title: Reverse-engineering the genetic circuitry of a cancer cell with predicted intervention in chronic lymphocytic leukemia.
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.
authors.affiliation: Laboratoire d'Immunogénétique Moléculaire Humaine, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1109, Centre de Recherche d'Immunologie et d'Hématologie, Faculté de Médecine, Université de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, 67085 Strasbourg Cedex, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vallat
authors.forename: Corey A
authors.initials: CA
authors.lastname: Kemper
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jung
authors.forename: Myriam
authors.initials: M
authors.lastname: Maumy-Bertrand
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bertrand
authors.forename: Nicolas
authors.initials: N
authors.lastname: Meyer
authors.forename: Arnaud
authors.initials: A
authors.lastname: Pocheville
authors.forename: John W
authors.initials: JW
authors.lastname: Fisher
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: Seiamak
authors.initials: S
authors.lastname: Bahram
mesh_terms: D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics*; D005818:Genetic Engineering / Q000379:methods; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D007945:Leukemia, Lymphoid / Q000235:genetics* / Q000378:metabolism*; D046228:Microarray Analysis; D008954:Models, Biological; D034622:RNA Interference; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D012044:Regression Analysis; D059386:Reverse Genetics / Q000379:methods
chemical_list: D011947:Receptors, Antigen, B-Cell