NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia
AbstractAberrant 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. View Full-Text
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Kakiuchi, S.; Minami, Y.; Miyata, Y.; Mizutani, Y.; Goto, H.; Kawamoto, S.; Yakushijin, K.; Kurata, K.; Matsuoka, H.; Minami, H. NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia. Int. J. Mol. Sci. 2017, 18, 486.
Kakiuchi S, Minami Y, Miyata Y, Mizutani Y, Goto H, Kawamoto S, Yakushijin K, Kurata K, Matsuoka H, Minami H. NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia. International Journal of Molecular Sciences. 2017; 18(3):486.Chicago/Turabian Style
Kakiuchi, Seiji; Minami, Yosuke; Miyata, Yoshiharu; Mizutani, Yu; Goto, Hideaki; Kawamoto, Shinichiro; Yakushijin, Kimikazu; Kurata, Keiji; Matsuoka, Hiroshi; Minami, Hironobu. 2017. "NANOG Expression as a Responsive Biomarker during Treatment with Hedgehog Signal Inhibitor in Acute Myeloid Leukemia." Int. J. Mol. Sci. 18, no. 3: 486.