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The pre-B-cell receptor checkpoint in acute lymphoblastic leukaemia

Leukemia volume 29, pages 1623–1631 (2015)Cite this article

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Abstract

The B-cell receptor (BCR) and its immature form, the precursor-BCR (pre-BCR), have a central role in the control of B-cell development, which is dependent on a sequence of cell-fate decisions at specific antigen-independent checkpoints. Pre-BCR expression provides the first checkpoint, which controls differentiation of pre-B to immature B-cells in normal haemopoiesis. Pre-BCR signalling regulates and co-ordinates diverse processes within the pre-B cell, including clonal selection, proliferation and subsequent maturation. In B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), B-cell development is arrested at this checkpoint. Moreover, malignant blasts avoid clonal extinction by hijacking pre-BCR signalling in favour of the development of BCP-ALL. Here, we discuss three mechanisms that occur in different subtypes of BCP-ALL: (i) blocking pre-BCR expression; (ii) activating pre-BCR-mediated pro-survival and pro-proliferative signalling, while inhibiting cell cycle arrest and maturation; and (iii) bypassing the pre-BCR checkpoint and activating pro-survival signalling through pre-BCR independent alternative mechanisms. A complete understanding of the BCP-ALL-specific signalling networks will highlight their application in BCP-ALL therapy.

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Acknowledgements

We are grateful for financial support from: Marie Curie International Incoming Fellowship (JE), European Research Council, Leukaemia and Lymphoma Research, Cancer Research UK, Kay Kendall Leukaemia Fund and Medical Research Council career development award MR/J008060/1 (DPC), the programme grant from CR‐UK (grant number C27943/A12788).

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Authors and Affiliations

  1. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK

    J Eswaran, P Sinclair, O Heidenreich, J Irving, L J Russell, A Hall, C J Harrison & J Vormoor

  2. Cancer Research UK, London Research Institute, London, UK

    D P Calado

  3. Peter Gorer Department of Immunobiology, Kings College London, London, UK

    D P Calado

  4. Great North Children’s Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

    J Vormoor

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  1. J Eswaran
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  2. P Sinclair
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  3. O Heidenreich
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  4. J Irving
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Correspondence to C J Harrison.

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Eswaran, J., Sinclair, P., Heidenreich, O. et al. The pre-B-cell receptor checkpoint in acute lymphoblastic leukaemia. Leukemia 29, 1623–1631 (2015). https://doi.org/10.1038/leu.2015.113

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  • DOI: https://doi.org/10.1038/leu.2015.113

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