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Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926
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Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926
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Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926
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Journal Article
Self-Renewal of Acute Lymphocytic Leukemia Cells Is Limited by the Hedgehog Pathway Inhibitors Cyclopamine and IPI-926
2010
Overview
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.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
/ Aldehyde Dehydrogenase - metabolism
/ Animals
/ Antigens, CD19 - biosynthesis
/ Antigens, CD34 - biosynthesis
/ Antineoplastic Agents - pharmacology
/ Cancer
/ Embryos
/ Hedgehog Proteins - metabolism
/ Humans
/ Kinases
/ Leukemia
/ Ligands
/ Medicine
/ Mice
/ Mutation
/ Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy
/ Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism
