Journal
PLOS ONE
Volume 5, Issue 12, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0015262
Keywords
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Categories
Funding
- American Society of Clinical Oncology Foundation
- National Institutes of Health [T32HL086345, R01CA127574, P01CA15396]
- Gabrielle's Angel Foundation for Cancer Research
- Sidney Kimmel Foundation for Cancer Research
- Leukemia and Lymphoma Society
- NIH [HL75826, HL83077]
- St. Baldrick's Foundation
- William Lawrence and Blanche Hughes Foundation
- Abbott Laboratories
- Genentech, Inc.
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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.
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