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Acute Leukemias

5T4 oncofetal antigen is expressed in high risk of relapse childhood pre-B acute lymphoblastic leukemia and is associated with a more invasive and chemotactic phenotype

Leukemia volume 26, pages 1487–1498 (2012)Cite this article

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Abstract

Although the overall prognosis in childhood acute lymphoblastic leukemia (ALL) is good, outcome after relapse is poor. Recurrence is frequently characterized by the occurrence of disease at extramedullary sites, such as the central nervous system and testes. Subpopulations of blasts able to migrate to such areas may have a survival advantage and give rise to disease recurrence. Gene expression profiling of 85 diagnostic pre-B-ALL bone marrow samples revealed higher 5T4 oncofetal antigen transcript levels in cytogenetic high-risk subgroups of patients (P<0.001). Flow cytometric analysis determined that bone marrow from relapse patients have a significantly higher percentage of 5T4-positive leukemic blasts than healthy donors (P=0.005). The high-risk Sup-B15 pre-B-ALL line showed heterogeneity in 5T4 expression, and the derived, 5T4+ (Sup5T4) and 5T4− (Sup) subline cells, displayed differential spread to the omentum and ovaries following intraperitoneal inoculation of immunocompromised mice. Consistent with this, Sup5T4 compared with Sup cells show increased invasion in vitro concordant with increased LFA-1 and VLA-4 integrin expression, adhesion to extracellular matrix and secretion of matrix metalloproteases (MMP-2/-9). We also show that 5T4-positive Sup-B15 cells are susceptible to 5T4-specific superantigen antibody-dependent cellular toxicity providing support for targeted immunotherapy in high-risk pre-B-ALL.

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Acknowledgements

We thank all people involved in the PICR core facilities and in particular the BRU. This work was supported by programme grants from Cancer Research UK to PLS (C480/A12328) and VS. AG was supported by Seville Health Authority Spain.

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Author notes

  1. F V Castro and O J McGinn: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Research UK Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK

    F V Castro, O J McGinn, G Marinov, J Li, A J Rutkowski, R Vaghjiani, A Gallego & P L Stern

  2. Children's Cancer Group, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

    S Krishnan, M Holland & V Saha

  3. Medical Oncology, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK

    E Elkord & D J Burt

  4. Paediatric and Adolescent Oncology, Central Manchester University Hospitals Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK

    V Saha

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Correspondence to P L Stern.

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Competing interests

Rights to use 5T4 as a target for superantigen therapy is licensed by Cancer Research Technology Ltd to Active Biotech and PLS has received payments from CRT relating to clinical trial milestones under this agreement. PLS is a member of the SAB of Oxford BioMedica. All other authors declare no conflict of interest.

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Castro, F., McGinn, O., Krishnan, S. et al. 5T4 oncofetal antigen is expressed in high risk of relapse childhood pre-B acute lymphoblastic leukemia and is associated with a more invasive and chemotactic phenotype. Leukemia 26, 1487–1498 (2012). https://doi.org/10.1038/leu.2012.18

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