AUTHOR=Xu Dan-dan , Wang Ying , Zhou Peng-jun , Qin Shu-rong , Zhang Rong , Zhang Yi , Xue Xue , Wang Jianping , Wang Xia , Chen Hong-ce , Wang Xiao , Pan Yu-wei , Zhang Li , Yan Hai-zhao , Liu Qiu-ying , Liu Zhong , Chen Su-hong , Chen Hong-yuan , Wang Yi-fei TITLE=The IGF2/IGF1R/Nanog Signaling Pathway Regulates the Proliferation of Acute Myeloid Leukemia Stem Cells JOURNAL=Frontiers in Pharmacology VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00687 DOI=10.3389/fphar.2018.00687 ISSN=1663-9812 ABSTRACT=

Acute myeloid leukemia is an aggressive disease characterized by clonal proliferation and differentiation into immature hematopoietic cells of dysfunctional myeloid precursors. Accumulating evidence shows that CD34+CD38- leukemia stem cells (LSCs) are responsible for drug resistance, metastasis, and relapse of leukemia. In this study, we found that Nanog, a transcription factor in stem cells, is significantly overexpressed in CD34+ populations from patients with acute myeloid leukemia and in LSCs from leukemia cell lines. Our data demonstrate that the knockdown of Nanog inhibited proliferation and induced cell cycle arrest and cell apoptosis. Moreover, Nanog silencing suppressed the leukemogenesis of LSCs in mice. In addition, we found that these functions of Nanog were regulated by the insulin-like growth factor receptor (IGF1R) signaling pathway. Nanog overexpression rescued the colony formation ability of LSCs treated with picropodophyllin (PPP), an IGF1R inhibitor. By contrast, knockdown of Nanog abolished the effects of IGF2 on the colony formation ability of these LSCs. These findings suggest that the IGF2/IGF1R/Nanog signaling pathway plays a critical role in LSC proliferation.