Affordable Access

Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML.

Authors
  • Zaitseva, Lyubov1
  • Murray, Megan Y1
  • Shafat, Manar S1
  • Lawes, Matthew J2
  • MacEwan, David J3
  • Bowles, Kristian M4
  • Rushworth, Stuart A1
  • 1 Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom.
  • 2 Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Colney Lane, Norwich United Kingdom.
  • 3 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
  • 4 Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom. Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Colney Lane, Norwich United Kingdom.
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
Oct 30, 2014
Volume
5
Issue
20
Pages
9930–9938
Identifiers
PMID: 25294819
Source
Medline
License
Unknown

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.

Report this publication

Statistics

Seen <100 times