Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML

Zaitseva, Lyubov, Murray, Megan Y, Shafat, Manar S, Lawes, Matthew J, MacEwan, David J ORCID: 0000-0002-2879-0935, Bowles, Kristian M and Rushworth, Stuart A (2014) Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML. Oncotarget, 5 (20). pp. 9930-9938.

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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
Uncontrolled Keywords:	AML, BTK, Ibrutinib, CXCR4, SDF1
Subjects:	?? RM ??
Depositing User:	Symplectic Admin
Date Deposited:	05 Dec 2014 15:30
Last Modified:	15 Dec 2022 12:31
DOI:	10.18632/oncotarget.2479
Publisher's Statement :	This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original author and source are credited.
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/2003004