Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein.
Författare
Summary, in English
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.
Avdelning/ar
- Avdelningen för klinisk genetik
- Avdelningen för molekylärmedicin och genterapi
- Avdelningen för hematologi och transfusionsmedicin
- Målinriktade behandlingar för leukemi
- Translationella genomiska och funktionella studier av leukemi
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publiceringsår
2010
Språk
Engelska
Sidor
16280-16285
Publikation/Tidskrift/Serie
Proceedings of the National Academy of Sciences
Volym
107
Issue
37
Länkar
Dokumenttyp
Artikel i tidskrift
Förlag
National Academy of Sciences
Ämne
- Hematology
Status
Published
Forskningsgrupp
- Targeted therapies in leukemia
- Translational Genomic and Functional Studies of Leukemia
ISBN/ISSN/Övrigt
- ISSN: 1091-6490