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

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 ex-press 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 quies-cent B-CLL lymphocytes. The construct rGel/BLyS specifically binds and internal-izes 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. Mechanisti-cally, the rGel/BLyS construct inhibits pro-tein synthesis with an IC50 of less than 3 nM compared with more than 5000 nM for rGel toxin alone. This rGel/BLyS-medi-ated 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 po-tential therapeutic efficacy for B-CLL pa-tients. (Blood. 2007;109:2557-2564) © 2007 by The American Society of Hematolog