title: 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.
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.
authors.affiliation: Cancer Research UK Immunology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK.
authors.forename: F V
authors.initials: FV
authors.lastname: Castro
authors.forename: O J
authors.initials: OJ
authors.lastname: McGinn
authors.forename: S
authors.initials: S
authors.lastname: Krishnan
authors.forename: G
authors.initials: G
authors.lastname: Marinov
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: A J
authors.initials: AJ
authors.lastname: Rutkowski
authors.forename: E
authors.initials: E
authors.lastname: Elkord
authors.forename: D J
authors.initials: DJ
authors.lastname: Burt
authors.forename: M
authors.initials: M
authors.lastname: Holland
authors.forename: R
authors.initials: R
authors.lastname: Vaghjiani
authors.forename: A
authors.initials: A
authors.lastname: Gallego
authors.forename: V
authors.initials: V
authors.lastname: Saha
authors.forename: P L
authors.initials: PL
authors.lastname: Stern
mesh_terms: D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002633:Chemotaxis; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C031192:oncofetal antigens