Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia.
BACKGROUND
Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL). However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential.


RESULTS
Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation.


CONCLUSIONS
We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo.
Samuels
Amy L
AL
Division of Children's Leukaemia and Cancer Research, Telethon Institute for Child Health Research, Perth, Western Australia.
Peeva
Violet K
VK
Papa
Rachael A
RA
Firth
Marin J
MJ
Francis
Richard W
RW
Beesley
Alex H
AH
Lock
Richard B
RB
Kees
Ursula R
UR
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D013045:Species Specificity; D013154:Spleen / Q000378:metabolism
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