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HongzhiXuShandongProvincialHospital,MyeloproliferativeDisorders,CONTENTS,PathogenesisandmanagementofessentialthrombocythemiaIdiopathicerythrocytosis:adisappearingentityTherapeuticpotentialofJAK2inhibitors,Pathogenesisandmanagementofessentialthrombocythemia,Pathogenesis,RelationshipofETtoPVandPMFThelevelofJAK2-STAT5signalingprovidesarheostatthatdetermineswhetherthediseasephenotypeispredominantlyerythroidormegakaryocytic.,Severallinesofevidencesuggestablurringofthedistinctionbetweenthesedisorders.AproporationofpatientsdiagnosedwithET(seeTable1forcriteria)harborincreasedlevelsofbonemarrowreticulinintheabsenceofotherfeaturessuggestingadiagnosisofPMF,Thevariabledegreeofreticulinaccumulationreflectsthecombinedeffectsofgeneticbackground,diseaseduration,therapy,clonalburdenandtheacquisitionofadditionalgeneticlesions.,Table1.Suggesteddiagnosticcriteriaforessentialthrombocythemia(ET),DiagnosisrequiresA1-A3ORA1+A3-A5A1Sustainedplateletcount450X109/L.A2Presenceofanacquiredpathogeneticmutation(eg,inJAK2orMPL).A3Noothermyeloidmalignancy,especiallypolycythemiavera(PV),primarymyelofibrosis(PMF),chronicmyeloidleukemia(CML)ormyelodysplasticsyndrome(MDS).A4Noreactivecauseforthrombocytosisandnormalironstores.A5Bonemarrowtrephinehistologyshowingincreasedmegakaryocyteswithprominentlargehyperlobatedforms;reticulinisgenerallynotincreased(2ona0-4scale).,FamilialPredispositiontoETandOtherMyeloproliferativeNeoplasmsArelativeriskof7.4fordevelopingETinthosewithanaffectedfirst-degreerelative.,AreMutationsinJAK2Disease-initiatingEvents?TheacquisitionofaJAK2mutationwasprecededbyeitheradeletionofchromosome20q24oramutationinTET2.DirectevidencenowexistsdemonstratingthatJAK2mutationsarenotthedisease-initiatingeventinsomepatients,althoughthefrequencyofthisscenarioremainsunclear.,ProgressiontoAcuteMyeloidLeukemiaProgressiontoacutemyeloidleukemia(AML)occursinasmallminorityofETpatientsandinvolvestheaccrualoffurthergeneticevents.,DiagnosisandManagementDiagnosticCriteriaMutationsinJAK2exon12arenotthoughttooccurinpatientswithET.Thecombinationofanisolatedthrombocytosiswithapathogeneticmutation,intheabsenceofirondeficiencyorfeaturesofPMF,isusuallysufficienttomakeadiagnosisofET.,TherapyLow-doseaspirinCytoreductivetherapyHydroxyureaAnagrelideJAK2inhibitors,Idiopathicerythrocytosis:adisappearingentity,ClassificationofErythrocytosesAnerythrocytosiscanbeclassifieddependingontheidentifiedcause.Themaindivisionisonthebasisofprimarycauses,whereanintrinsicdefectintheerythroidprogenitorcellisassociatedwithanenhancedresponsetocytokines;orsecondary,wheretheincreasedredcellproductionisdrivenbyfactorsexternaltotheerythroidcompartment,suchasincreasederythropoietin(EPO)productionforanyreason.Primaryandsecondarycausescanbeclassifiedfurtheraseithercongenitaloracquired(Table2).,Table2.Causesofanerythrocytosis,PrimaryErythrocytosisSecondaryerythrocytosisIdiopathicerythrocytosis,Table2.Causesofanerythrocytosis,PrimaryErythrocytosisCongenitalErythropoietin(EPO)receptormutationsAcquiredPolycythemiavera(includingJAK2exon12mutations),SecondaryerythrocytosisCongenitalDefectsoftheoxygensensingpathwayVHLgenemutation(Chuvasherythrocytosis)PHD2mutationsHIF-2amutationsOthercongenitaldefectsHighoxygen-affinityhemoglobinBisphosphoglyceratemutasedeficiency,AcquiredEPO-mediatedCentralhypoxiaChroniclungdiseaseRight-to-leftcardiopulmonaryvascularshuntsCarbonmonoxidepoisoningSmokerserythrocytosisHypoventilationsyndromesincludingobstru-ctivesleepapneaHigh-altitude,LocalhypoxiaRenalarterystenosisEnd-stagerenaldiseaseHydronephrosisRenalcysts(polycystickidneydisease)Post-renaltransplanterythrocytosis,PathologicEPOproductionTumorsCerebellarhemangioblastomaMeningiomaParathyriodcarcinoma/adenomasHepatocellularcarcinomaRenalcellcancerPheochromocytomaUterineleiomyomasDrugassociatedErythropoietinadministrationAndrogenadministration,InvestigationofanErythrocytosisOnceanerythrocytosishasbeenestablishedidentificationofthecauseisthenextfocus.ClinicalConsequencesAraisedredcellcountwillincreasetheviscosityandthusmayhaveclinicalconsequences.ManagementofanErythrocytosisReducingtheHctbyphlebotomy/venesectionreducesthebloodviscosityandmaybeofbenefit.CytoreductiveLow-doseaspirin,TherapeuticpotentialofJAK2inhibitors,TheV617Fmutationislocalizedinaregionoutsidetheadenosinetriphosphate(ATP)-bindingpocketofJAK2enzyme,ATP-competitiveinhibitorsofJAK2kinasearenotlikelytodiscriminatebetweenwild-typeandmutantJAK2enzymes.Therefore,JAK2inhibitors,byvirtueoftheirnearequipotentactivityagainstwild-typeJAK2thatisimportantfornormalhematopoiesis,mayhaveadversemyelosuppressionasanexpectedsideeffect,ifadministeredatdosesthataimtocompletelyinhibitthemutantJAK2enzyme.,Whiletheymayprovetobeeffectiveincontrollinghype
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