Journal article
Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma
Cancer research (Chicago, Ill.), Vol.75(3), pp.594-604
02/01/2015
DOI: 10.1158/0008-5472.CAN-14-2362
PMCID: PMC4384656
PMID: 25589346
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.
Details
- Title: Subtitle
- Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma
- Creators
- Ye Yang - Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IowaJumei Shi - Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, ChinaZhimin Gu - Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IowaMohamed E Salama - Department of Pathology, University of Utah, and Associated Regional University Pathologists (ARUP) Laboratories, Salt Lake City, UtahSatyabrata Das - Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IowaErik Wendlandt - Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IowaHongwei Xu - Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IowaJunwei Huang - Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IowaYi Tao - Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IowaMu Hao - Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IowaReinaldo Franqui - Interdisciplinary Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IowaDana Levasseur - Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IowaSiegfried Janz - Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IowaGuido Tricot - Department 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.eduFenghuang Zhan - Department 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
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.75(3), pp.594-604
- DOI
- 10.1158/0008-5472.CAN-14-2362
- PMID
- 25589346
- PMCID
- PMC4384656
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- R01 CA152105 / NCI NIH HHS R01 CA151354 / NCI NIH HHS T32 HL007344 / NHLBI NIH HHS R01CA152105 / NCI NIH HHS P30 CA042014 / NCI NIH HHS R01CA151354 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
- Language
- English
- Date published
- 02/01/2015
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Internal Medicine
- Record Identifier
- 9984083279102771
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