Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment: A potential new therapeutic target

Ganapati V. Hegde, Katie J. Peterson, Katy Emanuel, Amit K. Mittal, Avadhut D. Joshi, John D Dickinson, Gayathri J. Kollessery, Robert G Bociek, Philip Jay Bierman, Julie Marie Vose, Dennis D. Weisenburger, Shantaram S Joshi

Research output: Contribution to journalArticle

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Abstract

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by an accumulation of neoplastic B cells due to their resistance to apoptosis and increased survival. Among various factors, the tumor microenvironment is known to play a role in the regulation of cell proliferation and survival of many cancers. However, it remains unclear how the tumor microenvironment contributes to the increased survival of B-CLL cells. Therefore, we studied the influence of bone marrow stromal cell-induced hedgehog (Hh) signaling on the survival of B-CLL cells. Our results show that a Hh signaling inhibitor, cyclopamine, inhibits bone marrow stromal cell-induced survival of B-CLL cells, suggesting a role for Hh signaling in the survival of B-CLL cells. Furthermore, gene expression profiling of primary B-CLL cells (n = 48) indicates that the expression of Hh signaling molecules, such as GLI1, GLI2, SUFU, and BCL2, is significantly increased and correlates with disease progression of B-CLL patients with clinical outcome. In addition, SUFU and GLI1 transcripts, as determined by real-time PCR, are significantly overexpressed and correlate with adverse indicators of clinical outcome in B-CLL patients, such as cytogenetics or CD38 expression. Furthermore, selective downregulation of GLI1 by antisense oligodeoxynucleotides (GLI1-ASO) results in decreased BCL2 expression and cell survival, suggesting that GLI1 may regulate BCL2 and, thereby, modulate cell survival in B-CLL. In addition, there was significantly increased apoptosis of B-CLL cells when cultured in the presence of GLI1-ASO and fludarabine. Together, these results reveal that Hh signaling is important in the pathogenesis of B-CLL and, hence, may be a potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)1928-1936
Number of pages9
JournalMolecular Cancer Research
Volume6
Issue number12
DOIs
StatePublished - Dec 1 2008

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Cellular Microenvironment
B-Cell Chronic Lymphocytic Leukemia
Stromal Cells
Survival
Cell Survival
Therapeutics
Tumor Microenvironment
Oligodeoxyribonucleotides
Mesenchymal Stromal Cells
Apoptosis
Gene Expression Profiling
Cytogenetics
Disease Progression
Real-Time Polymerase Chain Reaction
Cultured Cells
B-Lymphocytes
Down-Regulation
Cell Proliferation

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment : A potential new therapeutic target. / Hegde, Ganapati V.; Peterson, Katie J.; Emanuel, Katy; Mittal, Amit K.; Joshi, Avadhut D.; Dickinson, John D; Kollessery, Gayathri J.; Bociek, Robert G; Bierman, Philip Jay; Vose, Julie Marie; Weisenburger, Dennis D.; Joshi, Shantaram S.

In: Molecular Cancer Research, Vol. 6, No. 12, 01.12.2008, p. 1928-1936.

Research output: Contribution to journalArticle

Hegde, Ganapati V. ; Peterson, Katie J. ; Emanuel, Katy ; Mittal, Amit K. ; Joshi, Avadhut D. ; Dickinson, John D ; Kollessery, Gayathri J. ; Bociek, Robert G ; Bierman, Philip Jay ; Vose, Julie Marie ; Weisenburger, Dennis D. ; Joshi, Shantaram S. / Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment : A potential new therapeutic target. In: Molecular Cancer Research. 2008 ; Vol. 6, No. 12. pp. 1928-1936.
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AU - Mittal, Amit K.

AU - Joshi, Avadhut D.

AU - Dickinson, John D

AU - Kollessery, Gayathri J.

AU - Bociek, Robert G

AU - Bierman, Philip Jay

AU - Vose, Julie Marie

AU - Weisenburger, Dennis D.

AU - Joshi, Shantaram S

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