Targeting Wnt pathway in mantle cell lymphoma-initiating cells

  • J Hematol Oncol. 2015 Jun 6:8:63. doi: 10.1186/s13045-015-0161-1.
Rohit Mathur  1 ,  Lalit Sehgal  2 ,  Frank K Braun  3 ,  Zuzana Berkova  4 ,  Jorge Romaguerra  5 ,  Michael Wang  6 ,  M Alma Rodriguez  7 ,  Luis Fayad  8 ,  Sattva S Neelapu  9 ,  Felipe Samaniego  10
Affiliations
  • 1. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 2. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 3. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 4. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 5. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 6. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 7. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 8. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 9. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
  • 10. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. [email protected].
PMID: 26048374 DOI: 10.1186/s13045-015-0161-1
Abstract

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.

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