The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease

Chronic lymphocytic leukemia ( CLL) B-cells are hyporesponsive to many proliferative signals that induce activation of normal B-lymphocytes. However, a heterogeneous response has recently been observed with immunostimulatory CpG-oligodeoxynucleotides ( CpG ODN). We now show that CpG ODN induce proliferation mainly in CLL B-cells from patients with progressive disease and unmutated immunoglobulin V-H genes, whereas G(1)/S cell cycle arrest and apoptosis are induced in leukemic B-cells from stable/V-H mutated CLL. Examination of early signaling events demonstrated that all CLL B-cells respond to CpG ODN stimulation by degradation of the NF-kappa B inhibitor I kappa B and activation of the Akt, ERK, JNK and p38 MAPK kinases, but the magnitude and duration of the signaling response was greater in the proliferating cases. Pharmacological inhibition of these pathways showed that simultaneous activation of Akt, ERK and JNK is required for cell cycle progression and proliferation. Conversely, introduction of constitutively active Akt in nonproliferating CLL B-cells resulted in induction of cyclin A following CpG ODN stimulation, indicating that increased Akt activation is sufficient to overcome the hyporesponsiveness of these cells to proliferative signals. Thus, the magnitude of Akt signaling may determine the distinct responses observed in leukemic B-cells belonging to the different prognostic subgroups.