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

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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 retroviralBCR/ABL1expression. 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.

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