lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1

We examined expression of B cell–activat-ing factor of the tumor necrosis factor (TNF) family (BAFF) and a proliferation-inducing ligand (APRIL) on chronic lym-phocytic leukemia (CLL) B cells and nurselike cells (NLCs), which differenti-ate from CD14 cells when cultured with CLL B cells. NLCs expressed signifi-cantly higher levels of APRIL than mono-cytes and significantly higher levels of BAFF and APRIL than CLL B cells. Also, the viability of CLL B cells cultured with NLCs was significantly reduced when CLL B cells were cultured with decoy receptor of B-cell maturation antigen (BCMA), which can bind both BAFF and APRIL, but not with BAFF receptor:Fc (BAFF-R:Fc), which binds only to BAFF. The effect(s) of BAFF or APRIL on leukemia cell survival appeared additive and distinct from that of stromal cell–derived factor-1 (SDF-1), which in contrast to BAFF or APRIL induced leukemia cell phosphorylation of p44/42 mitogen-activated protein kinase (extracellular signal-regulated kinase-1/2 [ERK1/2]) and AKT. Conversely, BAFF and APRIL, but not SDF-1, induced CLL-cell activation of the nuclear factor–B1 (NF-B1) and enhanced CLL-cell expression of the antiapoptotic protein Mcl-1. How-ever, BAFF, but not APRIL, also induced CLL-cell activation of NF-B2. We con-clude that BAFF and APRIL from NLCs can function in a paracrine manner to support leukemia cell survival via mecha-nisms that are distinct from those of SDF-1, indicating that NLCs use mul-tiple distinct pathways to support CLL-cell survival. (Blood. 2005;106:1012-1020) © 2005 by The American Society of Hematolog