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 Bierman, Julie M. Vose, Dennis D. Weisenburger, Shantaram S. Joshi

Research output: Contribution to journalArticle

88 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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