期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：37
页码：16280-16285
DOI：10.1073/pnas.1004408107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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.
关键词：antibody-dependent cell-mediated cytotoxicity ; cancer ; biomarker ; therapeutic antibody
