title: Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(-) fraction.
abstract: Leukemia-initiating cells (LICs) in acute myeloid leukemia (AML) are believed to be restricted to the CD34(+) fraction. However, one of the most frequently mutated genes in AML is nucleophosmin (NPM), and this is associated with low CD34 expression. We, therefore, investigated whether NPM-mutated AMLs have LICs restricted to the CD34(+) fraction. We transplanted sorted fractions of primary NPM-mutated AML into immunodeficient mice to establish which fractions initiate leukemia. Approximately one-half of cases had LICs exclusively within the CD34(-) fraction, whereas the CD34(+) fraction contained normal multilineage hematopoietic repopulating cells. Most of the remaining cases had LICs in both CD34(+) and CD34(-) fractions. When samples were sorted based on CD34 and CD38 expression, multiple fractions initiated leukemia in primary and secondary recipients. The data indicate that the phenotype of LICs is more heterogeneous than previously realized and can vary even within a single sample. This feature of LICs may make them particularly difficult to eradicate using therapies targeted against surface antigens.
authors.affiliation: Cancer Research UK Medical Oncology Unit, St Bartholomew's Hospital, Queen Mary University of London, London. d.taussig@qmul.ac.uk
authors.forename: David C
authors.initials: DC
authors.lastname: Taussig
authors.forename: Jacques
authors.initials: J
authors.lastname: Vargaftig
authors.forename: Farideh
authors.initials: F
authors.lastname: Miraki-Moud
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Griessinger
authors.forename: Kirsty
authors.initials: K
authors.lastname: Sharrock
authors.forename: Tina
authors.initials: T
authors.lastname: Luke
authors.forename: Debra
authors.initials: D
authors.lastname: Lillington
authors.forename: Heather
authors.initials: H
authors.lastname: Oakervee
authors.forename: Jamie
authors.initials: J
authors.lastname: Cavenagh
authors.forename: Samir G
authors.initials: SG
authors.lastname: Agrawal
authors.forename: T Andrew
authors.initials: TA
authors.lastname: Lister
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D002469:Cell Separation / Q000379:methods; D015672:Erythroid Precursor Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D050505:Mutant Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D010641:Phenotype; D023041:Xenograft Model Antitumor Assays
chemical_list: D018952:Antigens, CD34; D050505:Mutant Proteins; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D051997:ADP-ribosyl Cyclase 1