Gene expression profiling predicts sensitivity of chronic lymphocytic leukemia cells to dasatinib
In this study, we used RNA-sequencing to characterize the gene-expression profiles of CLL cells sensitive and resistant to dasatinib and define a specific gene-expression signature associated with drug sensitivity. Specifically, cells were isolated from the blood of 16 newly diagnosed, unselected CLL patients prior to any treatment and classified as responders or non-responders based on in vitro drug cytotoxicity assays. RNA-sequencing analysis of both treated and untreated samples revealed 154 genes differentially expressed between responders and non-responders and, among these, 31 genes were predictive of response in untreated samples. Cells sensitive to dasatinib exhibit increased expression of genes associated with stress signaling, metabolic pathways, including glycolysis, and immune response, including proinflammatory components. Neither of the responder and non-responder groups was enriched for any of the genetic aberrations commonly associated with CLL, as determined by gene mutation and copy-number analysis. We employed the Library of Integrated Network-Based Cellular Signatures (LINCS) database for validation of the obtained gene expression profiles and show, in sum, that dasatinib may represent a viable therapeutic option in a group of CLL patients preselected by gene-expression profiling. Overall design: RNA-sequencing was performed for peripheral blood lymphocytes of 16 newly diagnosed, untreated and unselected CLL patients, cultured in-vitro with and without dasatinib.