Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Blood, 2014-02, Vol.123 (8), p.1207-1213

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Chronic lymphocytic leukemia (CLL) is characterized by constitutive activation of the B-cell receptor (BCR) signaling pathway, but variable responsiveness of the BCR to antigen ligation. 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 used 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 small interfering RNA 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. •Kinase-functional BTK is important in the development and expansion of CLL.•Both targeted genetic inactivation of BTK and inhibition of BTK by ibrutinib inhibit the development of CLL in the TCL1 mouse model.