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Targeting Wnt pathway in mantle cell lymphoma-initiating cells.

Journal of hematology & oncology (2015-06-07)
Rohit Mathur, Lalit Sehgal, Frank K Braun, Zuzana Berkova, Jorge Romaguerra, Michael Wang, M Alma Rodriguez, Luis Fayad, Sattva S Neelapu, Felipe Samaniego
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
XAV939, ≥98% (HPLC)
Sigma-Aldrich
Methanol, NMR reference standard
Sigma-Aldrich
iCRT14, ≥98% (HPLC)
Sigma-Aldrich
Methanol-12C, 99.95 atom % 12C
Sigma-Aldrich
Methanol solution, NMR reference standard, 4% in methanol-d4 (99.8 atom % D), NMR tube size 3 mm × 8 in.
Sigma-Aldrich
Methanol solution, (Methanol:Dimethyl sulfoxide 1:1 (v/v))
Sigma-Aldrich
CCT036477, ≥98% (HPLC)
Sigma-Aldrich
DAPI, for nucleic acid staining