Targeting Wnt pathway in mantle cell lymphoma-initiating cells.

Rohit Mathur, Lalit Sehgal, Frank K Braun, Zuzana Berkova, Jorge Romaguerra, Michael Wang, M Alma Rodriguez, Luis Fayad, Sattva S Neelapu, Felipe Samaniego

Index: J. Hematol. Oncol. 8 , 63, (2015)

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Abstract

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.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.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 β-catenin-TCF4 interaction with CCT036477, iCRT14, or PKF118-310 preferentially eliminated the MCL-ICs.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.