Molecular Pathogenesis and Therapy of Polycythemia Induced in Mice by JAK2 V617F 英文参考文献.docVIP

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Molecular Pathogenesis and Therapy of Polycythemia Induced in Mice by JAK2 V617F 英文参考文献.doc

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Molecular Pathogenesis and Therapy of Polycythemia Induced in Mice by JAK2 V617F 英文参考文献

MolecularPathogenesisandTherapyofPolycythemia InducedinMicebyJAK2V617F VirginiaM.Zaleskas1,DanielaS.Krause1¤,KatherineLazarides1,NihalPatel1,YiguoHu2,ShaoguangLi2,RichardA.VanEtten1* 1Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts, United States of America, 2The Jackson Laboratory,BarHarbor,Maine,UnitedStatesofAmerica Background. A somaticactivating mutation(V617F)in the JAK2tyrosine kinasewasrecentlydiscoveredin the majorityof patients with polycythemia vera (PV), and some with essential thrombocythemia (ET) and chronic idiopathic myelofibrosis. However,theroleofmutantJAK2indiseasepathogenesisisunclear.MethodsandFindings.WeexpressedmurineJAK2WT orV617Fviaretroviralbonemarrowtransduction/transplantationinthehematopoieticsystemoftwodifferentinbredmouse strains,Balb/candC57Bl/6(B6).Inbothstrains,JAK2V617F,butnotJAK2WT,inducednon-fatalpolycythemiacharacterizedby increasedhematocritandhemoglobin,reticulocytosis,splenomegaly,lowplasmaerythropoietin(Epo),andEpo-independent erythroidcolonies.JAK2V617FalsoinducedleukocytosisandneutrophiliathatwasmuchmoreprominentinBalb/cmicethan inB6.PlateletcountswerenotaffectedineitherstraindespiteexpressionofJAK2V617Finmegakaryocytesandmarkedly prolongedtailbleedingtimes.Thepolycythemiatendedtoresolveafterseveralmonths,coincidentwithincreasedspleenand marrowfibrosis,butwasresurrectedbytransplantationtosecondaryrecipients.UsingdonormicewithmutationsinLyn,Hck, andFgr,wedemonstratedthatthepolycythemiawasindependentofSrckinases.Polycythemiaandreticulocytosisresponded to treatment with imatinib or a JAK2 inhibitor, but were unresponsive to the Src inhibitor dasatinib. Conclusions. These findingsdemonstratethatJAK2V617FinducesEpo-independentexpansionoftheerythroidlineageinvivo.Thefactthatthe centralerythroidfeaturesofPVarerecapitulatedbyexpressionofJAK2V617Farguesthatitistheprimaryanddirectcauseof human PV. The lack of thrombocytosis suggests that additional events may be required for JAK2 V