The Classical and Alternative NF-κB Activity Supports Cell Survival and Confers Chemo-Sensitivity Of Chronic Lymphocytic Leukemia Cells

Constitutive classical NF-κB activation protects chronic lymphocytic leukemia (CLL) B-cells from spontaneous cell death and plays a critical role in the chemo-resistance. RelB, representing the alternative NF-κB activity, functions specifically in lymphoid organogenesis and B-cell maturation. RelB indeed plays a tumor-supportive role and confer radiation-resistance in solid tumors. However, the involvement of RelB in CLL is unrevealed. Here, we analyzed the NF-κB activation in CLL bone marrow (BM). Both the RelA and RelB activity could be detected in CLL B-cells from BM, in spite of inevitable variability. High RelB activity, concomitant with high RelA activity, was linked to an unfavorable prognosis of CLL. CLL-derived BM stromal cells (BMSCs) were functionally similar to disease-free BMSCs in their capability to support CLL B-cells survival. The migration and adhesion ability of CLL B-cells was not affected by the RelB activity. High RelB activity, together with the RelA activity, maintained the basal survival of cells. The induction of RelA and RelB expression in the nuclear was responsible for the better survival of CLL B-cells supported by BMSCs. In addition, the presence of high RelB activity in CLL B-cells was correlated with the sensitivity to proteasome inhibitor but not fludarabine. Taken together, we provided evidences that not only RelA but also RelB, subunits of NF-κB family, plays an important role in the cellular behavior of CLL cells from BM. The strength of RelB activity influenced the prognosis of CLL patients.