Institute of Immunology, Ulm University Medical Center, 89081, Ulm, Germany.
Department of Pediatrics I, ALL-BFM Study Group, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
Nat Commun. 2020 Jun 24;11(1):3194. doi: 10.1038/s41467-020-16927-w.
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.
Ph 型急性淋巴细胞白血病（ALL）的特征是表达一种致癌融合激酶，称为 BCR-ABL1。在这里，我们表明白细胞介素 7 受体（IL7R）与趋化因子受体 CXCR4 相互作用，将 BCR-ABL1 和 JAK 激酶募集到近距离。用 BCR-ABL1 激酶抑制剂处理会导致 IL7R 的表达升高，当与激酶抑制剂一起添加 IL7 时，这使得转化细胞能够存活。重要的是，用抗 IL7R 抗体治疗可防止使用源自患者的 Ph 型 ALL 细胞的异种移植模型中的白血病发展。我们的结果表明，IL7R 和 CXCR4 之间的关联是 BCR-ABL1 诱导的转化和 Ph 型 ALL 发展的分子平台。用抗 IL7R 抗体靶向该平台可消除 Ph 型 ALL 细胞，包括对常用 ABL1 激酶抑制剂耐药的细胞。因此，抗 IL7R 抗体可能为 ALL 提供一般的替代治疗选择，并可能抑制无法治愈的耐药性白血病形式。
