Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway

Rosa Lapalombella, Leslie Andritsos, Qing Liu, Sarah E. May, Rebekah Browning, Lan V. Pham, Kristie A. Blum, William Blum, Asha Ramanunni, Chelsey A. Raymond, Lisa L. Smith, Amy Lehman, Xiaokui Mo, David Jarjoura, Ching Shih Chen, Richard Ford, Christoph Rader, Natarajan Muthusamy, Amy J. Johnson, John C. Byrd

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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-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.

Original languageEnglish (US)
Pages (from-to)2619-2629
Number of pages11
JournalBlood
Volume115
Issue number13
DOIs
StatePublished - Apr 1 2010

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1-Phosphatidylinositol 4-Kinase
B-Cell Chronic Lymphocytic Leukemia
Phosphatidylinositols
Antibody Formation
B-Lymphocytes
Phosphotransferases
Cells
Antibodies
Chemical activation
Defects
Tumors
Apoptosis
NFATC Transcription Factors
Gene therapy
CD40 Ligand
Transcription
Therapeutics
Neoplasm Antibodies
Stabilization
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway. / Lapalombella, Rosa; Andritsos, Leslie; Liu, Qing; May, Sarah E.; Browning, Rebekah; Pham, Lan V.; Blum, Kristie A.; Blum, William; Ramanunni, Asha; Raymond, Chelsey A.; Smith, Lisa L.; Lehman, Amy; Mo, Xiaokui; Jarjoura, David; Chen, Ching Shih; Ford, Richard; Rader, Christoph; Muthusamy, Natarajan; Johnson, Amy J.; Byrd, John C.

In: Blood, Vol. 115, No. 13, 01.04.2010, p. 2619-2629.

Research output: Contribution to journalArticle

Lapalombella, R, Andritsos, L, Liu, Q, May, SE, Browning, R, Pham, LV, Blum, KA, Blum, W, Ramanunni, A, Raymond, CA, Smith, LL, Lehman, A, Mo, X, Jarjoura, D, Chen, CS, Ford, R, Rader, C, Muthusamy, N, Johnson, AJ & Byrd, JC 2010, 'Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway', Blood, vol. 115, no. 13, pp. 2619-2629. https://doi.org/10.1182/blood-2009-09-242438
Lapalombella, Rosa ; Andritsos, Leslie ; Liu, Qing ; May, Sarah E. ; Browning, Rebekah ; Pham, Lan V. ; Blum, Kristie A. ; Blum, William ; Ramanunni, Asha ; Raymond, Chelsey A. ; Smith, Lisa L. ; Lehman, Amy ; Mo, Xiaokui ; Jarjoura, David ; Chen, Ching Shih ; Ford, Richard ; Rader, Christoph ; Muthusamy, Natarajan ; Johnson, Amy J. ; Byrd, John C. / Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B cells through a PI3-kinase-dependent pathway. In: Blood. 2010 ; Vol. 115, No. 13. pp. 2619-2629.
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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-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.",
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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.

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