CXCR4 antagonists disrupt leukaemia-meningeal cell adhesion and attenuate chemoresistance

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Abstract

The effective prophylaxis and treatment of central nervous system (CNS) involvement in acute lymphoblastic leukaemia (ALL) remains a significant clinical challenge. Developing novel and more effective CNS-directed therapies has been hampered, in part, by our limited understanding of the leukaemia niche in the CNS relative to the bone marrow. Accordingly, defining the molecular and cellular components critical for the establishment and maintenance of the CNS leukaemia niche may lead to new therapeutic opportunities. In prior work we showed that direct intercellular interactions between leukaemia and meningeal cells enhance leukaemia chemoresistance in the CNS. Herein, we show that the CXCR4/CXCL12 chemokine axis contributes to leukaemia-meningeal cell adhesion. Importantly, clinically tested CXCR4 antagonists, which are likely to cross the blood–brain and blood-cerebral spinal fluid barriers and penetrate the CNS, effectively disrupted leukaemia-meningeal cell adhesion. Moreover, by disrupting these intercellular interactions, CXCR4 antagonists attenuated leukaemia chemoresistance in leukaemia-meningeal cell co-culture experiments and enhanced the efficacy of cytarabine in targeting leukaemia cells in the meninges in vivo. This work identifies the CXCR4/CXCL12 axis as an important regulator of intercellular interactions within the CNS leukaemia niche and supports further testing of the therapeutic efficacy of CXCR4 antagonists in overcoming CNS niche-mediated chemoresistance.

Original languageEnglish (US)
Pages (from-to)459-469
Number of pages11
JournalBritish journal of haematology
Volume201
Issue number3
DOIs
StatePublished - May 2023

Bibliographical note

Funding Information:
This work utilized the University of Minnesota Masonic Cancer Center shared flow cytometry core, which is supported in part by NCI 5P30CA077598‐18, Minnesota Masonic Charities and the Killebrew‐Thompson Memorial Fund. Immunohistochemistry was performed at the Histology and Research Laboratory, part of the University of Minnesota Clinical and Translational Science Institute.

Funding Information:
This work was supported by National Institutes of Health R37CA240846 (PMG), the Timothy O'Connell Foundation (PMG) and the Children's Cancer Research Fund (PMG).

Publisher Copyright:
© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Keywords

  • CXCL12
  • CXCR4
  • acute lymphoblastic leukaemia
  • adhesion
  • chemoresistance

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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