title: Targeting Wnt pathway in mantle cell lymphoma-initiating cells.
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.
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. rmathur@mdanderson.org.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mathur
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. lsehgal@mdanderson.org.
authors.forename: Lalit
authors.initials: L
authors.lastname: Sehgal
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. fkbraun@outlook.com.
authors.forename: Frank K
authors.initials: FK
authors.lastname: Braun
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. zberkova@mdanderson.org.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Berkova
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. jromague@mdanderson.org.
authors.forename: Jorge
authors.initials: J
authors.lastname: Romaguerra
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. miwang@mdanderson.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. marodriguez@mdanderson.org.
authors.forename: M Alma
authors.initials: MA
authors.lastname: Rodriguez
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. lefayad@mdanderson.org.
authors.forename: Luis
authors.initials: L
authors.lastname: Fayad
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. sneelapu@mdanderson.org.
authors.forename: Sattva S
authors.initials: SS
authors.lastname: Neelapu
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. fsamaniego@mdanderson.org.
authors.forename: Felipe
authors.initials: F
authors.lastname: Samaniego
mesh_terms: D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D014411:Neoplastic Stem Cells / Q000473:pathology; D060449:Wnt Signaling Pathway