TY - JOUR
T1 - Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway
AU - Lapalombella, Rosa
AU - Andritsos, Leslie
AU - Liu, Qing
AU - May, Sarah E.
AU - Browning, Rebekah
AU - Pham, Lan V.
AU - Blum, Kristie A.
AU - Blum, William
AU - Ramanunni, Asha
AU - Raymond, Chelsey A.
AU - Smith, Lisa L.
AU - Lehman, Amy
AU - Mo, Xiaokui
AU - Jarjoura, David
AU - Chen, Ching Shih
AU - Ford, Richard
AU - Rader, Christoph
AU - Muthusamy, Natarajan
AU - Johnson, Amy J.
AU - Byrd, John C.
PY - 2010/4/1
Y1 - 2010/4/1
N2 - Chronic lymphocytic leukemia (CLL) involves a profound humoral immune defect and tumor-specific humoral tolerance that directly contribute to disease morbidity and mortality. CD154 gene therapy can reverse this immune defect, but attempts to do this pharmacologically have been unsuccessful. The immune-modulatory agent lenalidomide shows clinical activity in CLL, but its mechanism is poorly understood. Here, we demonstrate that lenalidomide induces expression of functional CD154 antigen on CLL cells both in vitro and in vivo. This occurs via enhanced CD154 transcription mediated by a Nuclear Factor of Activated T cells c1 (NFATc1)/Nuclear Factor-κB (NF-κB) complex and also through phosphoinositide-3 (PI3)-kinase pathway-dependent stabilization of CD154 mRNA. Importantly, CD154-positive CLL cells upregulate BID, DR5, and p73, become sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis, and promote costimulatory activation of normal B cells to produce antibodies. In CLL patients receiving lenalidomide, similar evidence of CD154 activation is observed including BID, DR5, and p73 induction and also development of anti-ROR1 tumor-directed antibodies. Our data demonstrate that lenalidomide promotes CD154 expression on CLL cells with subsequent activation phenotype, and may therefore reverse the humoral immune defect observed in this disease. This study is registered at http://clinicaltrials. gov as NCT00466895.
AB - Chronic lymphocytic leukemia (CLL) involves a profound humoral immune defect and tumor-specific humoral tolerance that directly contribute to disease morbidity and mortality. CD154 gene therapy can reverse this immune defect, but attempts to do this pharmacologically have been unsuccessful. The immune-modulatory agent lenalidomide shows clinical activity in CLL, but its mechanism is poorly understood. Here, we demonstrate that lenalidomide induces expression of functional CD154 antigen on CLL cells both in vitro and in vivo. This occurs via enhanced CD154 transcription mediated by a Nuclear Factor of Activated T cells c1 (NFATc1)/Nuclear Factor-κB (NF-κB) complex and also through phosphoinositide-3 (PI3)-kinase pathway-dependent stabilization of CD154 mRNA. Importantly, CD154-positive CLL cells upregulate BID, DR5, and p73, become sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis, and promote costimulatory activation of normal B cells to produce antibodies. In CLL patients receiving lenalidomide, similar evidence of CD154 activation is observed including BID, DR5, and p73 induction and also development of anti-ROR1 tumor-directed antibodies. Our data demonstrate that lenalidomide promotes CD154 expression on CLL cells with subsequent activation phenotype, and may therefore reverse the humoral immune defect observed in this disease. This study is registered at http://clinicaltrials. gov as NCT00466895.
UR - http://www.scopus.com/inward/record.url?scp=77950966887&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-09-242438
DO - 10.1182/blood-2009-09-242438
M3 - Article
C2 - 19965642
AN - SCOPUS:77950966887
SN - 0006-4971
VL - 115
SP - 2619
EP - 2629
JO - Blood
JF - Blood
IS - 13
ER -