRIATE PATIENT SELECTION AND DOSING SCHEDULES.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
12  1616 25 DNA METHYLTRANSFERASE AND HISTONE DEACETYLASE INHIBITORS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROMES. THE RECENTLY APPROVED DRUGS 5-AZACITIDINE (5AC) AND 5-AZA-2'-DEOXYAZACYTIDINE (DAC) ARE IN WIDE CLINICAL USE FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME (MDS) OF ALL TYPES AND CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). THESE AGENTS WERE DEVELOPED BASED UPON AN UNDERSTANDING OF THE IMPORTANCE OF EPIGENETIC CHANGES IN MALIGNANCY, AND THEY HAVE BEEN EVALUATED IN RANDOMIZED CLINICAL TRIALS, WHICH DEMONSTRATE RESPONSE RATES BETWEEN 20% AND 40% IN PATIENTS FOR WHOM NO PREVIOUS STANDARD OF CARE WAS AVAILABLE. AS UNDERSTANDING OF THE EPIGENETIC CHANGES CHARACTERISTIC OF THE MALIGNANT PHENOTYPE IMPROVES, WE ARE ABLE TO TARGET OTHER REGULATORS OF CHROMATIN CONFORMATION THAT CONTRIBUTE TO ABERRANT GENE TRANSCRIPTION AND DYSREGULATED CELL GROWTH. THE HISTONE DEACETYLASE (HDAC) INHIBITORS BELONG TO ONE CLASS OF THERAPEUTICS DEVELOPED USING THIS PARADIGM. ALTHOUGH RESPONSES USING HDAC INHIBITORS ALONE IN MDS HAVE BEEN MODEST, ROBUST PRECLINICAL DATA DRIVE CLINICAL TRIALS IN WHICH THEY ARE UTILIZED IN COMBINATION WITH DNA METHYLTRANSFERASE (DNMT) INHIBITORS. COMBINATION THERAPY OFFERS THE POSSIBILITY OF HEMATOLOGIC IMPROVEMENT AND REMISSION TO MYELODYSPLASTIC PATIENTS WITH PREVIOUSLY UNTREATABLE DISEASE.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  1288 20 DECITABINE. PURPOSE OF REVIEW: DECITABINE IS A CYTOSINE ANALOGUE SYNTHESIZED IN THE 1960S THAT IS CURRENTLY ENJOYING A REVIVAL OF INTEREST PROMPTED BY THE ELUCIDATION OF DNA METHYLATION INHIBITION AS ITS MAJOR MECHANISM OF ACTION, ALONG WITH INCREASED UNDERSTANDING OF THE ROLE OF DNA METHYLATION IN EPIGENETIC DYSREGULATION IN CANCER. THESE ADVANCES HAVE TURNED THIS AGENT FROM JUST ANOTHER CYTOSINE ANALOGUE INTO A TARGETED DRUG AIMED AT REVERSING EPIGENETIC SILENCING IN CANCER CELLS. HERE, RECENT CLINICAL AND TRANSLATIONAL STUDIES WITH DECITABINE ARE REVIEWED. RECENT FINDINGS: SCIENTISTS ARE NOW TAKING A CLOSER LOOK AT THIS DRUG AS A TARGETED AGENT, WITH PARTICULAR ATTENTION TO SCHEDULES OF ADMINISTRATION AND MECHANISMS OF IN VIVO EFFICACY. TWO PHASE II TRIALS HAVE REPORTED SUBSTANTIAL CLINICAL ACTIVITY OF DECITABINE IN THE MYELODYSPLASTIC SYNDROME AND IN CHRONIC MYELOGENOUS LEUKEMIA. THERE IS CONSIDERABLE INTEREST IN COMBINING DECITABINE WITH HISTONE DEACETYLASE INHIBITORS AND IN USING IT TO SENSITIZE CELLS TO CHEMOTHERAPY OR TO BIOLOGIC THERAPY. FINALLY, ONGOING EFFORTS ARE DECIPHERING THE IN VIVO MECHANISMS OF RESPONSES SEEN AFTER DECITABINE ADMINISTRATION. SUMMARY: DECITABINE, AN OLD DRUG, HAS NOW MADE A COMEBACK AS A TARGETED AGENT AND A PROTOTYPE FOR EPIGENETIC THERAPY IN CANCER. DOSES, SCHEDULES OF ADMINISTRATION, AND THE DEVELOPMENT OF RATIONAL COMBINATIONS INCLUDING THIS AGENT MUST ALL TAKE THIS CRITICAL MECHANISM OF ACTION INTO ACCOUNT.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
14  6573 26 TREATMENT OF ACUTE MYELOID LEUKEMIA IN THE ERA OF GENOMICS-ACHIEVEMENTS AND PERSISTING CHALLENGES. ACUTE MYELOID LEUKEMIA (AML) REPRESENTS A MALIGNANT DISORDER OF THE HEMATOPOIETIC SYSTEM THAT IS MAINLY CHARACTERIZED BY RAPID PROLIFERATION, DYSREGULATED APOPTOSIS, AND IMPAIRED DIFFERENTIATION OF LEUKEMIC BLASTS. FOR SEVERAL DECADES, THE DIAGNOSTIC APPROACH IN AML WAS LARGELY BASED ON HISTOLOGIC CHARACTERISTICS WITH LITTLE IMPACT ON THE TREATMENT DECISION-MAKING PROCESS. THIS PERSPECTIVE HAS DRASTICALLY CHANGED WITHIN THE PAST YEARS DUE TO THE ADVENT OF NOVEL MOLECULAR TECHNOLOGIES, SUCH AS WHOLE GENOME NEXT-GENERATION SEQUENCING (NGS), AND THE RESULTING KNOWLEDGE GAIN IN AML BIOLOGY AND PATHOGENESIS. AFTER MORE THAN FOUR DECADES OF INTENSIVE CHEMOTHERAPY AS A "ONE-SIZE-FITS-ALL" CONCEPT, SEVERAL TARGETED AGENTS HAVE RECENTLY BEEN APPROVED FOR THE TREATMENT OF AML, EITHER AS SINGLE AGENTS OR AS PART OF COMBINED TREATMENT REGIMENS. SEVERAL OTHER COMPOUNDS, DIRECTED AGAINST REGULATORS OF APOPTOTIC, EPIGENETIC, OR MICROENVIRONMENTAL PATHWAYS, AS WELL AS MODULATORS OF THE IMMUNE SYSTEM, ARE CURRENTLY IN DEVELOPMENT AND BEING INVESTIGATED IN CLINICAL TRIALS. THE CONSTANT PROGRESS IN AML RESEARCH HAS STARTED TO PRODUCE IMPROVED SURVIVAL RATES AND FUELED HOPES THAT A ONCE RAPIDLY FATAL DISEASE CAN BE TRANSFORMED INTO A CHRONIC CONDITION. IN THIS REVIEW, THE AUTHORS PROVIDE A SUMMARY OF RECENT ADVANCES IN THE DEVELOPMENT OF TARGETED AML THERAPIES AND DISCUSS PERSISTENT CHALLENGES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15  3234 24 HEMATOPOIETIC AND CHRONIC MYELOID LEUKEMIA STEM CELLS: MULTI-STABILITY VERSUS LINEAGE RESTRICTION. THERE IS COMPELLING EVIDENCE TO SUPPORT THE VIEW THAT THE CELL-OF-ORIGIN FOR CHRONIC MYELOID LEUKEMIA IS A HEMATOPOIETIC STEM CELL. UNLIKE NORMAL HEMATOPOIETIC STEM CELLS, THE PROGENY OF THE LEUKEMIA STEM CELLS ARE PREDOMINANTLY NEUTROPHILS DURING THE DISEASE CHRONIC PHASE AND THERE IS A MILD ANEMIA. THE HALLMARK ONCOGENE FOR CHRONIC MYELOID LEUKEMIA IS THE BCR-ABLP210 FUSION GENE. VARIOUS STUDIES HAVE EXCLUDED A ROLE FOR BCR-ABLP210 EXPRESSION IN MAINTAINING THE POPULATION OF LEUKEMIA STEM CELLS. STUDIES OF BCR-ABLP210 EXPRESSION IN EMBRYONAL STEM CELLS THAT WERE DIFFERENTIATED INTO HEMATOPOIETIC STEM CELLS AND OF THE EXPRESSION IN TRANSGENIC MICE HAVE REVEALED THAT BCR-ABLP210 IS ABLE TO VEER HEMATOPOIETIC STEM AND PROGENITOR CELLS TOWARDS A MYELOID FATE. FOR THE TRANSGENIC MICE, GLOBAL CHANGES TO THE EPIGENETIC LANDSCAPE WERE OBSERVED. IN CHRONIC MYELOID LEUKEMIA, THE ABILITY OF THE LEUKEMIA STEM CELLS TO CHOOSE FROM THE MANY FATES THAT ARE AVAILABLE TO NORMAL HEMATOPOIETIC STEM CELLS APPEARS TO BE DEREGULATED BY BCR-ABLP210 AND CHANGES TO THE EPIGENOME ARE ALSO IMPORTANT. EVEN SO, WE STILL DO NOT HAVE A PRECISE PICTURE AS TO WHY NEUTROPHILS ARE ABUNDANTLY PRODUCED IN CHRONIC MYELOID LEUKEMIA.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16   358 27 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17  6517 18 TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS OF ADDICTION. INVESTIGATIONS OF LONG-TERM CHANGES IN BRAIN STRUCTURE AND FUNCTION THAT ACCOMPANY CHRONIC EXPOSURE TO DRUGS OF ABUSE SUGGEST THAT ALTERATIONS IN GENE REGULATION CONTRIBUTE SUBSTANTIALLY TO THE ADDICTIVE PHENOTYPE. HERE, WE REVIEW MULTIPLE MECHANISMS BY WHICH DRUGS ALTER THE TRANSCRIPTIONAL POTENTIAL OF GENES. THESE MECHANISMS RANGE FROM THE MOBILIZATION OR REPRESSION OF THE TRANSCRIPTIONAL MACHINERY - INCLUDING THE TRANSCRIPTION FACTORS DELTAFOSB, CYCLIC AMP-RESPONSIVE ELEMENT BINDING PROTEIN (CREB) AND NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) - TO EPIGENETICS - INCLUDING ALTERATIONS IN THE ACCESSIBILITY OF GENES WITHIN THEIR NATIVE CHROMATIN STRUCTURE INDUCED BY HISTONE TAIL MODIFICATIONS AND DNA METHYLATION, AND THE REGULATION OF GENE EXPRESSION BY NON-CODING RNAS. INCREASING EVIDENCE IMPLICATES THESE VARIOUS MECHANISMS OF GENE REGULATION IN THE LASTING CHANGES THAT DRUGS OF ABUSE INDUCE IN THE BRAIN, AND OFFERS NOVEL INROADS FOR ADDICTION THERAPY.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  2083 22 EPIGENETIC DRUGS: A LONGSTANDING STORY. IN THIS CHAPTER, THE DEVELOPMENT OF DECITABINE FROM ITS SYNTHESIS IN 1964 TO THE SUBMISSION OF A REGISTRATION FILE IN 2004 IS REVIEWED. THE PROPER APPLICATION OF THE UNIQUE PROPERTIES OF DECITABINE TOOK QUITE SOME TIME TO ELUCIDATE. IN ADDITION, THE PRACTICAL HANDLING IN THE CLINIC WAS NOT EASY AS THE PROLONGED MYELOSUPPRESSION OF DECITABINE MADE IT DIFFICULT TO DETERMINE THE PREFERRED DOSE AND SCHEDULE. LABORATORY STUDIES ON DNA METHYLATION AND CELL DIFFERENTIATION SHOWED POSSIBLE APPLICATIONS IN SOLID AND HEMATOLOGIC MALIGNANCIES. HOWEVER, DESPITE MANY ATTEMPTS, RESULTS IN SOLID TUMORS HAVE BEEN DISAPPOINTING THUS FAR. AFTER THOROUGH INVESTIGATION, DECITABINE ACHIEVED THERAPEUTIC APPLICATION IN MYELODYSPLASTIC SYNDROME (MDS), IN PARTICULAR IN PATIENTS WITH A POOR PROGNOSIS. FURTHER INDICATIONS MAY INCLUDE ACUTE MYELOID LEUKEMIA (AML), CHRONIC MYELOGENOUS LEUKEMIA (CML), HEMATOPOIETIC STEM CELL TRANSPLANTATION, SICKLE CELL ANEMIA, AND THALASSEMIA. WHEREAS MOST DRUGS ARE ALREADY AT THE END OF THEIR LIFE CYCLE AFTER 40 YEARS, DECITABINE IS ONLY AT THE BEGINNING. ITS APPLICATION WILL BROADEN WITH THE INCREASE IN KNOWLEDGE OF EPIGENETIC MECHANISMS AND THEIR RELATIONSHIP TO DRUG THERAPY.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19  4639 23 NEURONAL EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) ACTIVITY AS MARKER AND MEDIATOR OF ALCOHOL AND OPIOID DEPENDENCE. EARLY PIONEERING WORK IN THE FIELD OF BIOCHEMISTRY IDENTIFIED PHOSPHORYLATION AS A CRUCIAL POST-TRANSLATIONAL MODIFICATION OF PROTEINS WITH THE ABILITY TO BOTH INDICATE AND ARBITRATE COMPLEX PHYSIOLOGICAL PROCESSES. MORE RECENT INVESTIGATIONS HAVE FUNCTIONALLY LINKED PHOSPHORYLATION OF EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) TO A VARIETY OF NEUROPHYSIOLOGICAL MECHANISMS RANGING FROM ACUTE NEUROTRANSMITTER ACTION TO LONG-TERM GENE EXPRESSION. ERK PHOSPHORYLATION SERVES AS AN INTRACELLULAR BRIDGING MECHANISM THAT FACILITATES NEURONAL COMMUNICATION AND PLASTICITY. DRUGS OF ABUSE, INCLUDING ALCOHOL AND OPIOIDS, ACT AS ARTIFICIAL YET POWERFUL REWARDS THAT IMPINGE UPON NATURAL REINFORCEMENT PROCESSES CRITICAL FOR SURVIVAL. THE GRADED PROGRESSION FROM INITIAL EXPOSURE TO ADDICTION (OR SUBSTANCE DEPENDENCE) IS BELIEVED TO RESULT FROM DRUG- AND DRUG CONTEXT-INDUCED ADAPTATIONS IN NEURONAL SIGNALING PROCESSES ACROSS BRAIN REWARD AND STRESS CIRCUITS FOLLOWING EXCESSIVE DRUG USE. IN THIS REGARD, COMMONLY ABUSED DRUGS AS WELL AS DRUG-ASSOCIATED EXPERIENCES ARE CAPABLE OF MODIFYING THE PHOSPHORYLATION OF ERK WITHIN CENTRAL REINFORCEMENT SYSTEMS. IN ADDITION, CHRONIC DRUG AND ALCOHOL EXPOSURE MAY DRIVE ERK-REGULATED EPIGENETIC AND STRUCTURAL ALTERATIONS THAT UNDERLIE A LONG-TERM PROPENSITY FOR ESCALATING DRUG USE. UNDER THE INFLUENCE OF SUCH A NEUROBIOLOGICAL VULNERABILITY, ENCOUNTERING DRUG-ASSOCIATED CUES AND CONTEXTS CAN PRODUCE SUBSEQUENT ALTERATIONS IN ERK SIGNALING THAT DRIVE RELAPSE TO DRUG AND ALCOHOL SEEKING. CURRENT STUDIES ARE DETERMINING PRECISELY WHICH MOLECULAR AND REGIONAL ERK PHOSPHORYLATION-ASSOCIATED EVENTS CONTRIBUTE TO THE ADDICTION PROCESS, AS WELL AS WHICH NEUROADAPTATIONS NEED TO BE TARGETED IN ORDER TO RETURN DEPENDENT INDIVIDUALS TO A HEALTHY STATE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20  1242 26 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