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

BMC Genomics

Richard B Lock²  Richard Saffery¹  Jeff M Craig¹  Jane Ng³  Mandy Parkinson-Bates³  Jovana Maksimovic³  Vivek A Bhadri²  Nicholas C Wong¹ 

[1] Department of Paediatrics, The University of Melbourne, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia;Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, PO Box 81, Sydney, NSW 2052, Australia;Murdoch Childrens Research Institute, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia

关键词: Glucocorticoid resistance;    Microarray analysis of gene expression;    Genome-wide DNA methylation;    Xenografts;    Acute lymphoblastic leukaemia;   

Others  :  1216756
DOI  :  10.1186/1471-2164-15-416

 received in 2013-11-29, accepted in 2014-05-20,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Wong et al.; licensee BioMed Central Ltd.

【 图 表 】

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