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Int. J. Mol. Sci. 2017, 18(3), 486; doi:10.3390/ijms18030486

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

1
Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
2
Department of Transfusion Medicine and Cell Therapy, Kobe University Hospital, Kobe 650-0017, Japan
3
Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe 650-0017, Japan
*
Author to whom correspondence should be addressed.
Academic Editors: Hiroyuki Tomita, Masahito Shimizu and Takuji Tanaka
Received: 23 January 2017 / Revised: 14 February 2017 / Accepted: 21 February 2017 / Published: 24 February 2017
(This article belongs to the Special Issue Cancer Stem Cells)
View Full-Text   |   Download PDF [1683 KB, uploaded 24 February 2017]   |  

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. View Full-Text
Keywords: hedgehog inhibitor; NANOG; acute myeloid leukemia; self-renewal; biomarker hedgehog inhibitor; NANOG; acute myeloid leukemia; self-renewal; biomarker
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

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.

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