title: Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma.
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.
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jumei
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Pathology, University of Utah, and Associated Regional University Pathologists (ARUP) Laboratories, Salt Lake City, Utah.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Salama
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
authors.forename: Satyabrata
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
authors.forename: Erik
authors.initials: E
authors.lastname: Wendlandt
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
authors.forename: Junwei
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
authors.forename: Mu
authors.initials: M
authors.lastname: Hao
authors.affiliation: Interdisciplinary Program in Molecular and Cellular Biology, University of Iowa, Iowa City, Iowa.
authors.forename: Reinaldo
authors.initials: R
authors.lastname: Franqui
authors.affiliation: Department of Internal Medicine, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
authors.forename: Dana
authors.initials: D
authors.lastname: Levasseur
authors.affiliation: Department of Pathology, The University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
authors.affiliation: 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.edu.
authors.forename: Guido
authors.initials: G
authors.lastname: Tricot
authors.affiliation: 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.
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001854:Bone Marrow Cells / Q000166:cytology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011720:Pyrazoles; D011743:Pyrimidines; D058985:Side-Population Cells / Q000166:cytology; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D051176:beta Catenin; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000225:Adenine