Functional Ramifications for the Loss of P-Selectin Expression on Hematopoietic and Leukemic Stem Cells 英文参考文献.docVIP

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Functional Ramifications for the Loss of P-Selectin Expression on Hematopoietic and Leukemic Stem Cells 英文参考文献.doc

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Functional Ramifications for the Loss of P-Selectin Expression on Hematopoietic and Leukemic Stem Cells 英文参考文献

FunctionalRamificationsfortheLossofP-Selectin ExpressiononHematopoieticandLeukemicStemCells ConSullivan1,3.,YaoyuChen2,3.¤,YiShan2,YiguoHu3,4,CongPeng2,3,HaojianZhang2,3 ,Linghong Kong3,ShaoguangLi2,3* 1MaineInstituteforHumanGeneticsandHealth,Bangor,Maine,UnitedStatesofAmerica,2DivisionofHematology/Oncology,DepartmentofMedicine,Universityof MassachusettsMedicalSchool,Worcester,Massachusetts,UnitedStatesofAmerica,3TheJacksonLaboratory,BarHarbor,Maine,UnitedStatesofAmerica,4DanaFarber CancerInstitute,Boston,Massachusetts,UnitedStatesofAmerica Abstract Hematopoiesisisatightlyregulatedbiologicalprocessthatreliesuponcomplicatedinteractionsbetweenbloodcellsand theirmicroenvironmenttopreservethehomeostaticbalanceoflong-termhematopoieticstemcells(LT-HSCs),short-term HSCs(ST-HSCs), multipotentprogenitors (MPPs),anddifferentiatedcells.AdhesionmoleculeslikeP-selectin(encodedby the Selp gene) are essential to hematopoiesis, and their dysregulation has been linked to leukemogenesis. Like HSCs, leukemicstemcells(LSCs)dependupontheirmicroenvironmentsforsurvivalandpropagation.P-selectinplaysacrucialrole + inPhiladelphiachromosome-positive(Ph )chronicmyeloidleukemia(CML).Inthispaper,weshowthatcellsdeficientinP- selectinexpressioncanrepopulatethemarrowmoreefficientlythanwildtypecontrols.ThisresultsfromanincreaseinHSC self-renewalratherthanalternativepossibilitieslikeincreasedhomingvelocityorcellcycledefects.WealsoshowthatP- selectinexpressiononLT-HSCs,butnotST-HSCsandMPPs,increaseswithaging.IntheabsenceofP-selectinexpression, miceat6monthsofagepossessincreasedlevelsofshort-termHSCsandmultipotentprogenitors.By11monthsofage, thereisashifttowardsincreasedlevelsoflong-termHSCs.RecipientsofBCR-ABL-transducedbonemarrowcellsfromP- selectin-deficient donors develop a more aggressive CML, with increased percentages of LSCs and progenitors. Taken together, our data reveal that P-selectin expression on HSCs and LSCs has important functional ramifications for both hematopoiesisandleukemogenes