TY - JOUR
T1 - Dichotomy in NF-kappaB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering
AU - Tromp, J. M.
AU - Tonino, S. H.
AU - Elias, J. A.
AU - Jaspers, A.
AU - Luijks, D. M.
AU - Kater, A. P.
AU - van Lier, R. A. W.
AU - van Oers, M. H. J.
AU - Eldering, E.
PY - 2010
Y1 - 2010
N2 - Chronic lymphocytic leukemia (CLL) cells circulating in peripheral blood (PB) differ from the leukemic fraction in lymph nodes (LNs) with respect to cell division and drug sensitivity. CD40 stimulation of PB CLL cells in vitro results in chemoresistance and provides a partial model for the LN microenvironment. The TLR9 ligand CpG induces proliferation in immunoglobulin variable heavy-chain-unmutated CLL, but apoptosis in immunoglobulin variable heavy-chain-mutated CLL. To juxtapose proliferative with antiapoptotic signals, we investigated the effects of CpG in the context of CD40 ligation in mutated versus unmutated CLL cells in this study. Prolonged CD40 ligation induced classical, followed by alternative nuclear factor-kappaB (NF-kappaB), activity in both subgroups, correlating with enhanced Bfl-1 and Bcl-X(L) levels, respectively. A dichotomy in NF-kappaB signaling occurred on combined CD40/TLR9 triggering. This induced declining p52 and Bcl-X(L) levels, and reversed chemoresistance only in mutated cells, whereas unmutated cells proliferated, maintained p52 and Bcl-X(L) and remained chemoresistant. The pivotal contribution of Bcl-X(L) to chemoresistance was shown by the BH3 mimetic ABT-737 and RNA interference. Finally, in ex vivo LN samples, p52, p65 and Bcl-X(L) levels were highly expressed, corroborating the in vitro findings. Thus, a distinction in NF-kappaB activation and drug susceptibility in mutated versus unmutated (LN-like) CLL cells was uncovered, which was causally linked to Bcl-X(L) levels
AB - Chronic lymphocytic leukemia (CLL) cells circulating in peripheral blood (PB) differ from the leukemic fraction in lymph nodes (LNs) with respect to cell division and drug sensitivity. CD40 stimulation of PB CLL cells in vitro results in chemoresistance and provides a partial model for the LN microenvironment. The TLR9 ligand CpG induces proliferation in immunoglobulin variable heavy-chain-unmutated CLL, but apoptosis in immunoglobulin variable heavy-chain-mutated CLL. To juxtapose proliferative with antiapoptotic signals, we investigated the effects of CpG in the context of CD40 ligation in mutated versus unmutated CLL cells in this study. Prolonged CD40 ligation induced classical, followed by alternative nuclear factor-kappaB (NF-kappaB), activity in both subgroups, correlating with enhanced Bfl-1 and Bcl-X(L) levels, respectively. A dichotomy in NF-kappaB signaling occurred on combined CD40/TLR9 triggering. This induced declining p52 and Bcl-X(L) levels, and reversed chemoresistance only in mutated cells, whereas unmutated cells proliferated, maintained p52 and Bcl-X(L) and remained chemoresistant. The pivotal contribution of Bcl-X(L) to chemoresistance was shown by the BH3 mimetic ABT-737 and RNA interference. Finally, in ex vivo LN samples, p52, p65 and Bcl-X(L) levels were highly expressed, corroborating the in vitro findings. Thus, a distinction in NF-kappaB activation and drug susceptibility in mutated versus unmutated (LN-like) CLL cells was uncovered, which was causally linked to Bcl-X(L) levels
U2 - https://doi.org/10.1038/onc.2010.248
DO - https://doi.org/10.1038/onc.2010.248
M3 - Article
C2 - 20581863
SN - 0950-9232
VL - 29
SP - 5071
EP - 5082
JO - Oncogene
JF - Oncogene
IS - 36
ER -