期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-16927-w
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资金
- Deutsche Krebshilfe
- Deutsche Forschungsgemeinschaft [SFB1074, SFB1279]
- ERC advanced grant [694992]
- Chief Scientist Office grant [ETM/374]
- Egyptian Ministry of Higher Education (MoHE)
- German Academic Exchange Service (DAAD) [91528030]
- Department of Molecular Biology, Genetic Engineering and Biotechnology Division, National Research Centre (NRC) in Egypt
- Wilhelm Sander Stiftung [2016.110.1]
- Deutsche Jose-Carreras Leukamiestiftung [DJCLS 17R/2017]
- NIH/NCI [R35CA197628, R01CA157644, R01CA213138]
- Norman and Sadie Lee Foundation for Pediatric Cancer
- California Institute for Regenerative Medicine (CIRM) [DISC2-10061]
Ph+ acute lymphoblastic leukemia (ALL) is characterized by the expression of an oncogenic fusion kinase termed BCR-ABL1. Here, we show that interleukin 7 receptor (IL7R) interacts with the chemokine receptor CXCR4 to recruit BCR-ABL1 and JAK kinases in close proximity. Treatment with BCR-ABL1 kinase inhibitors results in elevated expression of IL7R which enables the survival of transformed cells when IL7 was added together with the kinase inhibitors. Importantly, treatment with anti-IL7R antibodies prevents leukemia development in xenotransplantation models using patient-derived Ph+ ALL cells. Our results suggest that the association between IL7R and CXCR4 serves as molecular platform for BCR-ABL1-induced transformation and development of Ph+ ALL. Targeting this platform with anti-IL7R antibody eliminates Ph+ ALL cells including those with resistance to commonly used ABL1 kinase inhibitors. Thus, anti-IL7R antibodies may provide alternative treatment options for ALL in general and may suppress incurable drug-resistant leukemia forms.
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