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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

Wong, Nicholas C., Bhadri, Vivek A., Maksimovic, Jovana, Parkinson-Bates, Mandy, Ng, Jane, Craig, Jeff M., Saffery, Richard and Lock, Richard B. 2014, 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, vol. 15, pp. 1-13, doi: 10.1186/1471-2164-15-416.

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Title 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
Author(s) Wong, Nicholas C.ORCID iD for Wong, Nicholas C. orcid.org/0000-0002-6396-0338
Bhadri, Vivek A.
Maksimovic, Jovana
Parkinson-Bates, Mandy
Ng, Jane
Craig, Jeff M.
Saffery, Richard
Lock, Richard B.
Journal name BMC genomics
Volume number 15
Article ID 416
Start page 1
End page 13
Total pages 13
Publisher BioMed Central
Place of publication London, Eng.
Publication date 2014-06
ISSN 1471-2164
Keyword(s) Adolescent
Animals
Antineoplastic Agents, Hormonal
Child
DNA Methylation
Disease Models, Animal
Drug Resistance, Neoplasm
Epigenesis, Genetic
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Infant
Male
Mice, Inbred NOD
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Prednisolone
Xenograft Model Antitumor Assays
Science & Technology
Life Sciences & Biomedicine
Biotechnology & Applied Microbiology
Genetics & Heredity
Acute lymphoblastic leukaemia
Xenografts
Genome-wide DNA methylation
Microarray analysis of gene expression
Glucocorticoid resistance
ACUTE MYELOID-LEUKEMIA
MODELS
RELAPSE
CANCER
PAR-4
METHYLATION
MICROARRAY
AML1/ETO
REVEALS
POU4F1
Summary 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.
Language eng
DOI 10.1186/1471-2164-15-416
Field of Research 06 Biological Sciences
11 Medical And Health Sciences
08 Information And Computing Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2014, Wong et al.
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30110755

Document type: Journal Article
Collections: School of Medicine
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.