Targeting Wnt pathway in mantle cell lymphoma-initiating cells

Journal of Hematology & Oncology

Felipe Samaniego¹  Sattva S. Neelapu¹  Luis Fayad¹  M. Alma Rodriguez¹  Michael Wang¹  Jorge Romaguerra¹  Zuzana Berkova¹  Frank K. Braun¹  Lalit Sehgal¹  Rohit Mathur¹ 

[1] Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston 77030, TX, USA

关键词: PKF118-310;    iCRT14;    CCT036477;    MCL co-culture;    Mesenchymal stromal cells;    FZD1;    Wnt3;    Burton tyrosine kinase;    Tumor stem cells;    Lymphoma-initiating cells;   

Others  :  1217372
DOI  :  10.1186/s13045-015-0161-1

 received in 2015-02-16, accepted in 2015-05-25,  发布年份 2015

【 摘 要 】

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 β-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.

【 授权许可】

   
2015 Mathur et al.

【 图 表 】

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