Journal
JOURNAL OF HEMATOLOGY & ONCOLOGY
Volume 8, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s13045-015-0161-1
Keywords
Lymphoma-initiating cells; Tumor stem cells; Burton tyrosine kinase; Wnt3; FZD1; Mesenchymal stromal cells; MCL co-culture; CCT036477; iCRT14; PKF118-310
Categories
Funding
- NCI/NIH [CA153170, CA158692]
- NIDDK [DK091490]
- Richard Spencer Lewis Memorial Foundation
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Background: Mantle cell lymphoma (MCL) is an aggressive and incurable form of non-Hodgkin's lymphoma. Despite initial intense chemotherapy, up to 50 % of cases of MCL relapse often in a chemoresistant form. We hypothesized that the recently identified MCL-initiating cells (MCL-ICs) are the main reason for relapse and chemoresistance of MCL. Cancer stem cell-related pathways such as Wnt could be responsible for their maintenance and survival. Methods: We isolated MCL-ICs from primary MCL cells on the basis of a defined marker expression pattern (CD34-CD3-CD45+CD19-) and investigated Wnt pathway expression. We also tested the potential of Wnt pathway inhibitors in elimination of MCL-ICs. Results: We showed that MCL-ICs are resistant to genotoxic agents vincristine, doxorubicin, and the newly approved Burton tyrosine kinase (BTK) inhibitor ibrutinib. We confirmed the differential up-regulation of Wnt pathway in MCL-ICs. Indeed, MCL-ICs were particularly sensitive to Wnt pathway inhibitors. Targeting beta-catenin-TCF4 interaction with CCT036477, iCRT14, or PKF118-310 preferentially eliminated the MCL-ICs. Conclusions: Our results suggest that Wnt signaling is critical for the maintenance and survival of MCL-ICs, and effective MCL therapy should aim to eliminate MCL-ICs through Wnt signaling inhibitors.
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