Gab2 Promotes Hematopoietic Stem Cell Maintenance and Self-Renewal Synergistically with STAT5 英文参考文献.docVIP

Gab2PromotesHematopoieticStemCellMaintenance andSelf-RenewalSynergisticallywithSTAT5 GeqiangLi1,2,ZhengqiWang1,2,KristyL.Miskimen1,2,YiZhang1¤a,WilliamTse1,2¤b,KevinD. Bunting1,2,3 * 1DivisionofHematology-Oncology,DepartmentofMedicine,CaseWesternReserveUniversity,Cleveland,Ohio,UnitedStatesofAmerica, 2CenterforStemCelland RegenerativeMedicine,Cleveland,Ohio,UnitedStatesofAmerica,3CaseComprehensiveCancerCenter,Cleveland,Ohio,UnitedStatesofAmerica Abstract Background: Grb2-associated binding (Gab) adapter proteins play major roles in coordinating signaling downstream of hematopoieticcytokinereceptors.Inhematopoieticcells,Gab2canmodulatephosphatidylinositol–3kinaseandmitogen associated protein kinase activities and regulate the long-term multilineage competitive repopulating activity of hematopoieticstemcells(HSCs).Gab2mayalsoactinalinearpathwayupstreamordownstreamofsignaltransducerand activatoroftranscription-5(STAT5),amajorpositiveregulatorofHSCfunction.Therefore,weaimedtodeterminewhether Gab2andSTAT5functioninhematopoiesisinaredundantornon-redundantmanner. Methodology/Principal Findings: To do this we generated Gab2 mutant mice with heterozygous and homozygous deletions of STAT5. In heterozygous STAT5 mutant mice, deficiencies in HSC/multipotent progenitors were reflected by decreased long-term repopulating activity. This reduction in repopulation function was mirrored in the reduced growth + + response to early-acting cytokines from sorted double mutant c-Kit Lin2Sca-1 (KLS) cells. Importantly, in non-ablated newborn mice, the host steady-state engraftment ability was impaired by loss of Gab2 in heterozygous STAT5 mutant background.FetallivercellsisolatedfromhomozygousSTAT5mutantmicelackingGab2showedsignificantreductionin HSCnumber(KLSCD150+CD482),reducedHSCsurvival,anddramaticlossofself-renewalpotentialasmeasuredbyserial transplantation. Conclusions/Significance: These data demonstrate new functions for Gab2 in hematopoiesis in a manner that is non- re