title: Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein.
abstract: Chronic myeloid leukemia (CML) is genetically characterized by the Philadelphia (Ph) chromosome, formed through a reciprocal translocation between chromosomes 9 and 22 and giving rise to the constitutively active tyrosine kinase P210 BCR/ABL1. Therapeutic strategies aiming for a cure of CML will require full eradication of Ph chromosome-positive (Ph(+)) CML stem cells. Here we used gene-expression profiling to identify IL-1 receptor accessory protein (IL1RAP) as up-regulated in CML CD34(+) cells and also in cord blood CD34(+) cells as a consequence of retroviral BCR/ABL1 expression. To test whether IL1RAP expression distinguishes normal (Ph(-)) and leukemic (Ph(+)) cells within the CML CD34(+)CD38(-) cell compartment, we established a unique protocol for conducting FISH on small numbers of sorted cells. By using this method, we sorted cells directly into drops on slides to investigate their Ph-chromosome status. Interestingly, we found that the CML CD34(+)CD38(-)IL1RAP(+) cells were Ph(+), whereas CML CD34(+)CD38(-)IL1RAP(-) cells were almost exclusively Ph(-). By performing long-term culture-initiating cell assays on the two cell populations, we found that Ph(+) and Ph(-) candidate CML stem cells could be prospectively separated. In addition, by generating an anti-IL1RAP antibody, we provide proof of concept that IL1RAP can be used as a target on CML CD34(+)CD38(-) cells to induce antibody-dependent cell-mediated cytotoxicity. This study thus identifies IL1RAP as a unique cell surface biomarker distinguishing Ph(+) from Ph(-) candidate CML stem cells and opens up a previously unexplored avenue for therapy of CML.
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, 22185 Lund, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Järås
authors.forename: Petra
authors.initials: P
authors.lastname: Johnels
authors.forename: Nils
authors.initials: N
authors.lastname: Hansen
authors.forename: Helena
authors.initials: H
authors.lastname: Agerstam
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Tsapogas
authors.forename: Marianne
authors.initials: M
authors.lastname: Rissler
authors.forename: Carin
authors.initials: C
authors.lastname: Lassen
authors.forename: Tor
authors.initials: T
authors.lastname: Olofsson
authors.forename: Ole Weis
authors.initials: OW
authors.lastname: Bjerrum
authors.forename: Johan
authors.initials: J
authors.lastname: Richter
authors.forename: Thoas
authors.initials: T
authors.lastname: Fioretos
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology; D000906:Antibodies / Q000276:immunology*; D018952:Antigens, CD34 / Q000276:immunology; D017209:Apoptosis; D002469:Cell Separation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053577:Interleukin-1 Receptor Accessory Protein / Q000276:immunology / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000276:immunology; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
chemical_list: D000906:Antibodies; D018952:Antigens, CD34; C507765:IL1RAP protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D008562:Membrane Glycoproteins; D016044:Fusion Proteins, bcr-abl; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1
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