Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9 英文参考文献.docVIP

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Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9 英文参考文献.doc

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Dissection of the Transformation of Primary Human Hematopoietic Cells by the Oncogene NUP98-HOXA9 英文参考文献

DissectionoftheTransformationofPrimaryHuman HematopoieticCellsbytheOncogeneNUP98-HOXA9 EnasR.Yassin1,2,NayanJ.Sarma1,AnmaarM.Abdul-Nabi1,2,JamesDombrowski2,YeHan2 ,Akiko Takeda1,2,NabeelR.Yaseen1,2 * 1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America, 2Department of Pathology, FeinbergSchoolofMedicine,NorthwesternUniversity,Chicago,Illinois,UnitedStatesofAmerica Abstract NUP98-HOXA9 is theprototype ofagroupof oncoproteins associatedwith acutemyeloid leukemia. It consists ofanN- terminalportionofNUP98fusedtothehomeodomainofHOXA9andisbelievedtoactasanaberranttranscriptionfactor thatbindsDNAthroughthehomeodomain.HereweshowthatNUP98-HOXA9canregulatetranscriptionwithoutbinding toDNA.InordertodeterminetherelativecontributionsoftheNUP98andHOXA9portionstothetransformingabilityof NUP98-HOXA9,theeffectsofNUP98-HOXA9onprimaryhumanCD34+cellsweredissectedandcomparedtothoseofwild- type HOXA9. In contrast to previous findings in mouse cells, HOXA9 had only mild effects on the differentiation and proliferationofprimaryhumanhematopoieticcells.TheabilityofNUP98-HOXA9todisruptthedifferentiationofprimary human CD34+ cells was found to depend primarily on the NUP98 portion, whereas induction of long-term proliferation requiredboththeNUP98moietyandanintacthomeodomain.UsingoligonucleotidemicroarraysinprimaryhumanCD34+ cells,agroupofgeneswasidentifiedwhosedysregulationbyNUP98-HOXA9isattributableprimarilytotheNUP98portion. TheseincludeRAP1A,HEY1,andPTGS2(COX-2).TheirfunctionsmayreflectthecontributionoftheNUP98moietyofNUP98- HOXA9 to leukemic transformation. Taken together, these results suggest that the effects of NUP98-HOXA9 on gene transcriptionandcelltransformationaremediatedbyatleasttwodistinctmechanisms:onethatinvolvespromoterbinding throughthehomeodomainwithdirecttranscriptionalactivation,andanotherthatdependspredominantlyontheNUP98 moietyanddoesnotinvolvedirectDNAbinding. Citation:YassinER,SarmaNJ,Abdul-