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

Lookup NU author(s): Dr Jeyanthy Eswaran, Dr Paul Sinclair, Professor Olaf Heidenreich, Professor Julie Irving, Dr Lisa Russell, Emeritus Professor Andy Hall, Professor Christine Harrison, Dr Britta Vormoor

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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.


Publication metadata

Author(s): Eswaran J, Sinclair P, Heidenreich O, Irving J, Russell LJ, Hall A, Calado DP, Harrison CJ, Vormoor J

Publication type: Review

Publication status: Published

Journal: Leukemia

Year: 2015

Volume: 29

Issue: 8

Pages: 1623-1631

Print publication date: 01/08/2015

Online publication date: 22/05/2015

Acceptance date: 23/04/2015

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: NATURE PUBLISHING GROUP

URL: http://dx.doi.org/10.1038/leu.2015.113

DOI: 10.1038/leu.2015.113


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