Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-cell lymphoma cell lines to CD40-mediated cell death.

C Annette Hollmann, Trevor Owens, Josephine Nalbantoglu, Thomas J Hudson, Robert Sladek

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant B lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models. Although this makes CD40 an attractive target for antitumor therapies, the response of malignant B cells to CD40 signaling is variable, and CD40 stimulation can enhance proliferation and can increase chemoresistance in some cell lines. It would therefore be useful to identify markers that predict whether a specific cell line or tumor will undergo apoptosis when stimulated with CD40 and to identify targets downstream of CD40 that affect only the apoptotic arm of CD40 signaling. We have analyzed gene expression patterns in CD40-sensitive and CD40-resistant diffuse large B-cell lymphoma (DLBCL) cell lines to identify signaling pathways that are involved in CD40-mediated apoptosis. CD40-resistant lines expressed pre-B-cell markers, including RAG and VPREB, whereas CD40-sensitive cells resembled mature B cells and expressed higher levels of transcripts encoding several members of the CD40 signaling pathway, including LCK and VAV. In addition, CD40-sensitive DLBCL cell lines also displayed constitutive activation of extracellular signal-regulated kinase (ERK) and failed to undergo apoptosis when ERK phosphorylation was inhibited. In contrast, CD40-resistant lines showed no constitutive activation of ERK and no increase in ERK activity in response to CD40 stimulation. Our results suggest that constitutive activation of ERK may be required for death signaling by CD40.
Original languageEnglish
JournalCancer Research
Volume66
Issue number7
Pages (from-to)3550-7
Number of pages7
ISSN0008-5472
DOIs
Publication statusPublished - 1. Apr 2006

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Lymphoma, Large B-Cell, Diffuse
Cell Death
Cell Line
Apoptosis
CD40 Ligand
Tumor Cell Line
Heterografts
Lymphoma
Neoplasms

Keywords

  • Antigens, CD40
  • Apoptosis
  • Cell Line, Tumor
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases
  • Gene Expression Profiling
  • Humans
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Lymphoma, B-Cell
  • Lymphoma, Non-Hodgkin
  • MAP Kinase Signaling System
  • Phosphorylation
  • Proto-Oncogene Proteins c-vav

Cite this

Hollmann, C Annette ; Owens, Trevor ; Nalbantoglu, Josephine ; Hudson, Thomas J ; Sladek, Robert. / Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-cell lymphoma cell lines to CD40-mediated cell death. In: Cancer Research. 2006 ; Vol. 66, No. 7. pp. 3550-7.
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abstract = "CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant B lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models. Although this makes CD40 an attractive target for antitumor therapies, the response of malignant B cells to CD40 signaling is variable, and CD40 stimulation can enhance proliferation and can increase chemoresistance in some cell lines. It would therefore be useful to identify markers that predict whether a specific cell line or tumor will undergo apoptosis when stimulated with CD40 and to identify targets downstream of CD40 that affect only the apoptotic arm of CD40 signaling. We have analyzed gene expression patterns in CD40-sensitive and CD40-resistant diffuse large B-cell lymphoma (DLBCL) cell lines to identify signaling pathways that are involved in CD40-mediated apoptosis. CD40-resistant lines expressed pre-B-cell markers, including RAG and VPREB, whereas CD40-sensitive cells resembled mature B cells and expressed higher levels of transcripts encoding several members of the CD40 signaling pathway, including LCK and VAV. In addition, CD40-sensitive DLBCL cell lines also displayed constitutive activation of extracellular signal-regulated kinase (ERK) and failed to undergo apoptosis when ERK phosphorylation was inhibited. In contrast, CD40-resistant lines showed no constitutive activation of ERK and no increase in ERK activity in response to CD40 stimulation. Our results suggest that constitutive activation of ERK may be required for death signaling by CD40.",
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Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-cell lymphoma cell lines to CD40-mediated cell death. / Hollmann, C Annette; Owens, Trevor; Nalbantoglu, Josephine; Hudson, Thomas J; Sladek, Robert.

In: Cancer Research, Vol. 66, No. 7, 01.04.2006, p. 3550-7.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-cell lymphoma cell lines to CD40-mediated cell death.

AU - Hollmann, C Annette

AU - Owens, Trevor

AU - Nalbantoglu, Josephine

AU - Hudson, Thomas J

AU - Sladek, Robert

PY - 2006/4/1

Y1 - 2006/4/1

N2 - CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant B lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models. Although this makes CD40 an attractive target for antitumor therapies, the response of malignant B cells to CD40 signaling is variable, and CD40 stimulation can enhance proliferation and can increase chemoresistance in some cell lines. It would therefore be useful to identify markers that predict whether a specific cell line or tumor will undergo apoptosis when stimulated with CD40 and to identify targets downstream of CD40 that affect only the apoptotic arm of CD40 signaling. We have analyzed gene expression patterns in CD40-sensitive and CD40-resistant diffuse large B-cell lymphoma (DLBCL) cell lines to identify signaling pathways that are involved in CD40-mediated apoptosis. CD40-resistant lines expressed pre-B-cell markers, including RAG and VPREB, whereas CD40-sensitive cells resembled mature B cells and expressed higher levels of transcripts encoding several members of the CD40 signaling pathway, including LCK and VAV. In addition, CD40-sensitive DLBCL cell lines also displayed constitutive activation of extracellular signal-regulated kinase (ERK) and failed to undergo apoptosis when ERK phosphorylation was inhibited. In contrast, CD40-resistant lines showed no constitutive activation of ERK and no increase in ERK activity in response to CD40 stimulation. Our results suggest that constitutive activation of ERK may be required for death signaling by CD40.

AB - CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant B lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models. Although this makes CD40 an attractive target for antitumor therapies, the response of malignant B cells to CD40 signaling is variable, and CD40 stimulation can enhance proliferation and can increase chemoresistance in some cell lines. It would therefore be useful to identify markers that predict whether a specific cell line or tumor will undergo apoptosis when stimulated with CD40 and to identify targets downstream of CD40 that affect only the apoptotic arm of CD40 signaling. We have analyzed gene expression patterns in CD40-sensitive and CD40-resistant diffuse large B-cell lymphoma (DLBCL) cell lines to identify signaling pathways that are involved in CD40-mediated apoptosis. CD40-resistant lines expressed pre-B-cell markers, including RAG and VPREB, whereas CD40-sensitive cells resembled mature B cells and expressed higher levels of transcripts encoding several members of the CD40 signaling pathway, including LCK and VAV. In addition, CD40-sensitive DLBCL cell lines also displayed constitutive activation of extracellular signal-regulated kinase (ERK) and failed to undergo apoptosis when ERK phosphorylation was inhibited. In contrast, CD40-resistant lines showed no constitutive activation of ERK and no increase in ERK activity in response to CD40 stimulation. Our results suggest that constitutive activation of ERK may be required for death signaling by CD40.

KW - Antigens, CD40

KW - Apoptosis

KW - Cell Line, Tumor

KW - Enzyme Activation

KW - Extracellular Signal-Regulated MAP Kinases

KW - Gene Expression Profiling

KW - Humans

KW - Lymphocyte Specific Protein Tyrosine Kinase p56(lck)

KW - Lymphoma, B-Cell

KW - Lymphoma, Non-Hodgkin

KW - MAP Kinase Signaling System

KW - Phosphorylation

KW - Proto-Oncogene Proteins c-vav

U2 - 10.1158/0008-5472.CAN-05-2498

DO - 10.1158/0008-5472.CAN-05-2498

M3 - Journal article

C2 - 16585179

VL - 66

SP - 3550

EP - 3557

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 7

ER -