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PLoS One. 2010 Dec 28;5(12):e15262. doi: 10.1371/journal.pone.0015262.

Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926.

Author information

1
Section of Hematology and Oncology, Department of Internal Medicine, LSU Health Sciences Center, New Orleans, Louisiana, United States of America.tlin@lsuhsc.edu

Abstract

Conserved embryonic signaling pathways such as Hedgehog (Hh), Wingless and Notch have been implicated in the pathogenesis of several malignancies. Recent data suggests that Hh signaling plays a role in normal B-cell development, and we hypothesized that Hh signaling may be important in precursor B-cell acute lymphocytic leukemia (B-ALL). We found that the expression of Hh pathway components was common in human B-ALL cell lines and clinical samples. Moreover, pathway activity could be modulated by Hh ligand or several pathway inhibitors including cyclopamine and the novel SMOOTHENED (SMO) inhibitor IPI-926. The inhibition of pathway activity primarily impacted highly clonogenic B-ALL cells expressing aldehyde dehydrogenase (ALDH) by limiting their self-renewal potential both in vitro and in vivo. These data demonstrate that Hh pathway activation is common in B-ALL and represents a novel therapeutic target regulating self-renewal and persistence of the malignant clone.

PMID:
21203400
PMCID:
PMC3011010
DOI:
10.1371/journal.pone.0015262
[Indexed for MEDLINE]
Free PMC Article
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