NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia

• Published in: International journal of molecular sciences Vol. 18; no. 3; p. 486
• Main Authors: Kakiuchi, Seiji, Minami, Yosuke, Miyata, Yoshiharu, Mizutani, Yu, Goto, Hideaki, Kawamoto, Shinichiro, Yakushijin, Kimikazu, Kurata, Keiji, Matsuoka, Hiroshi, Minami, Hironobu
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 01.03.2017; MDPI AG
• Subjects: acute myeloid leukemia; Antineoplastic Agents - pharmacology; biomarker; Biomarkers; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Tumor; Cell Self Renewal - drug effects; Cell Self Renewal - genetics; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; hedgehog inhibitor; Hedgehog Proteins - metabolism; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; NANOG; Nanog Homeobox Protein - genetics; Nanog Homeobox Protein - metabolism; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; self-renewal; Signal Transduction - drug effects; Smoothened Receptor - genetics; Smoothened Receptor - metabolism; hedgehog inhibitor; NANOG; acute myeloid leukemia; biomarker; self-renewal
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms18030486

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.