High cystic fibrosis transmembrane conductance regulator expression in childhood B-cell acute lymphoblastic leukemia acts as a potential therapeutic target

Background: The role of cystic fibrosis transmembrane conductance regulator (CFTR) in hematopoiesis and adult leukemia has been demonstrated using a zebrafish model and leukemia cell lines in our previous works. Here, we continue to explore the association between CFTR and human childhood B-cell acute lymphoblastic leukemia (B-ALL). Methods: We continued to collect the peripheral blood and bone marrows of human childhood patients diagnosed with primary B-ALL as well as non-leukemia controls and isolated lymphocytes for analysis using western blotting and quantitative real-time polymerase chain reaction (qPCR) assay. Then, we used immunofluorescence, co-immunoprecipitation, western blotting, luciferase, MTT assays to identify the interaction of CFTR with Wnt signaling in B-ALL. Finally, we established B-ALL xenograft model in NOD/SCID mice using SUP-B15 cells, and examined whether the CFTR inhibitor CFTR-inh172 could active against SUP-B15-Dependent B-ALL in vivo. Results: Highly expressed CFTR protein and mRNA are associated with primary childhood B-ALL patients. Aberrantly upregulated CFTR and Wnt signaling, our previously reported CFTR-Dvl2-beta-catenin pathway, is found in human childhood B-ALL patients. Interference with CFTR in B-ALL cell lines induces the downregulation of DVL2/beta-catenin and Wnt downstream target accompanied by a reduction of cell proliferation. Furthermore, B-ALL cell lines SUP-B15 cell-transplanted NOD/SCID mice treated with CFTR inhibitor CFTRinh-172 had significantly longer survival and slower leukemia progression compared with mice treated with vehicle DMSO. Conclusions: These findings demonstrate that highly expressed CFTR is associated with human childhood B-ALL and the potential of CFTR inhibitor CFTR-inh172 for the treatment of human B-ALL.

Automated summary

This study found that high expression of CFTR is associated with childhood B-ALL, and the CFTR inhibitor CFTR-inh172 has the potential to treat B-ALL.