title: Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells.
abstract: Aberrant activation of the Hedgehog signaling pathway has been implicated in the maintenance of leukemia stem cell populations in several model systems. PF-04449913 (PF-913) is a selective, small-molecule inhibitor of Smoothened, a membrane protein that regulates the Hedgehog pathway. However, details of the proof-of-concept and mechanism of action of PF-913 following administration to patients with acute myeloid leukemia (AML) are unclear. This study examined the role of the Hedgehog signaling pathway in AML cells, and evaluated the in vitro and in vivo effects of the Smoothened inhibitor PF-913. In primary AML cells, activation of the Hedgehog signaling pathway was more pronounced in CD34+cells than CD34-cells. In vitro treatment with PF-913 induced a decrease in the quiescent cell population accompanied by minimal cell death. In vivo treatment with PF-913 attenuated the leukemia-initiation potential of AML cells in a serial transplantation mouse model, while limiting reduction of tumor burden in a primary xenotransplant system. Comprehensive gene set enrichment analysis revealed that PF-913 modulated self-renewal signatures and cell cycle progression. Furthermore, PF-913 sensitized AML cells to cytosine arabinoside, and abrogated resistance to cytosine arabinoside in AML cells cocultured with HS-5 stromal cells. These findings imply that pharmacologic inhibition of Hedgehog signaling attenuates the leukemia-initiation potential, and also enhanced AML therapy by sensitizing dormant leukemia stem cells to chemotherapy and overcoming resistance in the bone marrow microenvironment.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Fukushima
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kobe University Hospital, Kobe, Japan. minamiy@med.kobe-u.ac.jp.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Minami
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kakiuchi
authors.affiliation: Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Yachiyo
authors.initials: Y
authors.lastname: Kuwatsuka
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Hayakawa
authors.affiliation: Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Catoriona
authors.initials: C
authors.lastname: Jamieson
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
authors.affiliation: National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism*; D003561:Cytarabine / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D053823:Hedgehog Proteins; D003561:Cytarabine
keywords: Acute myeloid leukemia; Hedgehog; Smoothened; leukemia stem cells; self-renewal