Oncogenic RAS Enables DNA Damage- and p53-Dependent Differentiation of Acute Myeloid Leukemia Cells in Response to Chemotherapy 英文参考文献.docVIP

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Oncogenic RAS Enables DNA Damage- and p53-Dependent Differentiation of Acute Myeloid Leukemia Cells in Response to Chemotherapy 英文参考文献.doc

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Oncogenic RAS Enables DNA Damage- and p53-Dependent Differentiation of Acute Myeloid Leukemia Cells in Response to Chemotherapy 英文参考文献

OncogenicRASEnablesDNADamage-andp53- DependentDifferentiationofAcuteMyeloidLeukemia CellsinResponsetoChemotherapy MonaMeyer1,2,DanielaRu¨bsamen2,RobertSlany3,ThomasIllmer4,KathleenStabla1,PetraRoth1, ThorstenStiewe1,MartinEilers5.,AndreasNeubauer1. * 1Klinikfu¨rHa¨matologie, OnkologieundImmunologie,PhilippsUniversita¨t Marburg,Marburg,Germany,2Institutfu¨rMolekularbiologieundTumorforschung,Philipps Universita¨t Marburg, Marburg, Germany, 3Institut fu¨r Genetik, Friedrich Alexander Universita¨t Erlangen, Erlangen, Germany, 4Technische Universita¨t Dresden, MedizinischeKlinikI,Dresden,Germany,5Biocenter,Julius-Maximilians-Universita¨t Wu¨rzburg,Wu¨rzburg,Germany Abstract Acutemyeloidleukemia(AML)isaclonaldiseaseoriginatingfrommyeloidprogenitorcellswithaheterogeneousgenetic background. High-dose cytarabine is used as the standard consolidation chemotherapy. Oncogenic RAS mutations are frequentlyobservedinAML,andareassociatedwithbeneficialresponsetocytarabine.WhyAML-patientswithoncogenic RASbenefitmostfromhigh-dosecytarabinepost-remissiontherapyisnotwellunderstood.Hereweusedbonemarrow cellsexpressingaconditionalMLL-ENL-ERoncogenetoinvestigatetheinteractionofoncogenicRASandchemotherapeutic agents. We show that oncogenic RAS synergizes with cytotoxic agents such as cytarabine in activation of DNA damage checkpoints, resulting in a p53-dependent genetic program that reduces clonogenicity and increases myeloid differentiation. Our data can explain the beneficial effects observed for AML patients with oncogenic RAS treated with higherdosagesofcytarabineandsuggestthatinductionofp53-dependentdifferentiation,e.g.byinterferingwithMdm2- mediated degradation, may be a rational approach to increase cure rate in response to chemotherapy. The data also support the notion that the therapeutic success of cytotoxic drugs may depend on their ability to promote the differentiationoftumor-initiatingcells. Citation: MeyerM, Ru¨bsamen D,SlanyR, Illmer T,StablaK, et al.(2009) Onco