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Nature. 2016 Oct 27;538(7626):518-522. doi: 10.1038/nature19801. Epub 2016 Oct 17.

T-cell acute leukaemia exhibits dynamic interactions with bone marrow microenvironments.

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Department of Life Sciences, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia.
Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
The Francis Crick Institute, 1 Midland Road, London NW1A 1AT, UK.
The Francis Crick Institute, Haematopoietic Stem Cell Laboratory, 1 Midland Road, London NW1A 1AT, UK.
SIB Swiss Institute of Bioinformatics and Institute of Molecular Life Sciences, University of Zurich, Winterthurstrasse 190, 8057 Zurich, Switzerland.
Stem Cell Regulation Unit, St Vincent's Institute of Medical Research, 41 Victoria Parade Fitzroy, Victoria 3065 Australia.
Imperial College Facility for Imaging by Light Microscopy, Sir Alexander Fleming Building, Imperial College London, London SW7 2AZ, UK.
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.
Peter MacCallum Cancer Centre, Department of Haematology, Melbourne, Victoria 3000, Australia.
Department of Haematology, St Vincent's Hospital, Fitzroy, Victoria 3065, Australia.
Department of Medicine, The University of Melbourne, Fitzroy, Victoria 3065, Australia.
Centre of Haemato-Oncology, Cancer Research UK Clinical Centre, Barts Cancer Institute, St Bartholomew's Hospital, Queen Mary University of London, London EC1M 6BQ, UK.


It is widely accepted that complex interactions between cancer cells and their surrounding microenvironment contribute to disease development, chemo-resistance and disease relapse. In light of this observed interdependency, novel therapeutic interventions that target specific cancer stroma cell lineages and their interactions are being sought. Here we studied a mouse model of human T-cell acute lymphoblastic leukaemia (T-ALL) and used intravital microscopy to monitor the progression of disease within the bone marrow at both the tissue-wide and single-cell level over time, from bone marrow seeding to development/selection of chemo-resistance. We observed highly dynamic cellular interactions and promiscuous distribution of leukaemia cells that migrated across the bone marrow, without showing any preferential association with bone marrow sub-compartments. Unexpectedly, this behaviour was maintained throughout disease development, from the earliest bone marrow seeding to response and resistance to chemotherapy. Our results reveal that T-ALL cells do not depend on specific bone marrow microenvironments for propagation of disease, nor for the selection of chemo-resistant clones, suggesting that a stochastic mechanism underlies these processes. Yet, although T-ALL infiltration and progression are independent of the stroma, accumulated disease burden leads to rapid, selective remodelling of the endosteal space, resulting in a complete loss of mature osteoblastic cells while perivascular cells are maintained. This outcome leads to a shift in the balance of endogenous bone marrow stroma, towards a composition associated with less efficient haematopoietic stem cell function. This novel, dynamic analysis of T-ALL interactions with the bone marrow microenvironment in vivo, supported by evidence from human T-ALL samples, highlights that future therapeutic interventions should target the migration and promiscuous interactions of cancer cells with the surrounding microenvironment, rather than specific bone marrow stroma, to combat the invasion by and survival of chemo-resistant T-ALL cells.

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