title: NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia.
abstract: Aberrant activation of the Hedgehog (Hh) signaling pathway is involved in the maintenance of leukemic stem cell (LSCs) populations. PF-0444913 (PF-913) is a novel inhibitor that selectively targets Smoothened (SMO), which regulates the Hh pathway. Treatment with PF-913 has shown promising results in an early phase study of acute myeloid leukemia (AML). However, a detailed mode of action for PF-913 and relevant biomarkers remain to be elucidated. In this study, we examined bone marrow samples derived from AML patients under PF-913 monotherapy. Gene set enrichment analysis (GSEA) revealed that PF-913 treatment affected the self-renewal signature and cell-cycle regulation associated with LSC-like properties. We then focused on the expression of a pluripotency factor, NANOG, because previous reports showed that a downstream effector in the Hh pathway, GLI, directly binds to the NANOG promoter and that the GLI-NANOG axis promotes stemness and growth in several cancers. In this study, we found that a change in NANOG transcripts was closely associated with GLI-target genes and NANOG transcripts can be a responsive biomarker during PF-913 therapy. Additionally, the treatment of AML with PF-913 holds promise, possibly through inducing quiescent leukemia stem cells toward cell cycling.
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. kakiuchi@med.kobe-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Kakiuchi
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kobe University Hospital, Kobe 650-0017, 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 Graduate School of Medicine, Kobe 650-0017, Japan. yhmiyata@med.kobe-u.ac.jp.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Miyata
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. mizuyu@med.kobe-u.ac.jp.
authors.forename: Yu
authors.initials: Y
authors.lastname: Mizutani
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. hgoto@med.kobe-u.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe 650-0017, Japan. skawamo@med.kobe-u.ac.jp.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Kawamoto
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe 650-0017, Japan. kyakushi@med.kobe-u.ac.jp.
authors.forename: Kimikazu
authors.initials: K
authors.lastname: Yakushijin
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. kkurata@med.kobe-u.ac.jp.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kurata
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. matsuoh@med.kobe-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuoka
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. hminami@med.kobe-u.ac.jp.|Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe 650-0017, Japan. hminami@med.kobe-u.ac.jp.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D000071317:Nanog Homeobox Protein / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D053823:Hedgehog Proteins; D000071317:Nanog Homeobox Protein; C491023:SMO protein, human; D000072086:Smoothened Receptor
keywords: NANOG; acute myeloid leukemia; biomarker; hedgehog inhibitor; self-renewal