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

Abdelrasoul, Hend ; Vadakumchery, Anila ; Werner, Markus ; Lenk, Lennart ; Khadour, Ahmad ; Young, Marc ; El Ayoubi, Omar ; Vogiatzi, Fotini ; Krämer, Markus ; Schmid, Vera ; Chen, Zhengshan ; Yousafzai, Yasar ; Cario, Gunnar ; Schrappe, Martin ; Müschen, Markus ; Halsey, Christina ; Mulaw, Medhanie A ; Schewe, Denis M ; Hobeika, Elias ; Alsadeq, Ameera ; Jumaa, Hassan

Nature communications, 2020-06, Vol.11 (1), p.3194-12, Article 3194 [Periódico revisado por pares]

England: Nature Publishing Group

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Título:
Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia
Autor: Abdelrasoul, Hend ; Vadakumchery, Anila ; Werner, Markus ; Lenk, Lennart ; Khadour, Ahmad ; Young, Marc ; El Ayoubi, Omar ; Vogiatzi, Fotini ; Krämer, Markus ; Schmid, Vera ; Chen, Zhengshan ; Yousafzai, Yasar ; Cario, Gunnar ; Schrappe, Martin ; Müschen, Markus ; Halsey, Christina ; Mulaw, Medhanie A ; Schewe, Denis M ; Hobeika, Elias ; Alsadeq, Ameera ; Jumaa, Hassan
Assuntos: Abl protein ; Acute lymphoblastic leukemia ; Animals ; Antibodies ; BCR protein ; Cell Line, Tumor ; Cell survival ; Cell Transformation, Neoplastic - drug effects ; Chemokines ; Chromosomes ; CXCR4 protein ; Cytokines ; Drug resistance ; Female ; Forkhead Box Protein O1 - metabolism ; Fusion protein ; Fusion Proteins, bcr-abl - antagonists & inhibitors ; Fusion Proteins, bcr-abl - genetics ; Fusion Proteins, bcr-abl - metabolism ; Gene Expression Regulation, Neoplastic - drug effects ; Humans ; Inhibitors ; Interleukin ; Interleukin 7 ; Interleukin 7 receptors ; Interleukin-7 - pharmacology ; Interleukin-7 Receptor alpha Subunit - antagonists & inhibitors ; Interleukin-7 Receptor alpha Subunit - genetics ; Interleukin-7 Receptor alpha Subunit - metabolism ; Kinases ; Leukemia ; Lymphatic leukemia ; Mice ; Mice, Mutant Strains ; Philadelphia Chromosome ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Protein Kinase Inhibitors - pharmacology ; Receptors ; Receptors, CXCR4 - genetics ; Receptors, CXCR4 - metabolism ; Signal Transduction - drug effects ; Synergism ; Transformation ; Transformed cells ; Xenografts ; Xenotransplantation
É parte de: Nature communications, 2020-06, Vol.11 (1), p.3194-12, Article 3194
Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

England: Nature Publishing Group

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