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Stability of gene expression and epigenetic profiles highlights the utility of patient-derived paediatric acute lymphoblastic leukaemia xenografts for investigating molecular mechanisms of drug resistance
journal contributionposted on 2014-06-01, 00:00 authored by Nicholas C Wong, Vivek A Bhadri, Jovana Maksimovic, Mandy Parkinson-Bates, Jane Ng, Jeffrey CraigJeffrey Craig, Richard Saffery, Richard B Lock
BACKGROUND: Patient-derived tumour xenografts are an attractive model for preclinical testing of anti-cancer drugs. Insights into tumour biology and biomarkers predictive of responses to chemotherapeutic drugs can also be gained from investigating xenograft models. As a first step towards examining the equivalence of epigenetic profiles between xenografts and primary tumours in paediatric leukaemia, we performed genome-scale DNA methylation and gene expression profiling on a panel of 10 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) tumours that were stratified by prednisolone response. RESULTS: We found high correlations in DNA methylation and gene expression profiles between matching primary and xenograft tumour samples with Pearson's correlation coefficients ranging between 0.85 and 0.98. In order to demonstrate the potential utility of epigenetic analyses in BCP-ALL xenografts, we identified DNA methylation biomarkers that correlated with prednisolone responsiveness of the original tumour samples. Differential methylation of CAPS2, ARHGAP21, ARX and HOXB6 were confirmed by locus specific analysis. We identified 20 genes showing an inverse relationship between DNA methylation and gene expression in association with prednisolone response. Pathway analysis of these genes implicated apoptosis, cell signalling and cell structure networks in prednisolone responsiveness. CONCLUSIONS: The findings of this study confirm the stability of epigenetic and gene expression profiles of paediatric BCP-ALL propagated in mouse xenograft models. Further, our preliminary investigation of prednisolone sensitivity highlights the utility of mouse xenograft models for preclinical development of novel drug regimens with parallel investigation of underlying gene expression and epigenetic responses associated with novel drug responses.
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Publication classificationC1 Refereed article in a scholarly journal
Copyright notice2014, Wong et al.
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AdolescentAnimalsAntineoplastic Agents, HormonalChildDNA MethylationDisease Models, AnimalDrug Resistance, NeoplasmEpigenesis, GeneticFemaleGene Expression ProfilingGene Expression Regulation, NeoplasticHumansInfantMaleMice, Inbred NODPrecursor B-Cell Lymphoblastic Leukemia-LymphomaPrednisoloneXenograft Model Antitumor AssaysScience & TechnologyLife Sciences & BiomedicineBiotechnology & Applied MicrobiologyGenetics & HeredityAcute lymphoblastic leukaemiaXenograftsGenome-wide DNA methylationMicroarray analysis of gene expressionGlucocorticoid resistanceACUTE MYELOID-LEUKEMIAMODELSRELAPSECANCERPAR-4METHYLATIONMICROARRAYAML1\/ETOREVEALSPOU4F1