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

F. V. Castro, O. J. McGinn, S. Krishnan, G. Marinov, J. Li, A. J. Rutkowski, Eyad Elkord, D. J. Burt, M. Holland, R. Vaghjiani, A. Gallego, V. Saha, P. L. Stern

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 (P0.001). Flow cytometric analysis determined that bone marrow from relapse patients have a significantly higher percentage of 5T4-positive leukemic blasts than healthy donors (P0.005). 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.

Original languageEnglish
Pages (from-to)1487-1498
Number of pages12
JournalLeukemia
Volume26
Issue number7
DOIs
Publication statusPublished - Jul 2012
Externally publishedYes

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Phenotype
Recurrence
Bone Marrow
Integrin alpha4beta1
Superantigens
Lymphocyte Function-Associated Antigen-1
Omentum
Metalloproteases
Gene Expression Profiling
Matrix Metalloproteinases
Integrins
Cytogenetics
Immunotherapy
Extracellular Matrix
Testis
Ovary
Central Nervous System
Tissue Donors
Survival

Keywords

  • 5T4 oncofetal antigen
  • chemotaxis
  • CXCL12
  • CXCR4
  • immunotherapy
  • pre-B-cell acute lymphoblastic leukemia

ASJC Scopus subject areas

  • Medicine(all)
  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

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. / Castro, F. V.; McGinn, O. J.; Krishnan, S.; Marinov, G.; Li, J.; Rutkowski, A. J.; Elkord, Eyad; Burt, D. J.; Holland, M.; Vaghjiani, R.; Gallego, A.; Saha, V.; Stern, P. L.

In: Leukemia, Vol. 26, No. 7, 07.2012, p. 1487-1498.

Research output: Contribution to journalArticle

Castro, FV, McGinn, OJ, Krishnan, S, Marinov, G, Li, J, Rutkowski, AJ, Elkord, E, Burt, DJ, Holland, M, Vaghjiani, R, Gallego, A, Saha, V & Stern, PL 2012, '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, vol. 26, no. 7, pp. 1487-1498. https://doi.org/10.1038/leu.2012.18
Castro, F. V. ; McGinn, O. J. ; Krishnan, S. ; Marinov, G. ; Li, J. ; Rutkowski, A. J. ; Elkord, Eyad ; Burt, D. J. ; Holland, M. ; Vaghjiani, R. ; Gallego, A. ; Saha, V. ; Stern, P. L. / 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. In: Leukemia. 2012 ; Vol. 26, No. 7. pp. 1487-1498.
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AU - Castro, F. V.

AU - McGinn, O. J.

AU - Krishnan, S.

AU - Marinov, G.

AU - Li, J.

AU - Rutkowski, A. J.

AU - Elkord, Eyad

AU - Burt, D. J.

AU - Holland, M.

AU - Vaghjiani, R.

AU - Gallego, A.

AU - Saha, V.

AU - Stern, P. L.

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AB - 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 (P0.001). Flow cytometric analysis determined that bone marrow from relapse patients have a significantly higher percentage of 5T4-positive leukemic blasts than healthy donors (P0.005). 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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