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

Hend Abdelrasoul, Anila Vadakumchery, Markus Werner, Lennart Lenk, Ahmad Khadour, Marc Young, Omar El Ayoubi, Fotini Vogiatzi, Markus Krämer, Vera Schmid, Zhengshan Chen, Yasar Yousafzai, Gunnar Cario, Martin Schrappe, Markus Müschen, Christina Halsey, Medhanie A. Mulaw, Denis M. Schewe, Elias Hobeika, Ameera Alsadeq and Hassan Jumaa ()
Additional contact information
Hend Abdelrasoul: Ulm University Medical Center
Anila Vadakumchery: Ulm University Medical Center
Markus Werner: Ulm University Medical Center
Lennart Lenk: Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein
Ahmad Khadour: Ulm University Medical Center
Marc Young: Ulm University Medical Center
Omar El Ayoubi: Ulm University Medical Center
Fotini Vogiatzi: Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein
Markus Krämer: Ulm University Medical Center
Vera Schmid: Ulm University Medical Center
Zhengshan Chen: Department of Systems Biology and City of Hope Comprehensive Cancer Center
Yasar Yousafzai: Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow
Gunnar Cario: Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein
Martin Schrappe: Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein
Markus Müschen: Department of Systems Biology and City of Hope Comprehensive Cancer Center
Christina Halsey: Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow
Medhanie A. Mulaw: Institute of Experimental Cancer Research, Medical Faculty, University of Ulm
Denis M. Schewe: Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein
Elias Hobeika: Ulm University Medical Center
Ameera Alsadeq: Ulm University Medical Center
Hassan Jumaa: Ulm University Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16927-w

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