Murine Leukemias with Retroviral Insertions at Lmo2 Are Predictive of the Leukemias Induced in SCID-X1 Patients Following Retroviral Gene Therapy 英文参考文献.docVIP
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Murine Leukemias with Retroviral Insertions at Lmo2 Are Predictive of the Leukemias Induced in SCID-X1 Patients Following Retroviral Gene Therapy 英文参考文献
MurineLeukemiaswithRetroviralInsertionsatLmo2Are
PredictiveoftheLeukemiasInducedinSCID-X1Patients
FollowingRetroviralGeneTherapy
UtpalP.Dave′1,2*,KeikoAkagi3,RatiTripathi1,2,SusanM.Cleveland1,2,MaryA.Thompson4,MingYi5,
RobertStephens5,JamesR.Downing6,NancyA.Jenkins7,NealG.Copeland7
1DepartmentofMedicine,VanderbiltUniversityMedicalCenter,Nashville,Tennessee,UnitedStatesofAmerica,2DepartmentofCancerBiology,VanderbiltUniversity
Medical Center, Nashville, Tennessee, United States of America, 3Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, United States of
America,4DepartmentofPathology,VanderbiltUniversityMedicalCenter,Nashville,Tennessee,UnitedStatesofAmerica,5AdvancedBiomedicalComputingCenter,
NationalCancerInstitute,Frederick,Maryland,UnitedStatesofAmerica,6St.JudeChildren’sResearchHospital,Memphis,Tennessee,UnitedStatesofAmerica,7Institute
ofMolecularandCellBiology,Biopolis,Singapore,Singapore
Abstract
Five X-linked severe combined immunodeficiency patients (SCID-X1) successfully treated with autologous bone marrow
stemcellsinfectedexvivowithanIL2RG-containingretrovirussubsequentlydevelopedT-cellleukemiaandfourcontained
insertionalmutationsatLMO2.GeneticevidencealsosuggestsaroleforIL2RGintumorformation,althoughthisremains
controversial. Here, we show that the genes and signaling pathways deregulated in murine leukemias with retroviral
insertions at Lmo2 are similar to those deregulated in human leukemias with high LMO2 expression and are highly
predictiveoftheleukemiasinducedinSCID-X1patients.Wealsoprovideadditionalevidencesupportingthenotionthat
IL2RGandLMO2cooperateinleukemiainductionbutarenotsufficientandrequireadditionalcooperatingmutations.The
highlyconcordantnatureofthegeneticeventsgivingrisetomouseandhumanleukemiaswithmutationsatLmo2arean
encouraging sign to those wanting to use mice to model human cancer and may help in designing safer methods for
retroviralgenetherapy.
Citation: Dave′ UP, Akagi K, Tripathi R, Cleveland SM,
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