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Cancer Res. 2015 Feb 1;75(3):594-604. doi: 10.1158/0008-5472.CAN-14-2362. Epub 2015 Jan 14.

Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma.

Author information

  • 1Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
  • 2Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 3Department of Pathology, University of Utah, and Associated Regional University Pathologists (ARUP) Laboratories, Salt Lake City, Utah.
  • 4Interdisciplinary Program in Molecular and Cellular Biology, University of Iowa, Iowa City, Iowa.
  • 5Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
  • 6Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa. fenghuang-zhan@uiowa.edu guido-tricot@uiowa.edu.
  • 7Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa. Interdisciplinary Program in Molecular and Cellular Biology, University of Iowa, Iowa City, Iowa. fenghuang-zhan@uiowa.edu guido-tricot@uiowa.edu.

Abstract

Ibrutinib (Imbruvica), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients with multiple myeloma, yet important questions on the role of BTK in myeloma biology and treatment are outstanding. Using flow-sorted side population cells from human myeloma cell lines and multiple myeloma primary samples as surrogate for the elusive multiple myeloma stem cell, we found that elevated expression of BTK in myeloma cells leads to AKT/WNT/β-catenin-dependent upregulation of key stemness genes (OCT4, SOX2, NANOG, and MYC) and enhanced self-renewal. Enforced transgenic expression of BTK in myeloma cells increased features of cancer stemness, including clonogenicity and resistance to widely used myeloma drugs, whereas inducible knockdown of BTK abolished them. Furthermore, overexpression of BTK in myeloma cells promoted tumor growth in laboratory mice and rendered side population-derived tumors that contained high levels of BTK more sensitive to the selective, second-generation BTK inhibitor, CGI1746, than side population-derived tumors that harbored low levels of BTK. Taken together, these findings implicate BTK as a positive regulator of myeloma stemness and provide additional support for the clinical testing of BTK-targeted therapies in patients with myeloma.

©2014 American Association for Cancer Research.

PMID:
25589346
[PubMed - indexed for MEDLINE]
PMCID:
PMC4384656
Free PMC Article
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