Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia.
Hend AbdelrasoulAnila VadakumcheryMarkus WernerLennart LenkAhmad KhadourMarc YoungOmar El AyoubiFotini VogiatziMarkus KrämerVera SchmidZhengshan ChenYasar YousafzaiGunnar CarioMartin SchrappeMarkus MüschenChristina HalseyMedhanie A MulawDenis Martin ScheweElias HobeikaAmeera AlsadeqHassan JumaaPublished in: Nature communications (2020)
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.
Keyphrases
- acute lymphoblastic leukemia
- chronic myeloid leukemia
- tyrosine kinase
- drug resistant
- induced apoptosis
- cell cycle arrest
- poor prognosis
- acute myeloid leukemia
- multidrug resistant
- bone marrow
- signaling pathway
- high throughput
- cystic fibrosis
- cell proliferation
- dna methylation
- transcription factor
- diabetic rats
- high glucose
- cell migration
- endothelial cells
- single cell
- mouse model
- smoking cessation