The overall data add new support to the critical role played by the Ca2+ signaling in CLL outcome, and describe for the first time a novel STIM1PM-dependant and constitutively active Ca2+ entry, independent from BCR signaling, and that constitutively active CE can be modulated and targeted by an anti-STIM1 mAb. The gene discussed is BCR; the disease is B-cell chronic lymphocytic leukemia.