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.
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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)
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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
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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
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