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

Nicholas C. Wong, Vivek A. Bhadri, Jovana Maksimovic, Mandy Parkinson-Bates, Jane Ng, Jeff M. Craig, Richard Saffery, Richard B. Lock

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Article number416
Number of pages13
JournalBMC Genomics
Volume15
Issue number1
DOIs
Publication statusPublished - 1 Jun 2014
Externally publishedYes

Keywords

  • Acute lymphoblastic leukaemia
  • Genome-wide DNA methylation
  • Glucocorticoid resistance
  • Microarray analysis of gene expression
  • Xenografts

Cite this

Wong, Nicholas C. ; Bhadri, Vivek A. ; Maksimovic, Jovana ; Parkinson-Bates, Mandy ; Ng, Jane ; Craig, Jeff M. ; Saffery, Richard ; Lock, Richard B. / 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. In: BMC Genomics. 2014 ; Vol. 15, No. 1.
@article{005db66a312c41e7b72275a4c03129d4,
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",
abstract = "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.",
keywords = "Acute lymphoblastic leukaemia, Genome-wide DNA methylation, Glucocorticoid resistance, Microarray analysis of gene expression, Xenografts",
author = "Wong, {Nicholas C.} and Bhadri, {Vivek A.} and Jovana Maksimovic and Mandy Parkinson-Bates and Jane Ng and Craig, {Jeff M.} and Richard Saffery and Lock, {Richard B.}",
year = "2014",
month = "6",
day = "1",
doi = "10.1186/1471-2164-15-416",
language = "English",
volume = "15",
journal = "BMC Genomics",
issn = "1471-2164",
publisher = "BioMed Central",
number = "1",

}

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; Lock, Richard B.

In: BMC Genomics, Vol. 15, No. 1, 416, 01.06.2014.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - 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

AU - Wong, Nicholas C.

AU - Bhadri, Vivek A.

AU - Maksimovic, Jovana

AU - Parkinson-Bates, Mandy

AU - Ng, Jane

AU - Craig, Jeff M.

AU - Saffery, Richard

AU - Lock, Richard B.

PY - 2014/6/1

Y1 - 2014/6/1

N2 - 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.

AB - 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.

KW - Acute lymphoblastic leukaemia

KW - Genome-wide DNA methylation

KW - Glucocorticoid resistance

KW - Microarray analysis of gene expression

KW - Xenografts

UR - http://www.scopus.com/inward/record.url?scp=84902121562&partnerID=8YFLogxK

U2 - 10.1186/1471-2164-15-416

DO - 10.1186/1471-2164-15-416

M3 - Article

VL - 15

JO - BMC Genomics

JF - BMC Genomics

SN - 1471-2164

IS - 1

M1 - 416

ER -