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The Pre-B-Cell Receptor Checkpoint in Acute Lymphoblastic Leukaemia

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The Pre-B-Cell Receptor Checkpoint in Acute Lymphoblastic Leukaemia Leukemia (2015) 29, 1623–1631 © 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15 www.nature.com/leu REVIEW The pre-B-cell receptor checkpoint in acute lymphoblastic leukaemia J Eswaran1, P Sinclair1, O Heidenreich1, J Irving1, LJ Russell1, A Hall1, DP Calado2,3, CJ Harrison1 and J Vormoor1,4 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. Leukemia (2015) 29, 1623–1631; doi:10.1038/leu.2015.113 INTRODUCTION surface protein receptors (Figure 1).11,12 Initially, multipotent Acute lymphoblastic leukaemia (ALL) results from expansion of lymphoid progenitors, generated from haemopoietic stem cells, immature haematopoietic cells in the bone marrow and blood. It differentiate into early pro-B cells. Subsequent rearrangements of is the most common childhood malignancy, with a peak incidence the Ig heavy-chain (HC) variable (V), diversity (D) and joining (J) around 2–5 years of age. In children, the frequency is 3–4 cases gene segments give rise to expression of an IgM HC that interacts per 100 000 each year, while among adults, the annual incidence with non-polymorphic ‘surrogate’ light-chain (LC) components to 13,14 is lower, around 1 case per 100 000. Treatment modifications, form the pre-B-cell receptor (pre-BCR). In human BCP-ALL, the improved patient management and risk stratification have B-cell developmental process is arrested at this pre-B-cell stage dramatically improved survival rates to more than 80% for (Figure 1). In support of these observations, when expression of children and about 40% for adults.1 Acquired chromosomal pre-BCR was hampered through deletion of the exons coding for abnormalities are the hallmark of ALL, which define biologically the transmembrane region, IgHM (Immunoglobulin Heavy distinct subtypes of the disease. The strong association between Constant Mu), in μMT mice, it resulted in a complete arrest of cytogenetic subtypes and prognosis has further refined risk B-cell development with twofold enrichment of pro-B cells.15 stratification for treatment in a large number of protocols The pre-B-cell checkpoint is one of the first vital cell fate worldwide.2–4 Research into the biological and clinical roles of decision-making elements that controls critical B-cell develop- additional genetic alterations, including copy number abnormal- mental processes, such as clonal selection, expansion and 13,16 ities and gene mutations within key pathways, such as B-cell subsequent maturation to the pre-B-cell stage (Figure 1). differentiation and development, cell cycle control, RAS Once the pre-BCR complex is assembled, its transient expression (Rat sarcoma viral oncogene homologue) and cytokine signalling, induces signalling that initiates clonal expansion of IgHM positive 17 are ongoing.5–7 pre-B cells. When a number of cell proliferation cycles have been ALL is a clonal disease, originating from precursor B- or completed, pre-BCR signalling arrests the cell cycle, which is a T-lineage cells,1 which become the propagators of the leukaemia. pre-requisite for entry into small pre-B cell stage and further Almost all blasts have leukaemia-propagating potential in BCP- cell maturation. More importantly, B lymphocytes with a ALL,8,9 forming a model completely different from the hierarchical non-productive Ig HC are eliminated through programmed cell model of acute myeloid leukaemia and normal haemopoietic stem death. Thus, the function of pre-BCR checkpoint and its down- cells.8,10 These observations highlight the need to understand how stream signalling is to select pre-B cells that are suitable for BCP-ALL cells manage to evade early B-cell developmental continuing development or otherwise initiate cell death. After the checkpoints during the development of leukaemia. pre-BCR checkpoint positive selection, the occurrence of LC B-cell development is a highly complex process involving rearrangement leads to the next developmental stage, the rearrangement of the immunoglobulin (Ig) genes, as well as cell immature naive B cells. These naive immature B cells are positively 1Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; 2Cancer Research UK, London Research Institute, London, UK; 3Peter Gorer Department of Immunobiology, Kings College London, London, UK and 4Great North Children’s Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. Correspondence: Professor CJ Harrison, Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Level 5, Sir James Spence Institute, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK. E-mail: [email protected] Received 18 November 2014; revised 20 April 2015; accepted 23 April 2015; accepted article preview online 6 May 2015; advance online publication, 22 May 2015 pre-B-cell receptor checkpoint in leukaemia J Eswaran et al 1624 Figure 1. Normal B-cell development from the pro-B cell to immature B-cell stage in the bone marrow, showing how the blockade in pre-BCR expression, the pre-BCR regulated processes, such as cell cycle control, clonal extinction and apoptosis, lead to the development of BCP-ALL. selected for expression of a non-auto reactive, functional BCR and 3. Bypassing the pre-BCR checkpoint and activating pro-survival leave the bone marrow and differentiate into distinct B-cell signalling through pre-BCR independent alternative mechanisms. subtypes such as follicular B cells, marginal zone B cells and germinal centre B cells.13,18 The activation and clonal expansion of We review the application of these mechanisms in BCP-ALL these cells occur upon antigen-induced BCR signalling as well as and discuss pre-BCR-mediated BCP-ALL signalling pathways as signalling from cytokine and co-stimulatory receptors. Thus, the potential therapeutic targets. BCR structure, expression and signalling status (that is, tonic or chronic active) function as a ‘homoeostatic controller’ of B-cell development.13,19 BLOCKING PRE-BCR EXPRESSION AND FUNCTIONS FAVOUR Throughout lymphoid development, B-lineage cells undergo BCP-ALL DEVELOPMENT stringent selection for expression of pre-BCR and the appropriate Arrest in differentiation at the pre-BCR checkpoint is specificto BCR. Although expression of pre-BCR is blocked in the majority of BCP-ALL. Therefore, a key challenge is to understand why BCP-ALL, most mature B-cell malignancies express BCR and the differentiation is blocked at the pre-B-cell stage. A most recent development of the tumour is often driven by the intensity of study investigated the expression of pre-BCR components (IGLL1, – skewed BCR signalling.13,18 20 Using different BCR signalling IGLL3, VPREB1, VPREB3 and IGHM) and the presence of functional intensities, for example, (i) absent,21 (ii) basal/tonic22 and tonic pre-BCR signalling in 830 cases of BCP-ALL (including MLL, (iii) chronic active,21,23 and the regulators of BCR-mediated survival BCR-ABL1, ETV6-RUNX1, B-other, PBX1 rearrangement, 6q21 dele- pathways, mature B-cell malignancies are classified, which has led tion, duplication of 1q23 and high hyperdiploid ALL), and found to the development of new treatment strategies.19,24 In most only 112 (13%) to be positive for pre-BCR expression.20 Given the B-cell lymphomas, the tumour progression depends on BCR fact that pre-BCR induces pro-proliferative activity, a process expression, with few exceptions, namely classical Hodgkin’s which in itself would be assumed to promote the development lymphoma, primary mediastinal B-cell lymphoma, some post- of BCP-ALL, it is intriguing that the vast majority of the BCP-ALL transplant lymphomas, and rare primary effusion lymphomas.25,26 lack pre-BCR expression/function. It is possible that pre-BCR may In several lymphomas, BCRs arrested at a particular stage of function as a tumour suppressor under certain leukaemic differentiation, for example, tonic, auto reactive or antigen bound conditions. Such a role has been demonstrated in Philadelphia state, contribute to lymphoma pathogenesis. The role of BCR chromosome (Ph)/BCR-ABL1 (breakpoint cluster region protein— signalling pathways in B-cell development and malignancies have Abelson murine leukaemia viral oncogene homologue 1)-positive been extensively reviewed.13,18,19,27 In contrast, the status of pre- ALL. The leukaemic
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