B lymphocyte stimulator (BLyS) is a member of the TNF superfamily of cytokines. BLyS is expressed by cells of myeloid origin and is one of many soluble factors that regulate human B-cell activation. The biological activity of BLyS is mediated by three cell surface receptors: B-cell-activating factor-receptor (BAFF-R/BR3), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA). These receptors are expressed by normal and malignant B-cells at various stages of development. To target malignant B cells expressing BLyS receptors, the recombinant plant-derived toxin gelonin was fused to the N-terminus of BLyS to generate the fusion toxin BLyS-gel. Gelonin is an N-glycosidase that removes a critical adenine from eukaryotic 28S rRNA, disrupting ribosome function and inhibiting protein synthesis. Importantly, gelonin is not toxic to cells unless coupled with a targeting moiety that can enter the cell. BLyS-gel was used to treat a panel of nearly 50 malignant non-Hodgkin lymphoma (NHL) cell lines expressing BLyS receptors. NHL subtypes mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and B cell precursor-acute lymphocytic leukemia (BCP-ALL) were preferentially sensitive to BLyS-gel mediated cytotoxicity, with EC50 values in the low picomolar range. BLyS-gel cytotoxicity was mediated primarily by BR3 and TACI in sensitive cell lines; however, cell surface expression of these BLyS receptors did not necessarily confer sensitivity to BLyS-gel. The internalization of BLyS-gel was confirmed in both sensitive and resistant cell lines, indicating resistance was not due to a lack of internalization. As expected, BLyS-gel treatment inhibited protein synthesis in sensitive, but not resistant cell lines. In most cell lines, cell death seemed to be mediated by the “ribotoxic stress response.” This response involves activation of p38 MAPK and JNK/SAPK, and BLyS-gel mediated cytotoxicity was inhibited by the p38/JNK inhibitor SB203580. Finally, BLyS-gel treatment significantly prolonged survival in three distinct disseminated xenograft models (BCP-ALL, DLBCL & MCL) in SCID mice, and BLyS-gel was shown to specifically localize to sites of disease. Together, these findings suggest BLyS has potential as a targeting ligand for the therapeutic delivery of toxins and/or drugs directly to malignant B cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3861. doi:1538-7445.AM2012-3861