title: Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926.
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.
authors.affiliation: Section of Hematology and Oncology, Department of Internal Medicine, LSU Health Sciences Center, New Orleans, Louisiana, United States of America.tlin@lsuhsc.edu
authors.forename: Tara L
authors.initials: TL
authors.lastname: Lin
authors.forename: Qiuju H
authors.initials: QH
authors.lastname: Wang
authors.forename: Patrick
authors.initials: P
authors.lastname: Brown
authors.forename: Craig
authors.initials: C
authors.lastname: Peacock
authors.forename: Akil A
authors.initials: AA
authors.lastname: Merchant
authors.forename: Sarah
authors.initials: S
authors.lastname: Brennan
authors.forename: Evan
authors.initials: E
authors.lastname: Jones
authors.forename: Karen
authors.initials: K
authors.lastname: McGovern
authors.forename: D Neil
authors.initials: DN
authors.lastname: Watkins
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Sakamoto
authors.forename: William
authors.initials: W
authors.lastname: Matsui
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D018941:Antigens, CD19 / Q000096:biosynthesis; D018952:Antigens, CD34 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids / Q000494:pharmacology*
chemical_list: D018941:Antigens, CD19; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C541444:IPI-926; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D000444:Aldehyde Dehydrogenase; C000541:cyclopamine