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

Ye Yang, Jumei Shi, Zhimin Gu, Mohamed Salama, Satyabrata Das, Erik Wendlandt, Hongwei Xu, Junwei Huang, Yi Tao, Mu Hao, Reinaldo Franqui, Dana Levasseur, Siegfried Janz, Guido Tricot, Fenghuang Zhan

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)594-604
Number of pages11
JournalCancer Research
Volume75
Issue number3
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

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Multiple Myeloma
Stem Cells
Therapeutics
Neoplasms
Agammaglobulinaemia tyrosine kinase
Side-Population Cells
Catenins
Pharmaceutical Preparations
Population
Up-Regulation
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma. / Yang, Ye; Shi, Jumei; Gu, Zhimin; Salama, Mohamed; Das, Satyabrata; Wendlandt, Erik; Xu, Hongwei; Huang, Junwei; Tao, Yi; Hao, Mu; Franqui, Reinaldo; Levasseur, Dana; Janz, Siegfried; Tricot, Guido; Zhan, Fenghuang.

In: Cancer Research, Vol. 75, No. 3, 01.02.2015, p. 594-604.

Research output: Contribution to journalArticle

Yang, Y, Shi, J, Gu, Z, Salama, M, Das, S, Wendlandt, E, Xu, H, Huang, J, Tao, Y, Hao, M, Franqui, R, Levasseur, D, Janz, S, Tricot, G & Zhan, F 2015, 'Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma', Cancer Research, vol. 75, no. 3, pp. 594-604. https://doi.org/10.1158/0008-5472.CAN-14-2362
Yang, Ye ; Shi, Jumei ; Gu, Zhimin ; Salama, Mohamed ; Das, Satyabrata ; Wendlandt, Erik ; Xu, Hongwei ; Huang, Junwei ; Tao, Yi ; Hao, Mu ; Franqui, Reinaldo ; Levasseur, Dana ; Janz, Siegfried ; Tricot, Guido ; Zhan, Fenghuang. / Bruton tyrosine kinase is a therapeutic target in stem-like cells from multiple myeloma. In: Cancer Research. 2015 ; Vol. 75, No. 3. pp. 594-604.
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