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Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma. Cancer Res 2015 Feb 01;75(3):594-604

Date

01/16/2015

Pubmed ID

25589346

Pubmed Central ID

PMC4384656

DOI

10.1158/0008-5472.CAN-14-2362

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.

Author List

Yang Y, Shi J, Gu Z, Salama ME, Das S, Wendlandt E, Xu H, Huang J, Tao Y, Hao M, Franqui R, Levasseur D, Janz S, Tricot G, Zhan F

Author

Siegfried Janz MD Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Bone Marrow Cells
Cell Line, Tumor
Cell Movement
Cell Proliferation
Cell Survival
Humans
Lentivirus
Mice
Multiple Myeloma
Neoplastic Stem Cells
Protein-Tyrosine Kinases
Pyrazoles
Pyrimidines
Side-Population Cells
Signal Transduction
beta Catenin
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