The growth factor fusion construct containing B-lymphocyte stimulator (BLyS) and the toxin rGel induces apoptosis specifically in BAFF-R-positive CLL cells.

Abstract

The cytokine B lymphocyte stimulator (BLyS) mediates its effect through cell-surface receptors BAFF-R, TACI, and BCMA. BLyS receptors are expressed only on B cells and not present in other normal cells including normal T lymphocytes. Chronic lymphocytic leukemia (CLL) is a B-cell disease and CLL lymphocytes express BLyS receptors. Gelonin, a type 1 ribosome-inactivating toxin, lacks cell membrane binding domain and hence is nontoxic to intact cells. We generated a construct of recombinant gelonin (rGel) fused to BLyS to specifically target quiescent B-CLL lymphocytes. The construct rGel/BLyS specifically binds and internalizes through BAFF-R into CD19(+) B-CLL lymphocytes and induces apoptosis at nanomolar concentrations. In contrast, rGel alone was not able to internalize into these leukemic lymphocytes. Mechanistically, the rGel/BLyS construct inhibits protein synthesis with an IC(50) of less than 3 nM compared with more than 5000 nM for rGel toxin alone. This rGel/BLyS-mediated decrease in protein synthesis was associated with a decline in short-lived proteins such as MCL-1 and XIAP, the 2 survival proteins in B-CLL. There was a strong relationship between a decrease in these proteins and the cleavage of PARP, a hallmark feature of apoptosis. Taken together, these data suggest that the rGel/BLyS fusion toxin may have potential therapeutic efficacy for B-CLL patients.

• Authors: Ramadevi Nimmanapalli, Mi-Ae Lyu, Min Du, Michael J Keating, Michael G Rosenblum, Varsha Gandhi
• Journal: Blood (Blood) Vol. 109 Issue 6 Pg. 2557-64 (Mar 15 2007) ISSN: 0006-4971 [Print] United States
• PMID: 17119117 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD19
• B-Cell Activating Factor
• B-Cell Activation Factor Receptor
• Plant Proteins
• Recombinant Fusion Proteins
• Ribosome Inactivating Proteins, Type 1
• RNA
• GEL protein, Gelonium multiflorum

Topics

• Antigens, CD19 (genetics, metabolism)
• Apoptosis (drug effects)
• B-Cell Activating Factor (genetics, metabolism, pharmacology)
• B-Cell Activation Factor Receptor (genetics, metabolism)
• Cells, Cultured
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, metabolism, pathology)
• Lymphocytes (drug effects, metabolism)
• Plant Proteins (genetics, metabolism, pharmacology)
• RNA (biosynthesis)
• Recombinant Fusion Proteins (genetics, metabolism, pharmacology)
• Ribosome Inactivating Proteins, Type 1