Reverse-engineering the genetic circuitry of a cancer cell with predicted intervention in chronic lymphocytic leukemia

TitleReverse-engineering the genetic circuitry of a cancer cell with predicted intervention in chronic lymphocytic leukemia
Publication TypeJournal Article
Year of Publication2013
AuthorsVallat L, Kemper CA, Jung N, Maumy-Bertrand M, Bertrand F, Meyer N, Pocheville A, Fisher JW, Gribben JG, Bahram S
JournalPNAS
Volume110
Pagination459–464
ISSN0027-8424, 1091-6490
KeywordsB-cell antigen receptor, lasso penalty, lymphoproliferative disorder, predicted intervention, temporal gene network
Abstract

Cellular behavior is sustained by genetic programs that are progressively disrupted in pathological conditions—notably, cancer. High-throughput gene expression profiling has been used to infer statistical models describing these cellular programs, and development is now needed to guide orientated modulation of these systems. Here we develop a regression-based model to reverse-engineer a temporal genetic program, based on relevant patterns of gene expression after cell stimulation. This method integrates the temporal dimension of biological rewiring of genetic programs and enables the prediction of the effect of targeted gene disruption at the system level. We tested the performance accuracy of this model on synthetic data before reverse-engineering the response of primary cancer cells to a proliferative (protumorigenic) stimulation in a multistate leukemia biological model (i.e., chronic lymphocytic leukemia). To validate the ability of our method to predict the effects of gene modulation on the global program, we performed an intervention experiment on a targeted gene. Comparison of the predicted and observed gene expression changes demonstrates the possibility of predicting the effects of a perturbation in a gene regulatory network, a first step toward an orientated intervention in a cancer cell genetic program.

URLhttp://www.pnas.org/content/110/2/459
DOI10.1073/pnas.1211130110