title: Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway.
abstract: 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-kappaB (NF-kappaB) complex and also through phosphoinositide-3 (PI3)-kinase pathway-dependent stabilization of CD154 mRNA. Importantly, CD154-positive CLL cells up-regulate 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.
authors: Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA.
authors: Rosa
authors: R
authors: Lapalombella
authors: Leslie
authors: L
authors: Andritsos
authors: Qing
authors: Q
authors: Liu
authors: Sarah E
authors: SE
authors: May
authors: Rebekah
authors: R
authors: Browning
authors: Lan V
authors: LV
authors: Pham
authors: Kristie A
authors: KA
authors: Blum
authors: William
authors: W
authors: Blum
authors: Asha
authors: A
authors: Ramanunni
authors: Chelsey A
authors: CA
authors: Raymond
authors: Lisa L
authors: LL
authors: Smith
authors: Amy
authors: A
authors: Lehman
authors: Xiaokui
authors: X
authors: Mo
authors: David
authors: D
authors: Jarjoura
authors: Ching-Shih
authors: CS
authors: Chen
authors: Richard
authors: R
authors: Ford
authors: Christoph
authors: C
authors: Rader
authors: Natarajan
authors: N
authors: Muthusamy
authors: Amy J
authors: AJ
authors: Johnson
authors: John C
authors: JC
authors: Byrd
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000096:biosynthesis / Q000235:genetics; D023201:CD40 Ligand / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D016130:Immunophenotyping; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; D023201:CD40 Ligand; D004268:DNA-Binding Proteins; D000077269:Lenalidomide; D050778:NFATC Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D013792:Thalidomide; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; C494814:BID protein, human; C494003:NFATC1 protein, human; C000606460:TP73 protein, human