Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

Abdelrasoul, H. et al. (2020) Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia. Nature Communications, 11, 3194. (doi: 10.1038/s41467-020-16927-w) (PMID:32581241) (PMCID:PMC7314847)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Halsey, Professor Chris and Yousafzai, Dr Yasar
• Authors: Abdelrasoul, H., Vadakumchery, A., Werner, M., Lenk, L., Khadour, A., Young, M., El Ayoubi, O., Vogiatzi, F., Krämer, M., Schmid, V., Chen, Z., Yousafzai, Y., Cario, G., Schrappe, M., Müschen, M., Halsey, C., Mulaw, M. A., Schewe, D. M., Hobeika, E., Alsadeq, A., and Jumaa, H.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Nature Communications 11: 3194
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190794		Identifying Novel Targets for eradication of acute lymphoblastic leukaemia in the central nervous system	Christina Halsey	Chief Scientist Office (CSO)	ETM/374	III - Immunology