Abstract
Large, adherent nurse-like cells (NLC) can differentiate from the blood mononuclear cells of patients with chronic lymphocytic leukemia (CLL) that, in turn, can support leukemia cell survival in vitro, and presumably in vivo. These cells differentiate in the context of CLL B cells and can be found in the secondary lymphoid tissues of patients with this disease. NLC express high levels of B cell activating factor belonging to the tumor necrosis factor (TNF) family (BAFF), a factor that can support normal and leukemia B cell survival in vitro. BAFF binds to three distinct members of TNF-receptor superfamily : TACI (transmembrane activator and CAML interactor), BCMA (B cell maturation antigen) and BAFF-R, the latter two of which are expressed by CLL B cells. We found that addition of saturating amounts of a recombinant BAFF-receptor-Fc fusion protein (BAFF-R:Fc) to cultures of NLC and CLL B cells failed to inhibit the protective effect(s) of NLC on CLL B cell survival in vitro. This suggested that another factor(s) made by NLC can contribute to the survival effect(s) of BAFF on CLL B cells. A candidate for this is a proliferation-inducing ligand (APRIL), another member of the TNF family that can interact with TACI and BCMA, but not BAFF-R. We found that, in contrast to CLL B cells or blood mononuclear cells, NLC express high-levels of APRIL mRNA and protein, as assessed by quantitative RT-PCR and immunoblot analyses. Furthermore, recombinant human APRIL also could support CLL B cell survival via mechanism similar to that used by recombinant BAFF. Consistent with the fact that APRIL and BAFF each can function to support CLL B cell survival, we found that a recombinant BCMA-Fc fusion protein could significantly inhibit the protective effects of NLC on CLL B cells in vitro. These data suggest that BCMA-Fc might be better suited than BAFF-R:Fc to inhibit the interactions between NLC and CLL B cells in vivo.
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