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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2557-2564. Prepublished online as a Blood First Edition Paper on November 21, 2006; DOI 10.1182/blood-2006-08-042424. This Article Full Text (PDF) All Versions of this Article: blood-2006-08-042424v1 109/6/2557    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Nimmanapalli, R. Articles by Gandhi, V. Search for Related Content PubMed PubMed Citation Articles by Nimmanapalli, R. Articles by Gandhi, V. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 22, 2006 Accepted November 6, 2006 The growth factor fusion construct containing B-lymphocyte stimulator (BLyS) and the toxin rGel induces apoptosis specifically in BAFF-R positive CLL cells Ramadevi Nimmanapalli, Mi-Ae Lyu, Min Du, Michael J Keating, Michael Rosenblum, and Varsha Gandhi* Dept of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX Dept of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX * Corresponding author; email: vgandhi{at}mdanderson.org. 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 non-toxic 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+ve B-CLL lymphocytes and induces apoptosis at nanomolar concentrations. In contrast, rGel alone was not able to internalize in to these leukemic lymphocytes. Mechanistically, the rGel/BLyS construct inhibits protein synthesis with an IC50 of <3 nM compared to >5,000 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 two survival proteins in B-CLL. There was a strong relationship between a decrease in these proteins and the cleavage of PARP, a hall-mark feature of apoptosis. Taken together, these data suggest that the rGel/BLyS fusion toxin may have potential therapeutic efficacy for B-CLL patients. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. L. Martinez-Torrecuadrada, L. H. Cheung, P. Lopez-Serra, R. Barderas, M. Canamero, S. Ferreiro, M. G. Rosenblum, and J. I. Casal Antitumor activity of fibroblast growth factor receptor 3-specific immunotoxins in a xenograft mouse model of bladder carcinoma is mediated by apoptosis Mol. Cancer Ther., April 1, 2008; 7(4): 862 - 873. [Abstract] [Full Text] [PDF] M. C. Ryan, M. Hering, D. Peckham, C. F. McDonagh, L. Brown, K. M. Kim, D. L. Meyer, R. F. Zabinski, I. S. Grewal, and P. J. Carter Antibody targeting of B-cell maturation antigen on malignant plasma cells Mol. Cancer Ther., November 1, 2007; 6(11): 3009 - 3018. [Abstract] [Full Text] [PDF] A. Binard and P. Youinou BAFF, A newcomer to the lupus party Lupus, September 1, 2007; 16(9): 699 - 700. [PDF]

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