Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein.
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.
Järås
Marcus
M
Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, 22185 Lund, Sweden.
Johnels
Petra
P
Hansen
Nils
N
Agerstam
Helena
H
Tsapogas
Panagiotis
P
Rissler
Marianne
M
Lassen
Carin
C
Olofsson
Tor
T
Bjerrum
Ole Weis
OW
Richter
Johan
J
Fioretos
Thoas
T
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*
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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