Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML

Zaitseva, Lyubov, Murray, Megan Y, Shafat, Manar S., Lawes, Matthew J, MacEwan, David J, Bowles, Kristian M and Rushworth, Stuart A (2014) Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML. Oncotarget, 5 (20). pp. 9930-9938. ISSN 1949-2553

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Abstract

Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL.

Item Type: Article
Additional Information: Licensed under a Creative Commons Attribution 3.0 License.
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Biological Sciences
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Depositing User: Pure Connector
Date Deposited: 12 Nov 2014 16:46
Last Modified: 06 Nov 2020 00:57
URI: https://ueaeprints.uea.ac.uk/id/eprint/50842
DOI:

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