title: Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL).
abstract: 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.
authors: Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH;
authors: Jennifer A
authors: JA
authors: Woyach
authors: Engin
authors: E
authors: Bojnik
authors: Amy S
authors: AS
authors: Ruppert
authors: Matthew R
authors: MR
authors: Stefanovski
authors: Virginia M
authors: VM
authors: Goettl
authors: Kelly A
authors: KA
authors: Smucker
authors: Lisa L
authors: LL
authors: Smith
authors: Jason A
authors: JA
authors: Dubovsky
authors: William H
authors: WH
authors: Towns
authors: Jessica
authors: J
authors: MacMurray
authors: Bonnie K
authors: BK
authors: Harrington
authors: Melanie E
authors: ME
authors: Davis
authors: Stefania
authors: S
authors: Gobessi
authors: Luca
authors: L
authors: Laurenti
authors: Betty Y
authors: BY
authors: Chang
authors: Joseph J
authors: JJ
authors: Buggy
authors: Dimitar G
authors: DG
authors: Efremov
authors: John C
authors: JC
authors: Byrd
authors: Amy J
authors: AJ
authors: Johnson
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D000225:Adenine