The rGel/BLyS fusion toxin inhibits diffuse large B-cell lymphoma growth in vitro and in vivo

Neoplasia. 2010 May;12(5):366-75. doi: 10.1593/neo.91960.


Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL) and accounts for 30%to 40%of NHL. Molecules targeting nuclear factor-kappaB (NF-kappaB) are expected to be of therapeutic value in those tumors where NF-kappaB seems to play a unique survival role such as activated B-cell (ABC)-subtype DLBCL. We previously generated a rGel/BLyS fusion toxin for receptor-mediated delivery of the rGel toxin specifically to malignant B cells. In this study, we examined this fusion toxin for its ability to suppress DLBCL growth in vitro and in vivo. rGel/BLyS was specifically cytotoxic to DLBCL lines expressing all three BLyS receptors and constitutively active NF-kappaB. Treatment with rGel/BLyS induced down-regulation of the phosphorylation of inhibitory subunit of NF-kappaB (IkappaB-alpha), inhibition of NF-kappaB DNA-binding activity, and accumulation of IkappaB-alpha. In agreement with these results, we additionally found that rGel/BLyS downregulated levels of several NF-kappaB targets including Bcl-xL, Mcl-1, survivin, and x-chromosome linked inhibitor-of-apoptosis. Treatment also induced up-regulation of Bax and apoptosis through caspase-3 activation and poly ADP-ribose polymerase cleavage. Importantly, rGel/BLyS significantly inhibited tumor growth (P < .05) in a DLBCL xenograft model. Thus, our results indicate that rGel/BLyS is an excellent candidate for the treatment of aggressive NHLs that are both dependent on NF-kappaB and are resistant to conventional chemotherapeutic regimens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Apoptosis / drug effects
  • B-Cell Activating Factor / administration & dosage*
  • B-Cell Activating Factor / genetics
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Separation
  • Drug Delivery Systems / methods*
  • Electrophoretic Mobility Shift Assay
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • I-kappa B Proteins / drug effects
  • I-kappa B Proteins / metabolism
  • In Situ Nick-End Labeling
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Male
  • Mice
  • Mice, SCID
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Recombinant Fusion Proteins / administration & dosage*
  • Recombinant Fusion Proteins / genetics
  • Ribosome Inactivating Proteins, Type 1 / administration & dosage
  • Ribosome Inactivating Proteins, Type 1 / genetics
  • Toxins, Biological / administration & dosage*
  • Toxins, Biological / genetics
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • B-Cell Activating Factor
  • I kappa B beta protein
  • I-kappa B Proteins
  • NF-kappa B
  • Recombinant Fusion Proteins
  • Ribosome Inactivating Proteins, Type 1
  • Toxins, Biological
  • GEL protein, Gelonium multiflorum