1 255 115 ADVANCES IN MYELOFIBROSIS: A CLINICAL CASE APPROACH. PRIMARY MYELOFIBROSIS IS A MEMBER OF THE MYELOPROLIFERATIVE NEOPLASMS, A DIVERSE GROUP OF BONE MARROW MALIGNANCIES. SYMPTOMS OF MYELOFIBROSIS, PARTICULARLY THOSE ASSOCIATED WITH SPLENOMEGALY (ABDOMINAL DISTENTION AND PAIN, EARLY SATIETY, DYSPNEA, AND DIARRHEA) AND CONSTITUTIONAL SYMPTOMS, REPRESENT A SUBSTANTIAL BURDEN TO PATIENTS. MOST PATIENTS EVENTUALLY DIE FROM THE DISEASE, WITH A MEDIAN SURVIVAL RANGING FROM APPROXIMATELY 5-7 YEARS. MUTATIONS IN JANUS KINASE 2 (JAK2), A KINASE THAT IS ESSENTIAL FOR THE NORMAL DEVELOPMENT OF ERYTHROCYTES, GRANULOCYTES, AND PLATELETS, NOTABLY THE V617F MUTATION, HAVE BEEN IDENTIFIED IN APPROXIMATELY 50% OF PATIENTS WITH MYELOFIBROSIS. THE APPROVAL OF A JAK2 INHIBITOR IN 2011 HAS IMPROVED THE OUTLOOK OF MANY PATIENTS WITH MYELOFIBROSIS AND HAS CHANGED THE TREATMENT LANDSCAPE. THIS ARTICLE FOCUSES ON SOME OF THE IMPORTANT ISSUES IN CURRENT MYELOFIBROSIS TREATMENT MANAGEMENT, INCLUDING DIFFERENTIATION OF MYELOFIBROSIS FROM ESSENTIAL THROMBOCYTHEMIA AND POLYCYTHEMIA VERA, UP-DATED DATA ON THE RESULTS OF JAK2 INHIBITOR THERAPY, THE ROLE OF EPIGENETIC MECHANISMS IN MYELOFIBROSIS PATHOGENESIS, INVESTIGATIONAL THERAPIES FOR MYELOFIBROSIS, AND ADVANCES IN HEMATOPOIETIC STEM CELL TRANSPLANT. THREE MYELOFIBROSIS CASES ARE INCLUDED TO UNDERSCORE THE ISSUES IN DIAGNOSING AND TREATING THIS COMPLEX DISEASE. 2013 2 5953 35 TARGETS IN MPNS AND POTENTIAL THERAPEUTICS. PHILADELPHIA-NEGATIVE CLASSICAL MYELOPROLIFERATIVE NEOPLASMS (MPNS), INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF), ARE CLONAL HEMOPATHIES THAT EMERGE IN THE HEMATOPOIETIC STEM CELL (HSC) COMPARTMENT. MPN DRIVER MUTATIONS ARE RESTRICTED TO SPECIFIC EXONS (14 AND 12) OF JANUS KINASE 2 (JAK2), THROMBOPOIETIN RECEPTOR (MPL/TPOR) AND CALRETICULIN (CALR) GENES, ARE INVOLVED DIRECTLY IN CLONAL MYELOPROLIFERATION AND GENERATE THE MPN PHENOTYPE. AS A RESULT, AN INCREASED NUMBER OF FULLY FUNCTIONAL ERYTHROCYTES, PLATELETS AND LEUKOCYTES IS OBSERVED IN THE PERIPHERAL BLOOD. NEVERTHELESS, THE COMPLEXITY AND HETEROGENEITY OF MPN CLINICAL PHENOTYPES CANNOT BE SOLELY EXPLAINED BY THE TYPE OF DRIVER MUTATION. OTHER FACTORS, SUCH AS ADDITIONAL SOMATIC MUTATIONS AFFECTING EPIGENETIC REGULATORS OR SPLICEOSOMES COMPONENTS, MUTANT ALLELE BURDENS AND MODIFIERS OF SIGNALING BY DRIVER MUTANTS, CLONAL ARCHITECTURE AND THE ORDER OF MUTATION ACQUISITION, SIGNALING EVENTS THAT OCCUR DOWNSTREAM OF A DRIVER MUTATION, THE PRESENCE OF SPECIFIC GERM-LINE VARIANTS, THE INTERACTION OF THE NEOPLASTIC CLONE WITH BONE MARROW MICROENVIRONMENT AND CHRONIC INFLAMMATION, ALL CAN MODULATE THE DISEASE PHENOTYPE, INFLUENCE THE MPN CLINICAL COURSE AND THEREFORE, MIGHT BE USEFUL THERAPEUTIC TARGETS. 2022 3 6856 36 [NOT AVAILABLE]. BIOLOGICAL ASPECTS OF JAK/STAT SIGNALING IN BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: MYELOPROLIFERATIVE DISORDERS MORE RECENTLY NAMED MYELOPROLIFERATIVE NEOPLASMS (MPN) DISPLAY SEVERAL CLINICAL ENTITIES: CHRONIC MYELOID LEUKEMIA (CML), THE CLASSICAL MPN INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET), PRIMARY MYELOFIBROSIS (PMF) AND ATYPICAL AND UNCLASSIFIABLE NMP. THE TERM MPN IS MOSTLY USED FOR CLASSICAL BCR-ABL-NEGATIVE (MYELOPROLIFERATIVE DISORDER) (ET, PV, PMF). THESE ARE CLONAL DISEASES RESULTING FROM THE TRANSFORMATION OF AN HEMATOPOIETIC STEM CELL AND LEADING TO AN ABNORMAL PRODUCTION OF MYELOID CELLS. THE GENETIC DEFECTS RESPONSIBLE FOR THE MYELOPROLIFERATIVE ABNORMALITIES ARE CALLED << DRIVER >> MUTATIONS AND ALL RESULT IN DEREGULATION OF THE CYTOKINE RECEPTOR / JAK2 / STAT AXIS. AMONG THEM, JAK2, THE THROMBOPOIETIN RECEPTOR (MPL) AND CALRETICULIN (CALR) MUTATIONS ARE FOUND IN AROUND 90% OF THE CASES. THESE DRIVER MPN MUTATIONS CAN BE ASSOCIATED WITH OTHER DRIVER MUTATIONS ALSO FOUND IN OTHER HEMATOLOGICAL MALIGNANCIES, ESPECIALLY IN PMFS. THESE ARE CHRONIC DISEASES WITH MAJOR RISKS BEING THROMBOSIS, HEMORRHAGE AND CYTOPENIAS FOR PMF AND THE LONG-TERM PROGRESSION TO MYELOFIBROSIS AND THE TRANSFORMATION TO LEUKEMIA. MOST RECENT THERAPEUTIC HAVE FOCUSED ON TARGETING THE JAK2 SIGNALING PATHWAY DIRECTLY BY INHIBITORS OF JAK2 OR INDIRECTLY. INTERFERON A ALLOWS IN SOME CASES HEMATOLOGIC AND MOLECULAR REMISSION PATIENTS. 2016 4 5799 31 STEPPING OUT OF ANTIQUITY: AN UPDATE ON EMERGING DRUGS FOR THE TREATMENT OF POLYCYTHEMIA VERA. INTRODUCTION: POLYCYTHEMIA VERA IS A CHRONIC HEMATOLOGIC MALIGNANCY FREQUENTLY PRESENTED WITH CONSTITUTIONAL SYMPTOMS AND ASSOCIATED WITH AN INCREASED RISK OF THROMBOSIS, HEMORRHAGE, AND PROGRESSION TO MYELOFIBROSIS OR ACUTE MYELOID LEUKEMIA. CURRENT TREATMENT STRATEGIES REDUCE THROMBOHEMORRHAGIC RISK BY CONTROLLING BLOOD COUNTS AND INHIBITING PLATELETS, BUT OFTEN FAIL TO ADDRESS DISEASE-RELATED SYMPTOMS OR BIOLOGICALLY MODIFY THE DISEASE.AREAS COVERED: WE REVIEW THE CURRENT PARADIGM FOR TREATING POLYCYTHEMIA VERA, HIGHLIGHT AREAS OF UNMET NEED, REVIEW THERAPEUTIC AGENTS IN LATE STAGE CLINICAL DEVELOPMENT, AND PROVIDE AN OVERARCHING VIEW OF HOW THESE EMERGING AGENT MAY FIT INTO THE FUTURE ARMAMENTARIUM OF POLYCYTHEMIA VERA TREATMENTS.EXPERT OPINION: THE SHIFT FROM FOCUSING SOLELY ON SECONDARY PREVENTION OF THROMBOHEMORRHAGIC EVENTS TO A COMPREHENSIVE TREATMENT STRATEGY THAT ADDITIONALLY AIMS TO IMPROVE QUALITY OF LIFE AND PREVENT DISEASE PROGRESSION HAS RESULTED IN A RAPIDLY EVOLVING THERAPEUTIC LANDSCAPE THAT PROMISES TO MOVE THE TREATMENT OF POLYCYTHEMIA VERA OUT OF ANTIQUITY INTO THE MODERN AGE. 2021 5 960 35 CHRONIC MYELOMONOCYTIC LEUKEMIA: 2016 UPDATE ON DIAGNOSIS, RISK STRATIFICATION, AND MANAGEMENT. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. DIAGNOSIS IS BASED ON THE PRESENCE OF PERSISTENT (>3 MONTHS) PERIPHERAL BLOOD MONOCYTOSIS (>1 X 10(9) /L), ALONG WITH BONE MARROW DYSPLASIA. CLONAL CYTOGENETIC ABNORMALITIES OCCUR IN APPROXIMATELY 20-30% OF PATIENTS, WHILE >90% HAVE GENE MUTATIONS. MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT; WITH ONLY ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. TWO MOLECULARLY INTEGRATED, CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE; THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) AND THE MOLECULAR MAYO MODEL (MMM). THE GFM MODEL SEGREGATES PATIENTS INTO 3 GROUPS BASED ON: AGE >65 YEARS, WBC >15 X 10(9) /L, ANEMIA, PLATELETS <100 X 10(9) /L, AND ASXL1 MUTATION STATUS, WITH RESPECTIVE MEDIAN SURVIVALS OF 56 (LOW), 27.4 (INTERMEDIATE), AND 9.2 (HIGH) MONTHS. THE MMM IS BASED ON ASXL1 MUTATIONAL STATUS, ABSOLUTE MONOCYTE COUNT >10 X 10(9) /L, HEMOGLOBIN <10 G/DL, PLATELETS <100 X 109/L AND CIRCULATING IMMATURE MYELOID CELLS. THIS MODEL STRATIFIES PATIENTS INTO FOUR GROUPS; HIGH (>/=3 RISK FACTORS), INTERMEDIATE-2 (2 RISK FACTORS), INTERMEDIATE-1 (1 RISK FACTOR) AND LOW (NO RISK FACTORS), WITH MEDIAN SURVIVALS OF 16, 31, 59, AND 97 MONTHS, RESPECTIVELY. HYPOMETHYLATING AGENTS SUCH AS 5-AZACITIDINE AND DECITABINE ARE COMMONLY USED, WITH OVERALL RESPONSE RATES OF APPROXIMATELY 30-40% AND COMPLETE REMISSION RATES OF APPROXIMATELY 7-17%. ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY POTENTIALLY CURATIVE OPTION, BUT IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY. INDIVIDUALIZED THERAPY, INCLUDING EPIGENETIC MODIFIERS AND SMALL MOLECULE INHIBITORS, ARE EXCITING PROSPECTS. AM. J. HEMATOL. 91:632-642, 2016. (C) 2016 WILEY PERIODICALS, INC. 2016 6 6040 37 THE CHRONIC MYELOPROLIFERATIVE DISORDERS: CLONALITY AND CLINICAL HETEROGENEITY. THE CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD), POLYCYTHEMIA VERA (PV), CHRONIC IDIOPATHIC MYELOFIBROSIS (IMF), ESSENTIAL THROMBOCYTOSIS (ET), AND CHRONIC MYELOGENOUS LEUKEMIA (CML), ARE THOUGHT TO BE CLONAL DISORDERS ARISING IN A MULTIPOTENT HEMATOPOIETIC PROGENITOR CELL. HOWEVER, ESTABLISHING THE DIAGNOSIS OF AN MPD OTHER THAN CML IS PROBLEMATIC DUE TO A LACK OF CLINICALLY APPLICABLE CLONAL MARKERS. FURTHERMORE, IN SOME PATIENTS, IN WHOM A CLASSICAL MPD PHENOTYPE IS PRESENT, THE HEMATOPOIETIC STEM CELLS APPEAR TO BE POLYCLONAL, SUGGESTING THAT THE CHRONIC MPD OTHER THAN CML MAY ACTUALLY BE A GENETICALLY HETEROGENEOUS GROUP OF DISORDERS. FURTHERMORE, SINCE THE ABERRANT CLONE IS BELIEVED TO ARISE FROM A MULTIPOTENT HEMATOPOIETIC STEM CELL, THE NON-CML CHRONIC MPD-ET, PV, AND IMF-COULD BE RELATED. ADDITIONAL UNRESOLVED ISSUES REGARDING THE MPD INCLUDE: IDENTIFICATION OF THE MULTIPOTENT HEMATOPOIETIC PROGENITOR CELL INVOLVED, THE MOLECULAR BASIS FOR THE CLINICAL HETEROGENEITY AMONGST THE INDIVIDUAL MPD, THE CLINICAL SIGNIFICANCE OF CLONALITY IN NON-CML MPD, AND RECONCILIATION OF THERAPY WITH THE CLONAL AND CLINICAL HETEROGENEITY OF THESE DISORDERS. DETERMINATION OF CLONALITY HAS LARGELY BEEN CARRIED OUT USING X CHROMOSOME-LINKED POLYMORPHISMS, BUT SUCH STUDIES ARE LIMITED TO WOMEN AND WITH INCREASING PATIENT AGE ARE COMPROMISED BY SKEWING OF ALLELIC EXPRESSION IN BOTH NEUTROPHILS AND T LYMPHOCYTES, MAKING THE RESULTS DIFFICULT TO INTERPRET. X CHROMOSOME-LINKED POLYMORPHISM STUDIES HAVE INDICATED THAT IN PV THE TARGET STEM CELL IS ONE THAT GIVES RISE TO BOTH LYMPHOID AND MYELOID PROGENITORS. RECENTLY, TWO EPIGENETIC MARKERS HAVE BEEN IDENTIFIED IN THE MPD: IMPAIRED EXPRESSION OF THE THROMBOPOIETIN RECEPTOR, MPL, IN PLATELETS AND MEGAKARYOCYTES, AND OVEREXPRESSION IN NEUTROPHILS OF THE MRNA OF A GENE DESIGNATED POLYCYTHEMIA RUBRA VERA-1 (PRV-1). THE ROLE OF THESE EPIGENETIC ABNORMALITIES IN THE DIAGNOSIS OF THE MPD REMAINS TO BE ESTABLISHED. CURRENTLY, GIVEN THE UNRESOLVED ISSUES WITH RESPECT TO THE CLINICAL AND CLONAL HETEROGENEITY OF THE MPD, TREATMENT NEEDS TO BE TAILORED INDIVIDUALLY IN PATIENTS WITH AN MPD. 2004 7 961 30 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 8 4322 33 MICRORNAS IN MYELOPROLIFERATIVE NEOPLASMS. THE CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPN), INCLUDING POLYCYTHAEMIA VERA (PV), ESSENTIAL THROMBOCYTHAEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF), ARE CLONAL STEM CELL DISORDERS CHARACTERIZED BY DYSREGULATED HAEMATOPOIETIC STEM CELL EXPANSION AND PRODUCTION OF RED CELLS, WHITE CELLS AND PLATELETS ALONE OR IN COMBINATION. AN ACQUIRED MUTATION JAK2(V617F) CAN BE FOUND IN ALL THREE DISORDERS AND SHOWS MANY OF THE PHENOTYPIC ABNORMALITIES OF THE DISEASES IN MURINE MODELS. THE DISEASE PHENOTYPE IS ALSO INFLUENCED BY OTHER UNKNOWN GENETIC OR EPIGENETIC FACTORS. MICRORNAS (MIRNA) ARE 18-24 NUCLEOTIDE SINGLE-STRANDED NON-PROTEIN-CODING RNAS THAT FUNCTION PRIMARILY AS GENE REPRESSORS BY BINDING TO THEIR TARGET MESSENGER RNAS. THERE IS GROWING EVIDENCE THAT MIRNAS REGULATE HAEMATOPOIESIS IN BOTH HAEMATOPOIETIC STEM CELLS AND COMMITTED PROGENITOR CELLS. HERE, WE REVIEW THE FIELD OF MIRNA BIOLOGY AND ITS REGULATORY ROLES IN NORMAL HAEMATOPOIESIS WITH AN EMPHASIS ON MIRNA DEREGULATIONS IN MPNS. CONTINUED RESEARCH INTO HOW MIRNAS IMPACT JAK2(V617F) CLONAL EXPANSION, DIFFERENTIAL HAEMATOPOIESIS AMONG DIFFERENT MPNS, DISEASE PROGRESSION AND LEUKAEMIA TRANSFORMATION WILL LEAD TO A BETTER UNDERSTANDING OF THE DEVELOPMENT OF THESE DISORDERS, THEIR CLINICAL MANIFESTATIONS, AND THEIR TREATMENT. 2013 9 54 19 A DRY IMMERSION MODEL OF MICROGRAVITY MODULATES PLATELET PHENOTYPE, MIRNA SIGNATURE, AND CIRCULATING PLASMA PROTEIN BIOMARKER PROFILE. GROUND BASED RESEARCH MODALITIES OF MICROGRAVITY HAVE BEEN PROPOSED AS INNOVATIVE METHODS TO INVESTIGATE THE AETIOLOGY OF CHRONIC AGE-RELATED CONDITIONS SUCH AS CARDIOVASCULAR DISEASE. DRY IMMERSION (DI), HAS BEEN EFFECTIVELY USED TO INTERROGATE THE SEQUELAE OF PHYSICAL INACTIVITY (PI) AND MICROGRAVITY ON MULTIPLE PHYSIOLOGICAL SYSTEMS. HEREIN WE LOOK AT THE CAUSA ET EFFECTUS OF 3-DAY DI ON PLATELET PHENOTYPE, AND CORRELATE WITH BOTH MIROMIC AND CIRCULATING BIOMARKER EXPRESSION. THE MIROMIC PROFILE OF PLATELETS IS REFLECTIVE OF PHENOTYPE, WHICH ITSELF IS SENSITIVE AND MALLEABLE TO THE EXPOSOME, UNDERGOING RESPONSIVE TRANSITIONS IN ORDER TO FULFIL PLATELETS ROLE IN THROMBOSIS AND HAEMOSTASIS. HETEROGENEOUS PLATELET SUBPOPULATIONS CIRCULATE AT ANY GIVEN TIME, WITH VARYING DEGREES OF SENSITIVITY TO ACTIVATION. EMPLOYING A DI MODEL, WE INVESTIGATE THE EFFECT OF ACUTE PI ON PLATELET FUNCTION IN 12 HEALTHY MALES. 3-DAY DI RESULTED IN A SIGNIFICANT INCREASE IN PLATELET COUNT, PLATELETCRIT, PLATELET ADHESION, AGGREGATION, AND A MODEST ELEVATION OF PLATELET REACTIVITY INDEX (PRI). WE IDENTIFIED 15 PROTEIN BIOMARKERS AND 22 MIRNA WHOSE EXPRESSION LEVELS WERE ALTERED AFTER DI. A 3-DAY DI MODEL OF MICROGRAVITY/PHYSICAL INACTIVITY INDUCED A PROTHROMBOTIC PLATELET PHENOTYPE WITH AN UNIQUE PLATELET MIRNA SIGNATURE, INCREASED PLATELET COUNT AND PLATELETCRIT. THIS CORRELATED WITH A UNIQUE CIRCULATING PROTEIN BIOMARKER SIGNATURE. TAKEN TOGETHER, THESE FINDINGS HIGHLIGHT PLATELETS AS SENSITIVE ADAPTIVE SENTINELS AND FUNCTIONAL BIOMARKERS OF EPIGENETIC DRIFT WITHIN THE CARDIOVASCULAR COMPARTMENT. 2021 10 5257 40 PROGRESSION OF MYELOPROLIFERATIVE NEOPLASMS (MPN): DIAGNOSTIC AND THERAPEUTIC PERSPECTIVES. CLASSICAL BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS (MPN) ARE A HETEROGENEOUS GROUP OF HEMATOLOGIC MALIGNANCIES, INCLUDING ESSENTIAL THROMBOCYTHEMIA (ET), POLYCYTHEMIA VERA (PV), AND PRIMARY MYELOFIBROSIS (PMF), AS WELL AS POST-PV-MF AND POST-ET-MF. PROGRESSION TO MORE SYMPTOMATIC DISEASE, SUCH AS OVERT MF OR ACUTE LEUKEMIA, REPRESENTS ONE OF THE MAJOR CAUSES OF MORBIDITY AND MORTALITY. THERE ARE CLINICALLY EVIDENT BUT ALSO SUBCLINICAL TYPES OF MPN PROGRESSION. CLINICALLY EVIDENT PROGRESSION INCLUDES EVOLUTION FROM ET TO PV, ET TO POST-ET-MF, PV TO POST-PV-MF, OR PRE-PMF TO OVERT PMF, AND TRANSFORMATION OF ANY OF THESE SUBTYPES TO MYELODYSPLASTIC NEOPLASMS OR ACUTE LEUKEMIA. THROMBOSIS, MAJOR HEMORRHAGE, SEVERE INFECTIONS, OR INCREASING SYMPTOM BURDEN (E.G., PRURITUS, NIGHT SWEATS) MAY HERALD PROGRESSION. SUBCLINICAL TYPES OF PROGRESSION MAY INCLUDE INCREASES IN THE EXTENT OF BONE MARROW FIBROSIS, INCREASES OF DRIVER GENE MUTATIONAL ALLELE BURDEN, AND CLONAL EVOLUTION. THE UNDERLYING CAUSES OF MPN PROGRESSION ARE DIVERSE AND CAN BE ATTRIBUTED TO GENETIC ALTERATIONS AND CHRONIC INFLAMMATION. PARTICULARLY, BYSTANDER MUTATIONS IN GENES ENCODING EPIGENETIC REGULATORS OR SPLICING FACTORS WERE ASSOCIATED WITH PROGRESSION. FINALLY, COMORBIDITIES SUCH AS SYSTEMIC INFLAMMATION, CARDIOVASCULAR DISEASES, AND ORGAN FIBROSIS MAY AUGMENT THE RISK OF PROGRESSION. THE AIM OF THIS REVIEW WAS TO DISCUSS TYPES AND MECHANISMS OF MPN PROGRESSION AND HOW THEIR KNOWLEDGE MIGHT IMPROVE RISK STRATIFICATION AND THERAPEUTIC INTERVENTION. IN VIEW OF THESE ASPECTS, WE DISCUSS THE POTENTIAL BENEFITS OF EARLY DIAGNOSIS USING MOLECULAR AND FUNCTIONAL IMAGING AND EXPLOITABLE THERAPEUTIC STRATEGIES THAT MAY PREVENT PROGRESSION, BUT ALSO HIGHLIGHT CURRENT CHALLENGES AND METHODOLOGICAL PITFALLS. 2021 11 4562 32 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 12 3747 34 INSIGHTS INTO THE MOLECULAR GENETICS OF MYELOPROLIFERATIVE NEOPLASMS. THE MOLECULAR BIOLOGY OF THE BCR-ABL1-NEGATIVE CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPNS) HAS WITNESSED UNPRECEDENTED ADVANCES SINCE THE DISCOVERY OF THE ACQUIRED JAK2 V617F MUTATION IN 2005. DESPITE THE HIGH PREVALENCE OF JAK2 V617F IN POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET), AND PRIMARY MYELOFIBROSIS (PMF), AND THE COMMON FINDING OF DYSREGULATED JAK-STAT SIGNALING IN THESE DISORDERS, IT IS NOW APPRECIATED THAT MPN PATHOGENESIS CAN REFLECT THE ACQUISITION OF MULTIPLE GENETIC MUTATIONS THAT ALTER SEVERAL BIOLOGIC PATHWAYS, INCLUDING EPIGENETIC CONTROL OF GENE EXPRESSION. ALTHOUGH CERTAIN GENE MUTATIONS ARE IDENTIFIED AT HIGHER FREQUENCIES WITH DISEASE EVOLUTION TO THE BLAST PHASE, MPN INITIATION AND PROGRESSION ARE NOT EXPLAINED BY A SINGLE, TEMPORAL PATTERN OF CLONAL CHANGES. A COMPLEX INTERPLAY BETWEEN ACQUIRED MOLECULAR ABNORMALITIES AND HOST GENETIC BACKGROUND, IN ADDITION TO THE TYPE AND ALLELIC BURDEN OF MUTATIONS, CONTRIBUTES TO THE PHENOTYPIC HETEROGENEITY OF MPNS. AT THE POPULATION LEVEL, AN INHERITED PREDISPOSITION TO DEVELOPING MPNS IS LINKED TO A RELATIVELY COMMON JAK2-ASSOCIATED HAPLOTYPE (REFERRED TO AS '46/1'), BUT IT EXHIBITS A RELATIVELY LOW PENETRANCE. THIS REVIEW DETAILS THE CURRENT STATE OF KNOWLEDGE OF THE MOLECULAR GENETICS OF THE CLASSIC MPNS PV, ET, AND PMF AND DISCUSSES THE CLINICAL IMPLICATIONS OF THESE FINDINGS. 2012 13 3872 36 JUVENILE MYELOMONOCYTIC LEUKEMIA-A COMPREHENSIVE REVIEW AND RECENT ADVANCES IN MANAGEMENT. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A RARE PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP DISEASE. JMML IS ASSOCIATED WITH MUTATIONS IN THE RAS PATHWAY GENES RESULTING IN THE MYELOID PROGENITORS BEING SENSITIVE TO GRANULOCYTE MONOCYTE COLONY-STIMULATING FACTOR (GM-CSF). KARYOTYPE ABNORMALITIES AND ADDITIONAL EPIGENETIC ALTERATIONS CAN ALSO BE FOUND IN JMML. NEUROFIBROMATOSIS AND NOONAN'S SYNDROME HAVE A PREDISPOSITION FOR JMML. IN A FEW PATIENTS, THE RAS GENES (NRAS, KRAS, AND PTPN11) ARE MUTATED AT THE GERMLINE AND THIS USUALLY RESULTS IN A TRANSIENT MYELOPROLIFERATIVE DISORDER WITH A GOOD PROGNOSIS. JMML WITH SOMATIC RAS MUTATION BEHAVES AGGRESSIVELY. JMML PRESENTS WITH CYTOPENIAS AND LEUKEMIC INFILTRATION INTO ORGANS. THE LABORATORY FINDINGS INCLUDE HYPERLEUKOCYTOSIS, MONOCYTOSIS, INCREASED HEMOGLOBIN-F LEVELS, AND CIRCULATING MYELOID PRECURSORS. THE BLAST CELLS IN THE PERIPHERAL BLOOD/BONE-MARROW ASPIRATE ARE LESS THAN 20% AND THE ABSENCE OF THE BCR-ABL TRANSLOCATION HELPS TO DIFFERENTIATE FROM CHRONIC MYELOID LEUKEMIA. JMML SHOULD BE DIFFERENTIATED FROM IMMUNODEFICIENCIES, VIRAL INFECTIONS, INTRAUTERINE INFECTIONS, HEMOPHAGOLYMPHOHISTIOCYTOSIS, OTHER MYELOPROLIFERATIVE DISORDERS, AND LEUKEMIAS. CHEMOTHERAPY IS EMPLOYED AS A BRIDGE TO HSCT, EXCEPT IN FEW WITH LESS AGGRESSIVE DISEASE, IN WHICH CHEMOTHERAPY ALONE CAN RESULT IN LONG TERM REMISSION. AZACITIDINE HAS SHOWN PROMISE AS A SINGLE AGENT TO STABILIZE THE DISEASE. THE PROGNOSIS OF JMML IS POOR WITH ABOUT 50% OF PATIENTS SURVIVING AFTER AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). ALLOGENEIC HSCT IS THE ONLY KNOWN CURE FOR JMML TO DATE. MYELOABLATIVE CONDITIONING IS MOST COMMONLY USED WITH GRAFT VERSUS HOST DISEASE (GVHD) PROPHYLAXIS TAILORED TO THE AGGRESSIVENESS OF THE DISEASE. RELAPSES ARE COMMON EVEN AFTER HSCT AND A SECOND HSCT CAN SALVAGE A THIRD OF THESE PATIENTS. NOVEL OPTIONS IN THE TREATMENT OF JMML E.G., HYPOMETHYLATING AGENTS, MEK INHIBITORS, JAK INHIBITORS, TYROSINE KINASE INHIBITORS, ETC. ARE BEING EXPLORED. 2021 14 962 36 CHRONIC MYELOMONOCYTIC LEUKEMIA: FOCUS ON CLINICAL PRACTICE. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER WITH FEATURES THAT OVERLAP THOSE OF MYELODYSPLASTIC SYNDROMES (MDSS) AND MYELOPROLIFERATIVE NEOPLASMS (MPNS). CHRONIC MYELOMONOCYTIC LEUKEMIA OFTEN RESULTS IN PERIPHERAL BLOOD MONOCYTOSIS AND HAS AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKEMIA. CLONAL CYTOGENETIC CHANGES ARE SEEN IN APPROXIMATELY 30% OF PATIENTS, AND MOLECULAR ABNORMALITIES ARE SEEN IN MORE THAN 90%. GENE MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT, WITH NONSENSE AND FRAMESHIFT ASXL1 MUTATIONS BEING THE ONLY MUTATIONS IDENTIFIED THUS FAR TO HAVE AN INDEPENDENT NEGATIVE PROGNOSTIC EFFECT ON OVERALL SURVIVAL. CONTEMPORARY MOLECULARLY INTEGRATED PROGNOSTIC MODELS (INCLUSIVE OF ASXL1 MUTATIONS) INCLUDE THE MOLECULAR MAYO MODEL AND THE GROUPE FRANCAIS DES MYELODYSPLASIES MODEL. GIVEN THE LACK OF FORMAL TREATMENT AND RESPONSE CRITERIA, MANAGEMENT OF CMML IS OFTEN EXTRAPOLATED FROM MDS AND MPN, WITH ALLOGENEIC STEM CELL TRANSPLANT BEING THE ONLY CURATIVE OPTION. HYDROXYUREA AND OTHER CYTOREDUCTIVE AGENTS HAVE BEEN USED TO CONTROL MPN-LIKE FEATURES, WHILE EPIGENETIC MODIFIERS SUCH AS HYPOMETHYLATING AGENTS HAVE BEEN USED FOR MDS-LIKE FEATURES. GIVEN THE RELATIVELY POOR RESPONSE TO THESE AGENTS AND THE INHERENT RISKS ASSOCIATED WITH HEMATOPOIETIC STEM CELL TRANSPLANT, NEWER DRUGS EXPLOITING MOLECULAR AND EPIGENETIC ABNORMALITIES IN CMML ARE BEING DEVELOPED. THE CREATION OF CMML-SPECIFIC RESPONSE CRITERIA IS A MUCH NEEDED STEP IN ORDER TO IMPROVE CLINICAL OUTCOMES. 2016 15 1947 37 EPIGENETIC ABNORMALITIES IN MYELOPROLIFERATIVE NEOPLASMS: A TARGET FOR NOVEL THERAPEUTIC STRATEGIES. THE MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE A GROUP OF CLONAL HEMATOLOGICAL MALIGNANCIES CHARACTERIZED BY A HYPERCELLULAR BONE MARROW AND A TENDENCY TO DEVELOP THROMBOTIC COMPLICATIONS AND TO EVOLVE TO MYELOFIBROSIS AND ACUTE LEUKEMIA. UNLIKE CHRONIC MYELOGENOUS LEUKEMIA, WHERE A SINGLE DISEASE-INITIATING GENETIC EVENT HAS BEEN IDENTIFIED, A MORE COMPLICATED SERIES OF GENETIC MUTATIONS APPEAR TO BE RESPONSIBLE FOR THE BCR-ABL1-NEGATIVE MPNS WHICH INCLUDE POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA, AND PRIMARY MYELOFIBROSIS. RECENT STUDIES HAVE REVEALED A NUMBER OF EPIGENETIC ALTERATIONS THAT ALSO LIKELY CONTRIBUTE TO DISEASE PATHOGENESIS AND DETERMINE CLINICAL OUTCOME. INCREASING EVIDENCE INDICATES THAT ALTERATIONS IN DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA EXPRESSION PATTERNS CAN COLLECTIVELY INFLUENCE GENE EXPRESSION AND POTENTIALLY CONTRIBUTE TO MPN PATHOGENESIS. EXAMPLES INCLUDE MUTATIONS IN GENES ENCODING PROTEINS THAT MODIFY CHROMATIN STRUCTURE (EZH2, ASXL1, IDH1/2, JAK2V617F, AND IKZF1) AS WELL AS EPIGENETIC MODIFICATION OF GENES CRITICAL FOR CELL PROLIFERATION AND SURVIVAL (SUPPRESSORS OF CYTOKINE SIGNALING, POLYCYTHEMIA RUBRA VERA-1, CXC CHEMOKINE RECEPTOR 4, AND HISTONE DEACETYLASE (HDAC)). THESE EPIGENETIC LESIONS SERVE AS NOVEL TARGETS FOR EXPERIMENTAL THERAPEUTIC INTERVENTIONS. CLINICAL TRIALS ARE CURRENTLY UNDERWAY EVALUATING HDAC INHIBITORS AND DNA METHYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF PATIENTS WITH MPNS. 2011 16 3111 24 GENOTYPE-PHENOTYPE INTERACTIONS IN THE MYELOPROLIFERATIVE NEOPLASMS. THE CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL DISORDERS CHARACTERIZED BY OVERPRODUCTION OF MATURE MYELOID CELLS. THEY SHARE ASSOCIATIONS WITH MOLECULAR ABNORMALITIES SUCH AS THE JAK2V617F MUTATION BUT ARE DISTINGUISHED BY IMPORTANT PHENOTYPIC DIFFERENCES. THIS REVIEW FIRST CONSIDERS THE FACTORS THAT MAY INFLUENCE PHENOTYPE IN JAK2-MUTATED MPNS, ESPECIALLY POLYCYTHEMIA VERA (PV) AND ESSENTIAL THROMBOCYTHEMIA (ET), AND THEN DISCUSSES THE MUTATIONS IMPLICATED IN JAK2-NEGATIVE MPNS SUCH AS IN MPL AND EPIGENETIC REGULATORS. CURRENT EVIDENCE SUPPORTS A MODEL WHERE ET AND PV ARE DISORDERS OF RELATIVELY LOW GENETIC COMPLEXITY, WHEREAS EVOLUTION TO MYELOFIBROSIS OR BLAST-PHASE DISEASE REFLECTS ACCUMULATION OF A HIGHER MUTATION BURDEN. 2012 17 3129 33 GIVINOSTAT: AN EMERGING TREATMENT FOR POLYCYTHEMIA VERA. INTRODUCTION: POLYCYTHEMIA VERA (PV), A PHILADELPHIA CHROMOSOME-NEGATIVE MYELOPROLIFERATIVE NEOPLASM, IS CHARACTERIZED BY PANMYELOSIS, PANCYTOSIS, AND A JAK2 MUTATION. PATIENTS ARE AT INCREASED RISK OF THROMBOHEMORRHAGIC EVENTS, AND PROGRESSION TO MYELOFIBROSIS OR ACUTE LEUKEMIA. CURRENT TREATMENTS INCLUDE ASPIRIN, PHLEBOTOMY, AND CYTOREDUCTIVE DRUGS (MOST COMMONLY HYDROXYUREA). GIVINOSTAT IS A POTENT, CLASS I/II HISTONE DEACETYLASE (HDAC) INHIBITOR THAT IS IN PHASE I/II CLINICAL TRIALS IN PV. GIVINOSTAT WAS WELL TOLERATED AND YIELDED PROMISING CLINICO-HEMATOLOGICAL RESPONSES. A PHASE III STUDY OF GIVINOSTAT VERSUS HYDROXYUREA IN HIGH-RISK PV PATIENTS IS PLANNED. AREAS COVERED: WE PRESENT AN OVERVIEW OF PV, CURRENT TREATMENT GUIDELINES, AND THE PUTATIVE MECHANISM(S) OF ACTION OF GIVINOSTAT. WE DISCUSS THE PRECLINICAL AND CLINICAL STUDIES OF GIVINOSTAT IN PV AND BRIEFLY REVIEW APPROVED AND INVESTIGATIONAL COMPETITOR COMPOUNDS. EXPERT OPINION: HDAC INHIBITORS HAVE LONG BEEN KNOWN TO BE ACTIVE IN PV, BUT CHRONIC TOXICITIES CAN BE CHALLENGING. GIVINOSTAT, HOWEVER, IS ACTIVE AND WELL TOLERATED, AND IS ENTERING A PIVOTAL PHASE III RANDOMIZED TRIAL. GIVINOSTAT OFFERS THE POSSIBILITY OF REPLACING HYDROXYUREA AS THE STANDARD FIRST-LINE CYTOREDUCTIVE CHOICE FOR PV PATIENTS. THIS WOULD COMPLETELY CHANGE THE CURRENT THERAPEUTIC PARADIGM AND GUIDELINES FOR PV MANAGEMENT. ALTHOUGH SURROGATE CLINICAL STUDY ENDPOINTS MAY SUFFICE FOR REGULATORY PURPOSES, THROMBOSIS REDUCTION AND PREVENTION OF DISEASE PROGRESSION REMAIN MOST IMPORTANT TO PATIENTS AND CLINICIANS. 2020 18 6852 39 [MYELOPROLIFERATIVE NEOPLASMS: UPDATES ON MOLECULAR PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT STRATEGIES]. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CHRONIC HEMATOPOIETIC STEM CELL DISORDERS, INCLUDING POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTOSIS, AND PRIMARY MYELOFIBROSIS. THE JAK2V617F MUTATION WAS IDENTIFIED IN 2005, FOLLOWED BY THE DISCOVERY OF THE JAK2 EXON12, MPNW515 MUTATION, AND CALR MUTATION. ABOUT 90% OF PATIENTS WITH BCR/ABL NEGATIVE MPNS HAVE BEEN SHOWN TO HAVE ONE OF THESE DRIVER MUTATIONS. IN ADDITION, MUTATIONS IN EPIGENETIC REGULATORS AND RNA SPLICING GENES WERE FOUND TO CO-EXIST WITH DRIVER MUTATIONS AND TO PLAY CRITICAL ROLES IN THE DISEASE PROGRESSION OF MPNS. CURRENTLY, EVALUATIONS OF THESE GENE MUTATIONS ARE ESSENTIAL FOR THE DIAGNOSIS OF MPNS, AND ARE ALSO NECESSARY FOR ESTIMATING THE CLINICAL COURSE AND THE RISK OF DISEASE PROGRESSION. GUIDELINES FOR THE MANAGEMENT OF MPNS WERE BASED ON THE RESULTS OF LARGE CLINICAL TRIALS. FURTHERMORE, RECENT ADVANCEMENTS IN UNDERSTANDING THE PATHOGENESIS OF MPNS ARE ANTICIPATED TO PROMOTE THE DEVELOPMENT OF MPN-TARGETED THERAPIES SUCH AS JAK2 INHIBITORS. CLINICAL TRIALS FOR PATIENTS WITH PMF AND PV HAVE CONFIRMED THE EFFICACIES OF JAK2 INHIBITORS. 2016 19 957 23 CHRONIC MYELOMONOCYTIC LEUKAEMIA: A CONCISE CLINICAL AND PATHOPHYSIOLOGICAL REVIEW. CHRONIC MYELOMONOCYTIC LEUKAEMIA (CMML) IS A CLONAL HAEMATOPOIETIC STEM CELL DISORDER WITH MYELODYSPLASTIC AND MYELOPROLIFERATIVE OVERLAP FEATURES, AND AN INHERENT TENDENCY TO TRANSFORM TO ACUTE MYELOID LEUKAEMIA. APPROXIMATELY 30% OF PATIENTS PRESENT WITH CLONAL CYTOGENETIC ABNORMALITIES, WHILE ALMOST 90% HAVE MOLECULAR ABERRATIONS INVOLVING EPIGENETIC REGULATION, THE SPLICEOSOME COMPONENT MACHINERY, TUMOUR SUPPRESSOR GENES AND TRANSCRIPTION FACTORS/REGULATORS. NUMEROUS PROGNOSTIC MODELS EXIST FOR CMML, WITH MORE RECENT MODELS INCORPORATING PROGNOSTIC MUTATIONS, SUCH AS THOSE INVOLVING ASXL1. OTHER VARIABLES THAT SEEM TO CONSISTENTLY AFFECT OUTCOMES INCLUDE THE DEGREE OF LEUCOCYTOSIS/MONOCYTOSIS, ANAEMIA AND THROMBOCYTOPENIA. ALLOGENEIC STEM CELL TRANSPLANT REMAINS THE ONLY CURATIVE OPTION FOR CMML, WHILE HYPOMETHYLATING AGENTS CAN BE USED FOR TRANSPLANT-INELIGIBLE PATIENTS OR THOSE WITHOUT SUITABLE STEM CELL SOURCES. TARGETING BIOLOGICAL PATHWAYS ACTIVATED IN CMML OFFERS POTENTIAL HOPE FOR MORE EFFECTIVE AND LESS TOXIC THERAPIES. 2014 20 6442 46 THERAPEUTIC APPROACHES IN MYELOFIBROSIS AND MYELODYSPLASTIC/MYELOPROLIFERATIVE OVERLAP SYNDROMES. THE DISCOVERY OF JAK2 (V617F) A DECADE AGO LED TO OPTIMISM FOR A RAPIDLY DEVELOPING TREATMENT REVOLUTION IN PH(-) MYELOPROLIFERATIVE NEOPLASMS. UNLIKE BCR-ABL, HOWEVER, JAK2 WAS FOUND TO HAVE A MORE HETEROGENEOUS ROLE IN CARCINOGENESIS. THEREFORE, FOR YEARS, DEVELOPMENT OF NEW THERAPIES WAS SLOW, DESPITE STANDARD TREATMENT OPTIONS THAT DID NOT ADDRESS THE OVERWHELMING SYMPTOM BURDEN IN PATIENTS WITH PRIMARY MYELOFIBROSIS (MF), POST-ESSENTIAL THROMBOCYTHEMIA MF, POST-POLYCYTHEMIA VERA MF, AND MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) SYNDROMES. JAK-STAT INHIBITORS HAVE CHANGED THIS, DRASTICALLY AMELIORATING SYMPTOMS AND ULTIMATELY BEGINNING TO SHOW EVIDENCE OF IMPACT ON SURVIVAL. NOW, THE GENETIC FOUNDATIONS OF MYELOFIBROSIS AND MDS/MPN ARE RAPIDLY BEING ELUCIDATED AND CONTRIBUTING TO TARGETED THERAPY DEVELOPMENT. THIS HAS BEEN EMPOWERED THROUGH UPDATED RESPONSE CRITERIA FOR MDS/MPN AND REFINED PROGNOSTIC SCORING SYSTEMS IN THESE DISEASES. THE AIM OF THIS ARTICLE IS TO SUMMARIZE CONCISELY THE CURRENT AND RATIONALLY DESIGNED INVESTIGATIONAL THERAPEUTICS DIRECTED AT JAK-STAT, HEDGEHOG, PI3K-AKT, BONE MARROW FIBROSIS, TELOMERASE, AND ROGUE EPIGENETIC SIGNALING. THE REVOLUTION IN IMMUNOTHERAPY AND NOVEL TREATMENTS AIMED AT PREVIOUSLY UNTARGETED SIGNALING PATHWAYS PROVIDES HOPE FOR CONSIDERABLE ADVANCEMENT IN THERAPY OPTIONS FOR THOSE WITH CHRONIC MYELOID DISEASE. 2016