Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL)

Luca Laurenti, Jennifer A. Woyach, Engin Bojnik, Amy S. Ruppert, Matthew R. Stefanovski, Virginia M. Goettl, Kelly A. Smucker, Lisa L. Smith, Jason A. Dubovsky, William H. Towns, Jessica Macmurray, Bonnie K. Harrington, Melanie E. Davis, Stefania Gobessi, Betty Y. Chang, Joseph J. Buggy, Dimitar G. Efremov, John C. Byrd, Amy J. Johnson

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Chronic Lymphocytic Leukemia (CLL) demonstrates variable reactivity of the B cell receptor (BCR) to antigen ligation, but constitutive pathway activation. Bruton's Tyrosine Kinase (BTK) shows constitutive activity in CLL, and is the target of irreversible inhibition by ibrutinib, an orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. Early clinical results in CLL with other reversible and irreversible BTK inhibitors have been less promising, however, raising the question of whether BTK kinase activity is an important target of ibrutinib and also in CLL. To determine the role of BTK in CLL, we utilized patient samples and the Eμ-TCL1 (TCL1) transgenic mouse model of CLL which results in spontaneous leukemia development. Inhibition of BTK in primary human CLL cells by siRNA promotes apoptosis. Inhibition of BTK kinase activity through either targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly delays the development of CLL, demonstrating that BTK is a critical kinase for CLL development and expansion and thus an important target of ibrutinib. Collectively, our data confirm the importance of kinase-functional BTK in CLL.
Original languageEnglish
Pages (from-to)1207-1213
Number of pages7
JournalBlood
DOIs
Publication statusPublished - 2014

Keywords

  • INGLESE

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