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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
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 Acad Sciences

Abstract 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.

Keywords

  • Hematology

Other

Published
  • Targeted therapies in leukemia
  • ISSN: 1091-6490
Thoas Fioretos
E-mail: thoas.fioretos [at] med.lu.se

Principal investigator

Division of Clinical Genetics

+46 46 222 45 95

+46 70 334 33 67

BMC C13

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