Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia

Rushworth, Stuart A., Murray, Megan Y., Zaitseva, Lyubov, Bowles, Kristian M. ORCID: https://orcid.org/0000-0003-1334-4526 and Macewan, David J. (2014) Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia. Blood, 123 (8). pp. 1229-1238. ISSN 0006-4971

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Abstract

Bruton's tyrosine kinase (BTK) is a cytoplasmic protein found in all hematopoietic cell lineages except for T cells. BTK mediates signalling downstream of a number of receptors. Pharmacological targeting of BTK using ibrutinib (previously PCI-32765) has recently shown encouraging clinical activity in a range of lymphoid malignancies. This study reports for the first time that ibrutinib inhibits blast proliferation from human acute myeloid leukaemia (AML) and that treatment with ibrutinib significantly augmented cytotoxic activities of standard AML chemotherapy cytarabine or daunorubicin. Here we describe that BTK is constitutively phosphorylated in the majority of AML samples tested, with BTK phosphorylation correlating highly with the cell's cytotoxic sensitivity towards ibrutinib. BTK targeted RNAi knock-down reduced colony forming capacity of primary AML blasts and proliferation of AML cell lines. We showed ibrutinib binds at nanomolar range to BTK. Furthermore, we also showed ibrutinib's anti-proliferative effects in AML are mediated via an inhibitory effect on downstream nuclear factor-κB (NF-κB) survival pathways. Moreover, ibrutinib inhibited AML cell adhesion to bone marrow stroma. Furthermore, these effects of ibrutinib in AML were seen at comparable concentrations efficacious in chronic lymphocytic leukemia (CLL). These results provide a biologic rationale for clinical evaluation of BTK inhibition in AML patients.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Pharmacy Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Depositing User:	Pure Connector
Date Deposited:	06 Jan 2014 14:40
Last Modified:	27 Oct 2023 01:10
URI:	https://ueaeprints.uea.ac.uk/id/eprint/45978
DOI:	10.1182/blood-2013-06-511154

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