The Growth Factor Fusion Construct Containing B-lymphocyte Stimulator (Blys) and the Toxin Rgel Induces Apoptosis Specifically in Baff-r-positive Cll Cells.
From: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Blood
- Publish Date: Mar 2007
- ISSN: 0006-4971
- Volume: 109
- Issue: 6
- Pages: 2557-64
- Medium: Print
- Language: English
- Citation (JAMA): Nimmanapalli Ramadevi, Lyu Mi-Ae, Du Min, et al. The Growth Factor Fusion Construct Containing B-lymphocyte Stimulator (Blys) and the Toxin Rgel Induces Apoptosis Specifically in Baff-r-positive Cll Cells.. Blood Mar 2007;109:2557-64
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.
Mesh Headings (Keywords): Antigens, CD19, Apoptosis, B-Cell Activating Factor, B-Cell Activation Factor Receptor, Cells, Cultured, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytes, Plant Proteins, RNA, Recombinant Fusion Proteins, Ribosome Inactivating Proteins, Type 1
Check for Full Text / PubMed Unique Identifier (PMID): 17119117
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