1 4560 116 MUTATIONS WITH EPIGENETIC EFFECTS IN MYELOPROLIFERATIVE NEOPLASMS AND RECENT PROGRESS IN TREATMENT: PROCEEDINGS FROM THE 5TH INTERNATIONAL POST-ASH SYMPOSIUM. IMMEDIATELY FOLLOWING THE 2010 ANNUAL AMERICAN SOCIETY OF HEMATOLOGY (ASH) MEETING, THE 5TH INTERNATIONAL POST-ASH SYMPOSIUM ON CHRONIC MYELOGENOUS LEUKEMIA AND BCR-ABL1-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS (MPNS) TOOK PLACE ON 7-8 DECEMBER 2010 IN ORLANDO, FLORIDA, USA. DURING THIS MEETING, THE MOST RECENT ADVANCES IN LABORATORY RESEARCH AND CLINICAL PRACTICE, INCLUDING THOSE THAT WERE PRESENTED AT THE 2010 ASH MEETING, WERE DISCUSSED AMONG RECOGNIZED AUTHORITIES IN THE FIELD. THE CURRENT PAPER SUMMARIZES THE PROCEEDINGS OF THIS MEETING IN BCR-ABL1-NEGATIVE MPN. WE PROVIDE A DETAILED OVERVIEW OF NEW MUTATIONS WITH PUTATIVE EPIGENETIC EFFECTS (TET ONCOGENE FAMILY MEMBER 2 (TET2), ADDITIONAL SEX COMB-LIKE 1 (ASXL1), ISOCITRATE DEHYDROGENASE (IDH) AND ENHANCER OF ZESTE HOMOLOG 2 (EZH2)) AND AN UPDATE ON TREATMENT WITH JANUS KINASE (JAK) INHIBITORS, POMALIDOMIDE, EVEROLIMUS, INTERFERON-ALPHA, MIDOSTAURIN AND CLADRIBINE. IN ADDITION, THE NEW 'DYNAMIC INTERNATIONAL PROGNOSTIC SCORING SYSTEM (DIPSS)-PLUS' PROGNOSTIC MODEL FOR PRIMARY MYELOFIBROSIS (PMF) AND THE CLINICAL RELEVANCE OF DISTINGUISHING ESSENTIAL THROMBOCYTHEMIA FROM PREFIBROTIC PMF ARE DISCUSSED. 2011 2 6852 28 [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 3 4864 20 ORLANDO MAGIC: REPORT FROM THE 57TH MEETING OF THE AMERICAN SOCIETY OF HAEMATOLOGY, 5-7 DECEMBER 2015, ORLANDO, USA. THE 57TH AMERICAN SOCIETY OF HAEMATOLOGY (ASH) MEETING HELD IN ORLANDO, FL WAS CERTAINLY THE YEAR WHEN MYELOMA MANAGEMENT CHANGED FOR GOOD, WITH A PLETHORA OF NEWLY FOOD AND DRUG ADMINISTRATION (FDA)-APPROVED DRUGS SHOWING IMPRESSIVE OUTCOME IMPROVEMENTS AND THE INTRODUCTION OF NEW TECHNIQUES FOR DISEASE MONITORING. ALSO, CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS CONTINUED THEIR TRIUMPHAL MARCH, CONSOLIDATING THEIR SUCCESS IN LYMPHOMA AND CHRONIC LYMHOCYTIC LEUKAEMIA (CLL) AND VENTURING INTO NEW FIELDS SUCH AS AGAIN MULTIPLE MYELOMA. SOME EXPERIMENTAL DRUGS SHOWED LONG-AWAITED RESULTS (MIDOSTAURIN IN FLT3-MUTATED ACUTE MYELOID LEUKAEMIA (AML)) AND SOME BRAND NEW DRUGS SHOWED PROMISING RESULTS IN THE CLINIC AFTER EXTENSIVE PRECLINICAL STUDIES, SUCH AS THOSE TARGETING NEW EPIGENETIC FACTORS (HISTONE METHYLTRANSFERASES) AND APOPTOSIS. 2016 4 409 25 ANALYSIS OF GENES ENCODING EPIGENETIC REGULATORS IN MYELOPROLIFERATIVE NEOPLASMS: COEXISTENCE OF A NOVEL SETBP1 MUTATION IN A PATIENT WITH A P.V617F JAK2 POSITIVE MYELOFIBROSIS. IN RECENT YEARS IT HAS BEEN SHOWN THAT THE CAUSES OF CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE MORE COMPLEX THAN A SIMPLE SIGNALING ABERRATION AND MANY OTHER MUTATED GENES AFFECTING DIFFERENT CELL PROCESSES HAVE BEEN DESCRIBED. FOR INSTANCE, MUTATIONS IN GENES ENCODING EPIGENETIC REGULATORS ARE MORE FREQUENT THAN EXPECTED. ONE OF THE LATEST GENES DESCRIBED AS MUTATED IS SET BINDING PROTEIN 1 (SETBP1). IN SILICO TOOLS HAVE REVEALED THAT THERE ARE SEVERAL HUMAN SETBP1 PARALOGOUS TO NUCLEAR RECEPTOR BINDING SET DOMAIN PROTEIN 1 (NSD1), NSD2 AND NSD3, FOR EXAMPLE, WHICH ARE ALSO INVOLVED IN THE DEVELOPMENT OF OTHER HEMATOLOGICAL MALIGNANCIES. THEREFORE, THE PRESENT STUDY ANALYZED THE MUTATIONAL STATUS OF NSD1, NSD2, NSD3 AND SETBP1 IN BCR-ABL1 NEGATIVE MPNS WITH OR WITHOUT JANUS KINASE 2 (JAK2) P.V617F MUTATION. THE PRESENT STUDY REVEALED THAT THE NSD GENES ARE NOT FREQUENTLY MUTATED IN MPNS. HOWEVER, A NOVEL SETBP1 MUTATION WAS IDENTIFIED IN A PATIENT WITH P.V617F JAK2 POSITIVE PRIMARY MYELOFIBROSIS. THESE RESULTS PROVIDE FURTHER INSIGHT INTO THE GENETIC COMPLEXITY OF MPNS. 2019 5 1043 30 CLINICAL CHARACTERISTICS AND WHOLE EXOME/TRANSCRIPTOME SEQUENCING OF COEXISTING CHRONIC MYELOID LEUKEMIA AND MYELOFIBROSIS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL HEMATOPOIETIC STEM CELL (HSC) DISORDERS THAT CAN BE CLASSIFIED ON THE BASIS OF GENETIC, CLINICAL, PHENOTYPIC FEATURES. GENETIC LESIONS SUCH AS JAK2 MUTATIONS AND BCR-ABL TRANSLOCATION ARE OFTEN MUTUALLY EXCLUSIVE IN MPN PATIENTS AND LEAD TO ESSENTIAL THROMBOCYTHEMIA, POLYCYTHEMIA VERA, OR MYELOFIBROSIS OR CHRONIC MYELOID LEUKEMIA, RESPECTIVELY. NEVERTHELESS, COEXISTENCE OF THESE GENETIC ABERRATIONS IN THE SAME PATIENT HAS BEEN REPORTED. WHETHER THESE ABERRATIONS OCCUR IN THE SAME STEM CELL OR A DIFFERENT CELL IS UNCLEAR, BUT AN UNSTABLE GENOME IN THE HSCS SEEMS TO BE THE COMMON ANTECEDENT. IN AN EFFORT TO CHARACTERIZE THE UNDERLYING GENETIC EVENTS THAT MIGHT CONTRIBUTE TO THE APPEARANCE OF MORE THAN ONE MPN IN A PATIENT, WE STUDIED NEOPLASTIC CELLS FROM PATIENTS WITH DUAL MPNS BY NEXT-GENERATION SEQUENCING. WE OBSERVED THAT MOST PATIENTS WITH TWO MPNS HARBORED MUTATIONS IN GENES KNOWN TO CONTRIBUTE TO CLONAL HEMATOPOIESIS THROUGH ALTERED EPIGENETIC REGULATION SUCH AS TET2, ASXL1/2, SRSF2, AND IDH2 AT VARYING FREQUENCIES (1%-47%). IN ADDITION, WE FOUND THAT SOME PATIENTS ALSO HARBORED ONCOGENIC MUTATIONS IN N/KRAS, TP53, BRAF, EZH2, AND GNAS AT LOW FREQUENCIES, WHICH PROBABLY REPRESENT CLONAL EVOLUTION. THESE FINDINGS SUPPORT THE HYPOTHESIS THAT HEMATOPOIETIC CELLS FROM MPN PATIENTS HARBOR MULTIPLE GENETIC ABERRATIONS, SOME OF WHICH CAN CONTRIBUTE TO CLONAL DOMINANCE. ACQUIRING MUTATIONS IN JAK2/CALR/MPL OR THE BCR-ABL TRANSLOCATION PROBABLY DRIVE THE ONCOGENIC PHENOTYPE TOWARDS A SPECIFIC MPN. FURTHER, WE PROPOSE THAT THE ACQUISITION OF BCR-ABL IN THESE PATIENTS IS FREQUENTLY A SECONDARY EVENT RESULTING FROM AN UNSTABLE GENOME. 2017 6 3111 22 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 7 4554 26 MUTATIONAL PROFILING IN MYELOFIBROSIS: IMPLICATIONS FOR MANAGEMENT. MUTATIONAL PROFILING, USUALLY BY TARGETED NEXT-GENERATION SEQUENCING, IS INCREASINGLY PERFORMED ON PATIENTS WITH MYELOPROLIFERATIVE NEOPLASM-ASSOCIATED MYELOFIBROSIS (MF), WHETHER PRIMARY (PMF) OR POST-POLYCYTHEMIA VERA/ESSENTIAL THROMBOCYTHEMIA (POST-PV/ET MF). "DRIVER" MUTATIONS IN JAK2, MPL AND INDELS IN CALR UNDERLIE THE VAST MAJORITY OF CASES OF PMF AND POST-ET MF; THE REMAINDER ( APPROXIMATELY 10%) LACK IDENTIFIABLE DRIVER MUTATIONS, BUT OTHER CLONAL MARKERS ARE USUALLY DETECTABLE. NEARLY ALL PATIENTS WITH POST-PV MF CARRY ACTIVATING JAK2 MUTATIONS. IN BOTH PMF AND POST-ET MF, TYPE 1/-LIKE CALR MUTATIONS CONFER A FAVORABLE PROGNOSIS. SINCE BOTH TYPE 1/-LIKE AND TYPE 2/-LIKE CALR MUTATIONS HAVE ESSENTIALLY THE SAME FUNCTIONAL CONSEQUENCE, THIS IS A SUBJECT OF INTENSE RESEARCH. ADDITIONAL, "NON-DRIVER" MUTATIONS, MOSTLY AFFECTING GENES ENCODING EPIGENETIC MODIFIERS OR SPLICEOSOME COMPONENTS, E.G., ASXL1, EZH2, TET2, DNMT3A, SRSF2 AND U2AF1, ARE FREQUENTLY FOUND; SOME OF THESE ARE ASSOCIATED WITH INFERIOR SURVIVAL AND HAVE BEEN INCORPORATED INTO PROGNOSTIC MODELS. SOME MUTATIONS, E.G., IDH1/2, ARE RELATIVELY INFREQUENT IN CHRONIC PHASE BUT ARE SUBSTANTIALLY MORE COMMON IN BLAST PHASE, AND ARE NOW THERAPEUTICALLY TARGETABLE. WHILE MUTATIONAL INFORMATION DOES NOT CURRENTLY INFLUENCE CHOICE OF DRUG THERAPY IN CHRONIC-PHASE MF, THE PRESENCE OF A "HIGH MOLECULAR RISK" GENOTYPE IS NOW ROUTINELY TAKEN INTO ACCOUNT FOR TRANSPLANT DECISION-MAKING. 2020 8 4680 32 NEW MUTATIONS AND PATHOGENESIS OF MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL DISORDERS CHARACTERIZED BY EXCESSIVE PRODUCTION OF MATURE BLOOD CELLS. IN THE MAJORITY OF CLASSIC MPN--POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA, AND PRIMITIVE MYELOFIBROSIS--DRIVER ONCOGENIC MUTATIONS AFFECTING JANUS KINASE 2 (JAK2) OR MPL LEAD TO CONSTITUTIVE ACTIVATION OF CYTOKINE-REGULATED INTRACELLULAR SIGNALING PATHWAYS. LNK, C-CBL, OR SOCSS (ALL NEGATIVE REGULATORS OF SIGNALING PATHWAYS), ALTHOUGH INFREQUENTLY TARGETED, MAY EITHER DRIVE THE DISEASE OR SYNERGIZE WITH JAK2 AND MPL MUTATIONS. IZF1 DELETIONS OR TP53 MUTATIONS ARE MAINLY FOUND AT TRANSFORMATION PHASES AND ARE PRESENT AT GREATER FREQUENCY THAN IN DE NOVO ACUTE MYELOID LEUKEMIAS. LOSS-OF-FUNCTION MUTATIONS IN 3 GENES INVOLVED IN EPIGENETIC REGULATION, TET2, ASXL1, AND EZH2, MAY BE EARLY EVENTS PRECEDING JAK2V617F BUT MAY ALSO OCCUR LATE DURING DISEASE PROGRESSION. THEY ARE MORE FREQUENTLY OBSERVED IN PMF THAN PV AND ET AND ARE ALSO PRESENT IN OTHER TYPES OF MALIGNANT MYELOID DISEASES. A LIKELY HYPOTHESIS IS THAT THEY FACILITATE CLONAL SELECTION, ALLOWING THE DOMINANCE OF THE JAK2V617F SUBCLONE DURING THE CHRONIC PHASE AND, TOGETHER WITH COOPERATING MUTATIONS, PROMOTE BLAST CRISIS. THEIR PRECISE ROLES IN HEMATOPOIESIS AND IN THE PATHOGENESIS OF MPN, AS WELL AS THEIR PROGNOSTIC IMPACT AND POTENTIAL AS A THERAPEUTIC TARGET, ARE CURRENTLY UNDER INVESTIGATION. 2011 9 5249 25 PROGRAMMED CELL DEATH-1 PATHWAY INHIBITION IN MYELOID MALIGNANCIES: IMPLICATIONS FOR MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL HEMATOPOIETIC DISEASES THAT BELONG TO THE SPECTRUM OF MYELOID MALIGNANCIES (MYMS), WHICH ALSO INCLUDE MYELODYSPLASTIC SYNDROMES (MDS), ACUTE MYELOID LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). WHILE HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) IS A POTENTIALLY CURATIVE THERAPEUTIC APPROACH TO MANY MYMS, THE ASSOCIATED MORBIDITY AND MORTALITY HAVE NECESSITATED THE DEVELOPMENT OF NON-HSCT THERAPEUTICS FOR SYMPTOM MANAGEMENT AND DISEASE COURSE MODIFICATION. IMMUNE CHECKPOINT INHIBITION, IN PARTICULAR ALONG THE PROGRAMMED CELL DEATH PROTEIN 1 (PD-1)/B7-H1 (PD-L1) AXIS, IS AN ESTABLISHED STRATEGY IN SOLID TUMORS WITH POTENTIAL AS AN ADJUNCTIVE THERAPY IN HEMATOLOGIC MALIGNANCIES. SEMINAL STUDIES SUGGEST THAT THE PRO-INFLAMMATORY MICROENVIRONMENT OF MYMS CAN SUPPRESS T LYMPHOCYTE-MEDIATED IMMUNITY VIA PD-1 SIGNALING AND THAT RESPONSE TO MAINSTAY EPIGENETIC THERAPIES FOR MYMS MAY BE GOVERNED BY PD-1 GENE REGULATION. ALTHOUGH THE ROLE OF PD-1 SIGNALING IN MPN PATHOGENESIS AND PROGRESSION IS AS YET UNCLEAR, RESEARCH IN MPN PATIENTS HAS REVEALED EXPANSION OF MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS), WHICH MAY EFFECT HOST IMMUNE TOLERANCE OF TUMOR VIA TEMPORALLY AND SPATIALLY SPECIFIC ACTIVATION OF PD-1/PD-L1 SIGNALING. THE CURRENT UNDERSTANDING OF IMMUNE DYSFUNCTION IN MPNS AND ANALOGOUS MYMS OFFERS A COMPELLING RATIONALE TO STUDY PD-1/PD-L1 INHIBITION IN PATIENTS AS A NOVEL TREATMENT OPTION. 2017 10 3641 29 INCREASED GENE EXPRESSION OF HISTONE DEACETYLASES IN PATIENTS WITH PHILADELPHIA-NEGATIVE CHRONIC MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATION, MYELOACCUMULATION (DECREASED APOPTOSIS), INFLAMMATION, BONE MARROW FIBROSIS AND ANGIOGENESIS ARE CARDINAL FEATURES OF THE PHILADELPHIA-NEGATIVE CHRONIC MYELOPROLIFERATIVE NEOPLASMS: ESSENTIAL THROMBOCYTHEMIA (ET), POLYCYTHEMIA VERA (PV) AND PRIMARY MYELOFIBROSIS (PMF). HISTONE DEACETYLASES (HDACS) HAVE A CRITICAL ROLE IN MODULATING GENE EXPRESSION AND, ACCORDINGLY, IN THE CONTROL OF CELL PATHOBIOLOGY AND CANCER DEVELOPMENT. HDAC INHIBITION HAS BEEN SHOWN TO INHIBIT TUMOR GROWTH (IMPAIRED MYELOPROLIFERATION), TO MODULATE THE BALANCE BETWEEN PRO- AND ANTIAPOPTOTIC PROTEINS IN FAVOR OF APOPTOSIS (ENHANCED APOPTOSIS) AND ALSO TO INHIBIT ANGIOGENESIS. RECENTLY, ENHANCED HDAC ENZYME ACTIVITY HAS BEEN FOUND IN CD34+CELLS FROM PATIENTS WITH PMF, ENZYME ACTIVITY LEVELS HIGHLY EXCEEDING THOSE RECORDED IN OTHER CHRONIC MYELOPROLIFERATIVE NEOPLASMS (CMPNS). THE RAISED LEVELS CORRELATED TO THE DEGREE OF SPLENOMEGALY, SUGGESTING THAT HDAC MIGHT BE RECRUITED AS ET OR PV PROGRESSES INTO MYELOFIBROSIS OR PMF PROGRESSES INTO A MORE ADVANCED STAGE. ACCORDINGLY, HDAC INHIBITION IS AN OBVIOUS NOVEL THERAPEUTIC APPROACH IN THESE NEOPLASMS. USING GLOBAL GENE EXPRESSION PROFILING OF WHOLE BLOOD FROM PATIENTS WITH CMPNS, WE HAVE FOUND A PRONOUNCED DEREGULATION OF HDAC GENES, INVOLVING SIGNIFICANT UP-REGULATION OF THE HDAC GENES 9 AND 11, WITH THE HIGHEST EXPRESSION LEVELS BEING FOUND IN PATIENTS WITH ET (HDAC9 AND 11), PMF (HDAC9) AND CMPNS (BOTH HDAC9 AND HDAC11). FURTHERMORE, WE HAVE IDENTIFIED THAT THE HDAC6 GENE IS PROGRESSIVELY EXPRESSED IN PATIENTS WITH ET, PV AND PMF, REFLECTING A STEADY ACCUMULATION OF ABNORMALLY EXPRESSED HDAC6 DURING DISEASE EVOLUTION. OUR RESULTS LEND FURTHER SUPPORT TO HDACS AS IMPORTANT EPIGENETIC TARGETS IN THE FUTURE TREATMENT OF PATIENTS WITH CMPNS. SINCE THE HIGHEST EXPRESSION LEVELS OF HDAC GENES WERE RECORDED IN ET, IN PMF AND IN THE ENTIRE CMPN GROUP, THEIR DOWN-REGULATION BY HDAC INHIBITORS MIGHT BE ASSOCIATED WITH DECREASED DISEASE ACTIVITY, INCLUDING REDUCTION OF SPLENOMEGALY. 2012 11 255 32 ADVANCES IN MYELOFIBROSIS: A CLINICAL CASE APPROACH. PRIMARY MYELOFIBROSIS IS A MEMBER OF THE MYELOPROLIFERATIVE NEOPLASMS, A DIVERSE GROUP OF BONE MARROW MALIGNANCIES. SYMPTOMS OF MYELOFIBROSIS, PARTICULARLY THOSE ASSOCIATED WITH SPLENOMEGALY (ABDOMINAL DISTENTION AND PAIN, EARLY SATIETY, DYSPNEA, AND DIARRHEA) AND CONSTITUTIONAL SYMPTOMS, REPRESENT A SUBSTANTIAL BURDEN TO PATIENTS. MOST PATIENTS EVENTUALLY DIE FROM THE DISEASE, WITH A MEDIAN SURVIVAL RANGING FROM APPROXIMATELY 5-7 YEARS. MUTATIONS IN JANUS KINASE 2 (JAK2), A KINASE THAT IS ESSENTIAL FOR THE NORMAL DEVELOPMENT OF ERYTHROCYTES, GRANULOCYTES, AND PLATELETS, NOTABLY THE V617F MUTATION, HAVE BEEN IDENTIFIED IN APPROXIMATELY 50% OF PATIENTS WITH MYELOFIBROSIS. THE APPROVAL OF A JAK2 INHIBITOR IN 2011 HAS IMPROVED THE OUTLOOK OF MANY PATIENTS WITH MYELOFIBROSIS AND HAS CHANGED THE TREATMENT LANDSCAPE. THIS ARTICLE FOCUSES ON SOME OF THE IMPORTANT ISSUES IN CURRENT MYELOFIBROSIS TREATMENT MANAGEMENT, INCLUDING DIFFERENTIATION OF MYELOFIBROSIS FROM ESSENTIAL THROMBOCYTHEMIA AND POLYCYTHEMIA VERA, UP-DATED DATA ON THE RESULTS OF JAK2 INHIBITOR THERAPY, THE ROLE OF EPIGENETIC MECHANISMS IN MYELOFIBROSIS PATHOGENESIS, INVESTIGATIONAL THERAPIES FOR MYELOFIBROSIS, AND ADVANCES IN HEMATOPOIETIC STEM CELL TRANSPLANT. THREE MYELOFIBROSIS CASES ARE INCLUDED TO UNDERSCORE THE ISSUES IN DIAGNOSING AND TREATING THIS COMPLEX DISEASE. 2013 12 1260 24 CURRENT VIEWS ON THE INTERPLAY BETWEEN TYROSINE KINASES AND PHOSPHATASES IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY BCR-ABL1 ONCOGENE EXPRESSION. THIS DYSREGULATED PROTEIN-TYROSINE KINASE (PTK) IS KNOWN AS THE PRINCIPAL DRIVER OF THE DISEASE AND IS TARGETED BY TYROSINE KINASE INHIBITORS (TKIS). EXTENSIVE DOCUMENTATION HAS ELUCIDATED HOW THE TRANSFORMATION OF MALIGNANT CELLS IS CHARACTERIZED BY MULTIPLE GENETIC/EPIGENETIC CHANGES LEADING TO THE LOSS OF TUMOR-SUPPRESSOR GENES FUNCTION OR PROTO-ONCOGENES EXPRESSION. THE IMPAIRMENT OF ADEQUATE LEVELS OF SUBSTRATES PHOSPHORYLATION, THUS AFFECTING THE BALANCE PTKS AND PROTEIN PHOSPHATASES (PPS), REPRESENTS A WELL-ESTABLISHED CELLULAR MECHANISM TO ESCAPE FROM SELF-LIMITING SIGNALS. IN THIS REVIEW, WE FOCUS OUR ATTENTION ON THE CHARACTERIZATION OF AND INTERACTIONS BETWEEN PTKS AND PPS, EMPHASIZING THEIR BIOLOGICAL ROLES IN DISEASE EXPANSION, THE REGULATION OF LSCS AND TKI RESISTANCE. WE DECIDED TO SEPARATE THOSE PPS THAT HAVE BEEN VALIDATED IN PRIMARY CELL MODELS OR LEUKEMIA MOUSE MODELS FROM THOSE WHOSE STUDIES HAVE BEEN PERFORMED ONLY IN CELL LINES (AND, THUS, REQUIRE VALIDATION), AS THERE MAY BE DIFFERENCES IN THE MANNER THAT THE ASSOCIATED PATHWAYS ARE MODIFIED UNDER THESE TWO CONDITIONS. THIS REVIEW SUMMARIZES THE ROLES OF DIVERSE PPS, WITH HOPE THAT BETTER KNOWLEDGE OF THE INTERPLAY AMONG PHOSPHATASES AND KINASES WILL EVENTUALLY RESULT IN A BETTER UNDERSTANDING OF THIS DISEASE AND CONTRIBUTE TO ITS ERADICATION. 2021 13 1076 25 CLONAL HEMATOPOIESIS IN MYELOPROLIFERATIVE NEOPLASMS CONFERS A PREDISPOSITION TO BOTH THROMBOSIS AND CANCER. PURPOSE OF REVIEW: THIS REVIEW FOCUSES ON VASCULAR COMPLICATIONS ASSOCIATED WITH CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPN) AND MORE SPECIFICALLY AIMS TO DISCUSS THE CLINICAL AND BIOLOGICAL EVIDENCE SUPPORTING THE EXISTENCE OF A LINK BETWEEN CLONAL HEMATOPOIESIS, CARDIOVASCULAR EVENTS (CVE), AND SOLID CANCER (SC). RECENT FINDINGS: THE MPN NATURAL HISTORY IS DRIVEN BY UNCONTROLLED CLONAL MYELOPROLIFERATION SUSTAINED BY ACQUIRED SOMATIC MUTATIONS IN DRIVER (JAK2, CALR, AND MPL) AND NON-DRIVER GENES, INVOLVING EPIGENETIC (E.G., TET2, DNMT3A) REGULATORS, CHROMATIN REGULATOR GENES (E.G., ASXL1, EZH2), AND SPLICING MACHINERY GENES (E.G., SF3B1). THE GENOMIC ALTERATIONS AND ADDITIONAL THROMBOSIS ACQUIRED RISK FACTORS ARE DETERMINANTS FOR CVE. THERE IS EVIDENCE THAT CLONAL HEMATOPOIESIS CAN ELICIT A CHRONIC AND SYSTEMIC INFLAMMATION STATUS THAT ACTS AS DRIVING FORCE FOR THE DEVELOPMENT OF THROMBOSIS, MPN EVOLUTION, AND SECOND CANCER (SC). THIS NOTION MAY EXPLAIN THE MECHANISM THAT LINKS ARTERIAL THROMBOSIS IN MPN PATIENTS AND SUBSEQUENT SOLID TUMORS. IN THE LAST DECADE, CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP) HAS BEEN DETECTED IN THE GENERAL POPULATION PARTICULARLY IN THE ELDERLY AND INITIALLY FOUND IN MYOCARDIAL INFARCTION AND STROKE, RISING THE HYPOTHESIS THAT THE INFLAMMATORY STATUS CHIP-ASSOCIATED COULD CONFER PREDISPOSITION TO BOTH CARDIOVASCULAR DISEASES AND CANCER. IN SUMMARY, CLONAL HEMATOPOIESIS IN MPN AND CHIP CONFER A PREDISPOSITION TO CARDIOVASCULAR EVENTS AND CANCER THROUGH CHRONIC AND SYSTEMIC INFLAMMATION. THIS ACQUISITION COULD OPEN NEW AVENUES FOR ANTITHROMBOTIC THERAPY BOTH IN MPNS AND IN GENERAL POPULATION BY TARGETING BOTH CLONAL HEMATOPOIESIS AND INFLAMMATION. 2023 14 1070 28 CLONAL ARCHITECTURE OF CHRONIC MYELOMONOCYTIC LEUKEMIAS. GENOMIC STUDIES IN CHRONIC MYELOID MALIGNANCIES, INCLUDING MYELOPROLIFERATIVE NEOPLASMS (MPN), MYELODYSPLASTIC SYNDROMES (MDS), AND MPN/MDS, HAVE IDENTIFIED COMMON MUTATIONS IN GENES ENCODING SIGNALING, EPIGENETIC, TRANSCRIPTION, AND SPLICING FACTORS. IN THE PRESENT STUDY, WE INTERROGATED THE CLONAL ARCHITECTURE BY MUTATION-SPECIFIC DISCRIMINATION ANALYSIS OF SINGLE-CELL-DERIVED COLONIES IN 28 PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIAS (CMML), THE MOST FREQUENT MPN/MDS. THIS ANALYSIS REVEALS A LINEAR ACQUISITION OF THE STUDIED MUTATIONS WITH LIMITED BRANCHING THROUGH LOSS OF HETEROZYGOSITY. SERIAL ANALYSIS OF UNTREATED AND TREATED SAMPLES DEMONSTRATES A DYNAMIC ARCHITECTURE ON WHICH MOST CURRENT THERAPEUTIC APPROACHES HAVE LIMITED EFFECTS. THE MAIN DISEASE CHARACTERISTICS ARE EARLY CLONAL DOMINANCE, ARISING AT THE CD34(+)/CD38(-) STAGE OF HEMATOPOIESIS, AND GRANULOMONOCYTIC DIFFERENTIATION SKEWING OF MULTIPOTENT AND COMMON MYELOID PROGENITORS. COMPARISON OF CLONAL EXPANSIONS OF TET2 MUTATIONS IN MDS, MPN, AND CMML, TOGETHER WITH FUNCTIONAL INVALIDATION OF TET2 IN SORTED PROGENITORS, SUGGESTS A CAUSATIVE LINK BETWEEN EARLY CLONAL DOMINANCE AND SKEWED GRANULOMONOCYTIC DIFFERENTIATION. ALTOGETHER, EARLY CLONAL DOMINANCE MAY DISTINGUISH CMML FROM OTHER CHRONIC MYELOID NEOPLASMS WITH SIMILAR GENE MUTATIONS. 2013 15 4549 20 MUTATION ANALYSIS OF THERAPY-RELATED MYELOID NEOPLASMS. WE ANALYZED THE GENETIC MUTATION STATUS OF 13 PATIENTS WITH THERAPY-RELATED MYELOID NEOPLASMS (T-MN). CONSISTENT WITH PREVIOUS REPORTS, T-MN CELLS PREFERENTIALLY ACQUIRED MUTATIONS IN TP53 AND EPIGENETIC MODIFYING GENES, INSTEAD OF MUTATIONS IN TYROSINE KINASE AND SPLICEOSOME GENES. FURTHERMORE, WE COMPARED THE MUTATION STATUS OF THREE T-MN CELLS WITH EACH OF THE INITIAL LYMPHOID MALIGNANT CELLS, AND IDENTIFIED COMMON MUTATIONS AMONG T-MN AND THE INITIAL MALIGNANT CELLS IN TWO PATIENTS. IN A PATIENT WHO DEVELOPED CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AFTER FOLLICULAR LYMPHOMA (FL), TET2 MUTATION WAS IDENTIFIED IN BOTH CMML AND FL CELLS. NOTABLY, THE TET2 MUTATION WAS ALSO IDENTIFIED IN PERIPHERAL BLOOD CELLS IN THE DISEASE-FREE PERIOD WITH THE SAME ALLELIC FREQUENCY AS CMML AND FL CELLS, BUT NOT IN A GERM-LINE CONTROL, INDICATING THAT THE TET2 MUTATION OCCURRED SOMATICALLY IN THE INITIATING CLONE FOR BOTH MALIGNANT CELLS. ON THE OTHER HAND, A GERM-LINE MYB MUTATION WAS IDENTIFIED IN A PATIENT WHO DEVELOPED MYELODYSPLASTIC SYNDROMES (MDS) AFTER FL. THESE RESULTS SUGGEST THAT GERM-LINE DEPOSITION AND CLONAL HEMATOPOIESIS ARE CLOSELY ASSOCIATED WITH T-MN SUSCEPTIBILITY; HOWEVER, FURTHER ANALYSIS IS NECESSARY TO CLARIFY THE MECHANISM REQUIRED TO PROVIDE THE INITIATING CLONE WITH LINEAGE COMMITMENT AND CLONAL EXPANSION. 2018 16 5455 19 RESCUE OF A PRIMARY MYELOFIBROSIS MODEL BY RETINOID-ANTAGONIST THERAPY. MOLECULAR TARGETING OF THE TWO RECEPTOR INTERACTION DOMAINS OF THE EPIGENETIC REPRESSOR SILENCING MEDIATOR OF RETINOID AND THYROID HORMONE RECEPTORS (SMRT(MRID)) PRODUCED A TRANSPLANTABLE SKELETAL SYNDROME THAT REDUCED RADIAL BONE GROWTH, INCREASED NUMBERS OF BONE-RESORBING PERIOSTEAL OSTEOCLASTS, AND INCREASED BONE FRACTURE RISK. FURTHERMORE, SMRT(MRID) MICE DEVELOP SPONTANEOUS PRIMARY MYELOFIBROSIS, A CHRONIC, USUALLY IDIOPATHIC DISORDER CHARACTERIZED BY PROGRESSIVE BONE MARROW FIBROSIS. FREQUENTLY LINKED TO POLYCYTHEMIA VERA AND CHRONIC MYELOID LEUKEMIA, MYELOFIBROSIS DISPLAYS HIGH PATIENT MORBIDITY AND MORTALITY, AND CURRENT TREATMENT IS MOSTLY PALLIATIVE. TO DECIPHER THE ETIOLOGY OF THIS DISEASE, WE IDENTIFIED THE THROMBOPOIETIN (TPO) GENE AS A TARGET OF THE SMRT-RETINOIC ACID RECEPTOR SIGNALING PATHWAY IN BONE MARROW STROMAL CELLS. CHRONIC INDUCTION OF TPO IN SMRT(MRID) MICE RESULTS IN UP-REGULATION OF TGF-BETA AND PDGF IN MEGAKARYOCYTES, UNCONTROLLED PROLIFERATION OF BONE MARROW RETICULAR CELLS, AND FIBROSIS OF THE MARROW COMPARTMENT. OF THERAPEUTIC RELEVANCE, WE SHOW THAT THIS SYNDROME CAN BE RESCUED BY RETINOID ANTAGONISTS, DEMONSTRATING THAT THE PHYSICAL INTERFACE BETWEEN SMRT AND RETINOIC ACID RECEPTOR CAN BE A POTENTIAL THERAPEUTIC TARGET TO BLOCK PRIMARY MYELOFIBROSIS DISEASE PROGRESSION. 2013 17 5782 21 SPLICING ANOMALIES IN MYELOPROLIFERATIVE NEOPLASMS: PAVING THE WAY FOR NEW THERAPEUTIC VENUES. SINCE THE DISCOVERY OF SPLICEOSOME MUTATIONS IN MYELOID MALIGNANCIES, ABNORMAL PRE-MRNA SPLICING, WHICH HAS BEEN WELL STUDIED IN VARIOUS CANCERS, HAS ATTRACTED NOVEL INTEREST IN HEMATOLOGY. HOWEVER, DESPITE THE COMMON OCCURRENCE OF SPLICEOSOME MUTATIONS IN MYELO-PROLIFERATIVE NEOPLASMS (MPN), NOT MUCH IS KNOWN REGARDING THE CHARACTERIZATION AND MECHANISMS OF SPLICING ANOMALIES IN MPN. IN THIS ARTICLE, WE REVIEW THE CURRENT SCIENTIFIC LITERATURE REGARDING "SPLICING AND MYELOPROLIFERATIVE NEOPLASMS". WE FIRST ANALYSE THE CLINICAL SERIES REPORTING SPLICEOSOME MUTATIONS IN MPN AND THEIR CLINICAL CORRELATES. WE THEN PRESENT THE CURRENT KNOWLEDGE ABOUT MOLECULAR MECHANISMS BY WHICH THESE MUTATIONS PARTICIPATE IN THE PATHOGENESIS OF MPN OR OTHER MYELOID MALIGNANCIES. BESIDE SPLICEOSOME MUTATIONS, SPLICING ANOMALIES HAVE BEEN DESCRIBED IN MYELOPROLIFERATIVE NEOPLASMS, AS WELL AS IN ACUTE MYELOID LEUKEMIAS, A DREADFUL COMPLICATION OF THESE CHRONIC DISEASES. BASED ON SPLICING ANOMALIES REPORTED IN CHRONIC MYELOGENOUS LEUKEMIA AS WELL AS IN ACUTE LEUKEMIA, AND THE MECHANISMS PRESIDING SPLICING DEREGULATION, WE PROPOSE THAT ABNORMAL SPLICING PLAYS A MAJOR ROLE IN THE EVOLUTION OF MYELOPROLIFERATIVE NEOPLASMS AND MAY BE THE TARGET OF SPECIFIC THERAPEUTIC STRATEGIES. 2020 18 4759 25 NOVEL TREATMENTS FOR MYELOFIBROSIS: BEYOND JAK INHIBITORS. MYELOFIBROSIS IS A CHRONIC HEMATOLOGIC MALIGNANCY CHARACTERIZED BY CONSTITUTIONAL SYMPTOMS, BONE MARROW FIBROSIS, EXTRAMEDULLARY HEMATOPOIESIS RESULTING IN SPLENOMEGALY AND A PROPENSITY TOWARD LEUKEMIC PROGRESSION. GIVEN THE CENTRAL ROLE OF THE JAK-STAT PATHWAY IN THE PATHOBIOLOGY OF MYELOFIBROSIS, JAK INHIBITORS ARE THE MAINSTAY OF CURRENT PHARMACOLOGIC MANAGEMENT. ALTHOUGH THESE THERAPIES HAVE PRODUCED MEANINGFUL IMPROVEMENTS IN SPLENOMEGALY AND SYMPTOM BURDEN, JAK INHIBITORS DO NOT SIGNIFICANTLY IMPACT DISEASE PROGRESSION. IN ADDITION, MANY PATIENTS ARE INELIGIBLE BECAUSE OF DISEASE-RELATED CYTOPENIAS, WHICH ARE EXACERBATED BY JAK INHIBITORS. THEREFORE, THERE IS A CONTINUED EFFORT TO IDENTIFY TARGETS OUTSIDE THE JAK-STAT PATHWAY. IN THIS REVIEW, WE DISCUSS NOVEL THERAPIES IN DEVELOPMENT FOR MYELOFIBROSIS. WE FOCUS ON THE PRECLINICAL RATIONALE, EFFICACY AND SAFETY DATA FOR NON-JAK INHIBITOR THERAPIES THAT HAVE PUBLISHED OR PRESENTED CLINICAL DATA. SPECIFICALLY, WE DISCUSS AGENTS THAT TARGET EPIGENETIC MODIFICATION (PELABRESIB, BOMEDEMSTAT), APOPTOSIS (NAVITOCLAX, NAVTEMDALIN), SIGNALING PATHWAYS (PARSACLISIB), BONE MARROW FIBROSIS (AVID200, PRM-151), IN ADDITION TO OTHER TARGETS INCLUDING TELOMERASE (IMETELSTAT), SELECTIVE INHIBITOR OF NUCLEAR TRANSPORT (SELINEXOR), CD123 (TAGRAXOFUSP) AND ERYTHROID MATURATION (LUSPATERCEPT). WE END BY PROVIDING COMMENTARY ON THE ONGOING AND FUTURE THERAPEUTIC DEVELOPMENT IN MYELOFIBROSIS. 2022 19 6847 25 [MOLECULAR DIAGNOSIS OF CHRONIC MYELOPROLIFERATIVE DISEASES AND MYELODYSPLASTIC SYNDROMES]. HISTOMORPHOLOGICAL EVALUATION OF BONE MARROW TREPHINES AND SMEARS REPRESENTS THE MAJOR APPROACH TO DIAGNOSE THE CHRONIC MYELOPROLIFERATIVE DISEASES (CMPD) AND THE MYELODYSPLASTIC SYNDROMES (MDS). HOWEVER, RISING INSIGHTS INTO MOLECULAR PATHOGENESIS OF HUMAN DISEASES STRENGTHEN THE ATTEMPT OF PATHOLOGISTS TO DEFINE AND TO DETECT UNDERLYING DEFECTS BEYOND THE MICROSCOPE. SINCE DISCOVERY OF THE PHILADELPHIA CHROMOSOME IN CHRONIC MYELOID LEUKEMIA AS THE FIRST SPECIFIC MOLECULAR ABNORMALITY EVER DETECTED IN A HUMAN NEOPLASIA THE GAIN OF KNOWLEDGE OF MOLECULAR PATHOMECHANISMS IN PHILADELPHIA CHROMOSOME NEGATIVE (PH-) CMPD WAS RATHER SPARSE. A DECISIVE BREAKTHROUGH IN PH CMPD WAS THE FINDING OF JAK2 (V617F) DERIVED FROM A SOMATIC POINT MUTATION IN THE MAJORITY OF PATIENTS WITH POLYCYTHEMIA VERA (P.VERA) AND HALF OF PATIENTS WITH ESSENTIAL THROMBOCYTHEMIA (ET) AND PRIMARY MYELOFIBROSIS (PMF). IT THEREFORE CAN NOT BE OVERESTIMATED THAT DETECTION OF JAK2 (V617F) IN A SUSPECTIVE MYELOPROLIFERATION NOW ENABLES A CLEARCUT DISCRIMINATION OF A TRUE PH CMPD FROM A REACTIVE STATE, E.G. P.VERA FROM REACTIVE ERYTHROCYTOSIS. INTERESTINGLY, A BASIC PRINCIPLE OF MOLECULAR DEFECTS DEMONSTRABLE IN CMPD AND RELATED DISORDERS SEEMS TO BE THE INVOLVEMENT OF GENES WITH KINASE ACTIVITIES. SOME OF THOSE GENES WILL BE DISCUSSED IN MORE DETAIL. IN PRIMARY MDS, KARYOTYPING VIA CLASSICAL CYTOGENETICS IS THE PREDOMINANT MOLECULAR APPROACH TO ESTIMATE PROGNOSIS, E.G. -Y, DEL(5Q) AND DEL(20Q) REPRESENT FAVOURABLE ANOMALIES. INDEED, IN 5Q- SYNDROMES KARYOTYPING ENABLES DEFINITE SUBTYPING AND ALLOWS CLINICIANS AND PATIENTS TO EXPECT A GOOD PROGNOSIS. UNTIL NOW, DOZENS OF MOLECULAR ABNORMALITIES SUCH AS MUTATIONS IN AML1, FLT3 AND RAS AS WELL AS EPIGENETIC ALTERATIONS OF GENES HAVE BEEN IDENTIFIED TO VARIOUS DEGREES IN MDS SUBTYPES. SOME OF THEM SEEM TO BE INVOLVED IN DISEASE INITIATION ("MASTER EVENT") AND OTHERS MIGHT INDICATE DISEASE PROGRESSION. HOWEVER, EVEN THOUGH USEFUL FOR FURTHER DISSECTION OF MOLECULAR PATHOMECHANISMS THE MAJORITY OF ABERRATIONS CURRENTLY DOES NOT SERVE AS POTENT MARKERS IN THE DAILY ROUTINE. NEVERTHELESS, IN CMPD AND MDS THE IMPORTANCE OF MOLECULAR ANALYSES FOR DIAGNOSIS, ESTIMATION OF PROGNOSIS, AND DISEASE MONITORING WILL FURTHER INCREASE IN A FORESEEABLE PERIOD OF TIME. 2007 20 2911 28 GENE EXPRESSION PROFILING OF LOSS OF TET2 AND/OR JAK2V617F MUTANT HEMATOPOIETIC STEM CELLS FROM MOUSE MODELS OF MYELOPROLIFERATIVE NEOPLASMS. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLINICALLY CHARACTERIZED BY THE CHRONIC OVERPRODUCTION OF DIFFERENTIATED PERIPHERAL BLOOD CELLS AND THE GRADUAL EXPANSION OF MALIGNANT INTRAMEDULLARY/EXTRAMEDULLARY HEMATOPOIESIS. IN MPNS MUTATIONS IN JAK2 MPL OR CALR ARE DETECTED MUTUALLY EXCLUSIVE IN MORE THAN 90% OF CASES [1,2]. MUTATIONS IN THEM LEAD TO THE ABNORMAL ACTIVATION OF JAK/STAT SIGNALING AND THE AUTONOMOUS GROWTH OF DIFFERENTIATED CELLS THEREFORE THEY ARE CONSIDERED AS "DRIVER" GENE MUTATIONS. IN ADDITION TO THE ABOVE DRIVER GENE MUTATIONS MUTATIONS IN EPIGENETIC REGULATORS SUCH AS TET2 DNMT3A ASXL1 EZH2 OR IDH1/2 ARE DETECTED IN ABOUT 5%-30% OF CASES RESPECTIVELY [3]. MUTATIONS IN TET2 DNMT3A EZH2 OR IDH1/2 COMMONLY CONFER THE INCREASED SELF-RENEWAL CAPACITY ON NORMAL HEMATOPOIETIC STEM CELLS (HSCS) BUT THEY DO NOT LEAD TO THE AUTONOMOUS GROWTH OF DIFFERENTIATED CELLS AND ONLY EXHIBIT SUBTLE CLINICAL PHENOTYPES [4,6-8,5]. IT WAS UNCLEAR HOW MUTATIONS IN SUCH EPIGENETIC REGULATORS INFLUENCED ABNORMAL HSCS WITH DRIVER GENE MUTATIONS HOW THEY INFLUENCED THE DISEASE PHENOTYPE OR WHETHER A SINGLE DRIVER GENE MUTATION WAS SUFFICIENT FOR THE INITIATION OF HUMAN MPNS. THEREFORE WE FOCUSED ON JAK2V617F AND LOSS OF TET2-THE FORMER AS A REPRESENTATIVE OF DRIVER GENE MUTATIONS AND THE LATTER AS A REPRESENTATIVE OF MUTATIONS IN EPIGENETIC REGULATORS-AND EXAMINED THE INFLUENCE OF SINGLE OR DOUBLE MUTATIONS ON HSCS (LINEAGE(-)SCA-1(+)C-KIT(+) CELLS (LSKS)) BY FUNCTIONAL ANALYSES AND MICROARRAY WHOLE-GENOME EXPRESSION ANALYSES [9]. GENE EXPRESSION PROFILING SHOWED THAT THE HSC FINGERPRINT GENES [10] WAS STATISTICALLY EQUALLY ENRICHED IN TET2-KNOCKDOWN-LSKS BUT NEGATIVELY ENRICHED IN JAK2V617F-LSKS COMPARED TO THAT IN WILD-TYPE-LSKS. DOUBLE-MUTANT-LSKS SHOWED THE SAME TENDENCY AS JAK2V617F-LSKS IN TERMS OF THEIR HSC FINGERPRINT GENES BUT THE EXPRESSION OF INDIVIDUAL GENES DIFFERED BETWEEN THE TWO GROUPS. AMONG 245 HSC FINGERPRINT GENES 100 WERE MORE HIGHLY EXPRESSED IN DOUBLE-MUTANT-LSKS THAN IN JAK2V617F-LSKS. THESE ALTERED GENE EXPRESSIONS MIGHT PARTLY EXPLAIN THE MECHANISMS OF INITIATION AND PROGRESSION OF MPNS WHICH WAS OBSERVED IN THE FUNCTIONAL ANALYSES [9]. HERE WE DESCRIBE GENE EXPRESSION PROFILES DEPOSITED AT THE GENE EXPRESSION OMNIBUS (GEO) UNDER THE ACCESSION NUMBER GSE62302 INCLUDING EXPERIMENTAL METHODS AND QUALITY CONTROL ANALYSES. 2015