TY - JOUR
T1 - Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma
AU - Yang, Ye
AU - Shi, Jumei
AU - Gu, Zhimin
AU - Salama, Mohamed E.
AU - Das, Satyabrata
AU - Wendlandt, Erik
AU - Xu, Hongwei
AU - Huang, Junwei
AU - Tao, Yi
AU - Hao, Mu
AU - Franqui, Reinaldo
AU - Levasseur, Dana
AU - Janz, Siegfried
AU - Tricot, Guido
AU - Zhan, Fenghuang
N1 - Publisher Copyright:
©2014 AACR.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - Ibrutinib (Imbruvica), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients withmultiplemyeloma, 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 withmyeloma.
AB - Ibrutinib (Imbruvica), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients withmultiplemyeloma, 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 withmyeloma.
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U2 - 10.1158/0008-5472.CAN-14-2362
DO - 10.1158/0008-5472.CAN-14-2362
M3 - Article
C2 - 25589346
AN - SCOPUS:84961289380
SN - 0008-5472
VL - 75
SP - 594
EP - 604
JO - Cancer Research
JF - Cancer Research
IS - 3
ER -
