A core proliferative program induced by B-cell receptor stimulation in chronic lymphocytic leukemia cells

The B-cell receptor (BCR) signaling is crucial for the pathophysiology of chronic lymphocytic leukemia (CLL). Although the BCR has recently emerged as a new therapeutic target the precise mechanisms by which BCR signaling controls neoplastic B-cell proliferation are still ill characterized. Here, by comparing proliferating vs. non-proliferating cells from aggressive CLL patients, we longitudinally characterized the transcriptional and proteomic response of CLL cells after BCR engagement ex vivo. Of the 5,733 genes and/or proteins which expression was modulated after BCR activation, we identified a CLL proliferative signature including 430 genes and 374 proteins. Mathematical modelling of this signature revealed a nested sub-regulatory network comprising transcription factors activated within hours after cell activation linked to proteins involved in cell proliferation days after stimulation. The mining of this core cellular program sustaining primary human cancer cells proliferation provides an evidence based-resource for innovative therapeutic perspectives.