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)

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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 > Institute 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

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190794Identifying Novel Targets for eradication of acute lymphoblastic leukaemia in the central nervous systemChristina HalseyChief Scientist Office (CSO)ETM/374III - Immunology