BAFF Support Survival of Chronic Lymphocytic Leukemia B Cells by a Pathway Independent of Stromal Derived Factor-1α.

We examined the peripheral blood mononuclear cells (PBMC) of patients with chronic lymphocytic leukemia (CLL) for expression of B cell-activating factor of the TNF family (BAFF). Isolated CLL B cells had significantly lower levels of BAFF mRNA than did non-separated PBMC. Most of the BAFF mRNA in PBMC was due to contaminating CD14⁺ cells that previous studies found could differentiate into “nurselike” cells (NLC) when cultured with CLL B cells in vitro. We found NLC expressed high-levels of BAFF and stromal cell-derived factor-1 alpha (SDF-1α), in contrast to CLL B cells. CLL B cells cultured with exogenous recombinant human BAFF (rhBAFF), SDF-1α, or NLC sustained significantly greater viability than isolated CLL B cells cultured alone. The effect(s) of rhBAFF on leukemia cell survival appeared additive and distinct from that of SDF-1α, which in contrast to rhBAFF induced leukemia-cell phosphorylation of p44/42 mitogen-activated protein-kinase (ERK 1/2) and phosphorylation and activation of AKT at Ser⁴⁷³. However, rhBAFF, but not SDF-1α, could induce processing of p100 NF-κB2 to p52 and, like NLC, enhance and/or maintain CLL-cell expression of the anti-apoptotic protein Mcl-1. We conclude that BAFF can function in a paracrine manner to support leukemia cell survival via mechanisms that are distinct from those of SDF-1α and that NLC use multiple distinct pathways to support CLL-cell survival.