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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein.

Author

  • Marcus Järås
  • Petra Johnels
  • Nils Hansen
  • Helena Ågerstam
  • Panagiotis Tsapogas
  • Marianne Rissler
  • Carin Lassen
  • Tor Olofsson
  • Ole Weis Bjerrum
  • Johan Richter
  • Thoas Fioretos
Show all

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.

Department/s

  • Division of Clinical Genetics
  • Division of Molecular Medicine and Gene Therapy
  • Division of Hematology and Transfusion Medicine
  • Targeted therapies in leukemia
  • Translational Genomic and Functional Studies of Leukemia
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation

Publishing year

2010

Language

English

Pages

16280-16285

Publication/Series

Proceedings of the National Academy of Sciences

Volume

107

Issue

37

Document type

Journal article

Publisher

National Academy of Sciences

Topic

  • Hematology

Status

Published

Research group

  • Targeted therapies in leukemia
  • Translational Genomic and Functional Studies of Leukemia

ISBN/ISSN/Other

  • ISSN: 1091-6490