title: Fenretinide targets chronic myeloid leukemia stem/progenitor cells by regulation of redox signaling.
abstract: OBJECTIVE
  We have recently shown that fenretinide preferentially targets CD34(+) cells of acute myeloid leukemia (AML), and here, we test whether this agent exerts the effect on CD34(+) cells of chronic myeloid leukemia (CML), which are refractory to imatinib.
  
  
  RESULTS
  As tested by colony-forming cell assays using clinical specimens, both number and size of total colonies derived from CD34(+) CML cells were significantly reduced by fenretinide, and by combining fenretinide with imatinib. In particular, colonies derived from erythroid progenitors and more primitive pluripotent/multipotent progenitors were highly sensitive to fenretinide/fenretinide plus imatinib. Accordantly, fenretinide appeared to induce apoptosis in CD34(+) CML cells, particularly with regard to the cells in the subpopulation of CD34(+)CD38(-). Through cell quiescent assays, including Ki-67 negativity test, we added evidence that nonproliferative CD34(+) CML cells were largely eliminated by fenretinide. Transcriptome and molecular data further showed that mechanisms underlying the apoptosis in CD34(+) CML cells were highly complex, involving multiple events of oxidative stress responses.
  
  
  CONCLUSIONS
  As compared with CD34(+) AML cells, the apoptotic effects of fenretinide on CD34(+) CML cells were more prominent whereas less varied among the samples of different patients, and also various stress-responsive events appeared to be more robust in fenretinide-treated CD34(+) CML cells. Thus, the combination of fenretinide with imatinib may represent a more sophisticated strategy for CML treatment, in which imatinib mainly targets leukemic blast cells through the intrinsic pathway of apopotosis, whereas fenretinide primarily targets CML stem/progenitor cells through the oxidative/endoplasmic reticulum stress-mediated pathway.
authors.affiliation: 1 Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai Jiao Tong University School of Medicine (SJTU-SM) , Shanghai, China .
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Du
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xia
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Pan
authors.forename: Zi
authors.initials: Z
authors.lastname: Chen
authors.forename: Aihua
authors.initials: A
authors.lastname: Wang
authors.forename: Kankan
authors.initials: K
authors.lastname: Wang
authors.forename: Junmin
authors.initials: J
authors.lastname: Li
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
mesh_terms: D018952:Antigens, CD34 / Q000276:immunology; D001549:Benzamides / Q000494:pharmacology; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D018952:Antigens, CD34; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D017313:Fenretinide; D000068877:Imatinib Mesylate
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