Targeting Wnt pathway in mantle cell lymphoma-initiating cells.

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

doi:10.1186/s13045-015-0161-1

Rohit Mathur, Frank K Braun + Show 8 more

Open Access

https://doi.org/10.1186/s13045-015-0161-1

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Abstract

BackgroundMantle 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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0161-1) contains supplementary material, which is available to authorized users.

Highlights

Mantle cell lymphoma (MCL) is an aggressive and incurable form of non-Hodgkin’s lymphoma
Sox2 expression was not significantly elevated in Mantle cell lymphoma-initiating cells (MCL-IC) (1.07-fold) compared with B-cells. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis showed significantly higher (>100fold) expression of aldehyde dehydrogenase 1 (ALDH1) and ALDH2 in MCL-ICs than in MCL-non-ICs (Fig. 2b); this observation concurs with the high Aldehyde dehydrogenase (ALDH) activity detected in MCL-ICs (Fig. 2e)
These results indicate that MCL-ICs possess characteristic gene expression of cancer stem cells

Summary

Introduction

Mantle cell lymphoma (MCL) is an aggressive and incurable form of non-Hodgkin’s lymphoma. Up to 50 % of cases of MCL relapse often in a chemoresistant form. Mantle cell lymphoma (MCL) is considered as an incurable subtype of non-Hodgkin’s lymphoma that causes significant morbidity and early death presumably due to relapsed disease [1,2,3]. A small fraction of cells within tumors have tumorinitiating properties and are believed to be the source of relapsed cancer. These cells are referred to as cancer stem cells (CSCs) or tumor-initiating cells [6,7,8,9]. The most current therapies target dividing tumor cells while sparing non-dividing and inherently chemoresistant CSCs; they fail to provide long-term cures and result in tumor relapse [10, 11]

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