Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML
Metrics: PDF 1966 views | HTML 2331 views | ?
Lyubov Zaitseva1, Megan Y. Murray1, Manar S. Shafat1, Matthew J. Lawes3, David J. MacEwan2, Kristian M. Bowles1,3 and Stuart A. Rushworth1
1 Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom
2 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
3 Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Colney Lane, Norwich United Kingdom
Stuart Rushworth, email:
Keywords: AML, BTK, Ibrutinib, CXCR4, SDF1
Received: July 04, 2014 Accepted: September 15, 2014 Published: September 16, 2014
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.