Reciprocal t(9;22) ABLBCR Fusion Proteins Leukemogenic Potential and Effects on B Cell Commitment 英文参考文献.docVIP

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Reciprocal t(9;22) ABLBCR Fusion Proteins Leukemogenic Potential and Effects on B Cell Commitment 英文参考文献.doc

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Reciprocal t(9;22) ABLBCR Fusion Proteins Leukemogenic Potential and Effects on B Cell Commitment 英文参考文献

Reciprocalt(9;22)ABL/BCRFusionProteins: LeukemogenicPotentialandEffectsonBCell Commitment XiaominZheng1,2,ClaudiaOancea1,ReinhardHenschler3,MalcolmA.S.Moore2,MartinRuthardt1* 1DepartmentofHematology,LaboratoryforTumorStemCellBiology,GoetheUniversity,Frankfurt,Germany,2CellBiologyProgram,MemorialSloan-KetteringCancer Center,NewYork,NewYork,UnitedStatesofAmerica,3DepartmentofTransfusionMedicineandImmunohematology,GoetheUniversity,Frankfurt,Germany Abstract Background: t(9;22) is a balanced translocation, and the chromosome 22 breakpoints (Philadelphia chromosome – Ph+) determineformationofdifferentfusiongenesthatareassociatedwitheitherPh acutelymphaticleukemia(Ph ALL)or + + + chronicmyeloidleukemia(CML).The‘‘minor’’breakpointinPh ALLencodesp185BCR/ABL fromder22andp96ABL/BCR from der9. The ‘‘major’’ breakpoint in CML encodes p210BCR/ABL and p40ABL/BCR. Herein, we investigated the leukemogenic potential of the der9-associated p96ABL/BCR and p40ABL/BCR fusion proteins and their roles in the lineage commitment of hematopoieticstemcellsincomparisontoBCR/ABL. Methodology: All t(9;22) derived proteins were retrovirally expressed in murine hematopoietic stem cells (SL cells) and human umbilical cord blood cells (UCBC). Stem cell potential was determined by replating efficiency, colony forming - spleenandcompetitiverepopulatingassays.TheleukemicpotentialoftheABL/BCRfusionproteinswasassessedbyina transduction/transplantationmodel.Effectsonthelineagecommitmentanddifferentiationwereinvestigatedbyculturing the cells under conditions driving either myeloid or lymphoid commitment. Expression of key factors of the B-cell differentiationandcomponentsofthepreB-cellreceptorweredeterminedbyqRT-PCR. PrincipalFindings:Bothp96ABL/BCR andp40ABL/BCR increasedproliferationofearlyprogenitorsandtheshorttermstemcell capacityofSL-cellsandexhibitedownleukemogenicpotential.Interestingly,BCR/ABLgaveoriginexclusivelytoamyeloid phenotypeindependentlyfromthecultureconditionswhereasp96AB