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

被引：17

作者：

Kakiuchi, Seiji ^{[1
]}

Minami, Yosuke ^{[2
]}

Miyata, Yoshiharu ^{[1
]}

Mizutani, Yu ^{[1
]}

Goto, Hideaki ^{[1
]}

Kawamoto, Shinichiro ^{[3
]}

Yakushijin, Kimikazu ^{[3
]}

Kurata, Keiji ^{[1
]}

Matsuoka, Hiroshi ^{[1
]}

Minami, Hironobu ^{[1
,3
]}

机构：

[1] Kobe Univ, Dept Med Oncol & Hematol, Grad Sch Med, Kobe, Hyogo 6500017, Japan

[2] Kobe Univ Hosp, Dept Transfus Med & Cell Therapy, Kobe, Hyogo 6500017, Japan

[3] Kobe Univ Hosp, Dept Med Oncol & Hematol, Kobe, Hyogo 6500017, Japan

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2017年 / 18卷 / 03期

关键词：

hedgehog inhibitor; NANOG; acute myeloid leukemia; self-renewal; biomarker; CANCER STEM-CELL; TARGETING HEDGEHOG; SELF-RENEWAL; PATHWAY;

D O I：

10.3390/ijms18030486

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：9

共 26 条

[21] The Hedgehog's tale: developing strategies for targeting cancer [J].