title: Preferential eradication of acute myelogenous leukemia stem cells by fenretinide.
abstract: Leukemia stem cells (LSCs) play important roles in leukemia initiation, progression, and relapse, and thus represent a critical target for therapeutic intervention. However, relatively few agents have been shown to target LSCs, slowing progress in the treatment of acute myelogenous leukemia (AML). Based on in vitro and in vivo evidence, we report here that fenretinide, a well-tolerated vitamin A derivative, is capable of eradicating LSCs but not normal hematopoietic progenitor/stem cells at physiologically achievable concentrations. Fenretinide exerted a selective cytotoxic effect on primary AML CD34(+) cells, especially the LSC-enriched CD34(+)CD38(-) subpopulation, whereas no significant effect was observed on normal counterparts. Methylcellulose colony formation assays further showed that fenretinide significantly suppressed the formation of colonies derived from AML CD34(+) cells but not those from normal CD34(+) cells. Moreover, fenretinide significantly reduced the in vivo engraftment of AML stem cells but not normal hematopoietic stem cells in a nonobese diabetic/SCID mouse xenotransplantation model. Mechanistic studies revealed that fenretinide-induced cell death was linked to a series of characteristic events, including the rapid generation of reactive oxygen species, induction of genes associated with stress responses and apoptosis, and repression of genes involved in NF-κB and Wnt signaling. Further bioinformatic analysis revealed that the fenretinide-down-regulated genes were significantly correlated with the existing poor-prognosis signatures in AML patients. Based on these findings, we propose that fenretinide is a potent agent that selectively targets LSCs, and may be of value in the treatment of AML.
authors.affiliation: State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Mi
authors.forename: Hai
authors.initials: H
authors.lastname: Fang
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.forename: Chun
authors.initials: C
authors.lastname: Wang
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Minden
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Yang
authors.forename: Huan-Wei
authors.initials: HW
authors.lastname: Wang
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Li
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Xi
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Kan-Kan
authors.initials: KK
authors.lastname: Wang
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D003114:Colony-Forming Units Assay; D019295:Computational Biology; D017313:Fenretinide / Q000494:pharmacology* / Q000627:therapeutic use; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D046228:Microarray Analysis; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018952:Antigens, CD34; D017382:Reactive Oxygen Species; D017313:Fenretinide