Abstract
BackgroundDespite high cure rates for pediatric B-lineage acute lymphoblastic leukemia (B-ALL), short-term and long-term toxicities and chemoresistance are shortcomings of standard chemotherapy. Immunotherapy and chemoimmunotherapy based on monoclonal antibodies (mAbs) that target cell surface antigens with restricted expression in pediatric B-ALL may offer the potential to reduce toxicities and prevent or overcome chemoresistance. The receptor tyrosine kinase ROR1 has emerged as a candidate for mAb targeting in select B-cell malignancies.Methodology and Principal FindingsUsing flow cytometry, Western blotting, immunohistochemistry, and confocal immunofluorescence microscopy, we analyzed the cell surface expression of ROR1 across major pediatric ALL subtypes represented by 14 cell lines and 56 primary blasts at diagnosis or relapse as well as in normal adult and pediatric tissues. Cell surface ROR1 expression was found in 45% of pediatric ALL patients, all of which were B-ALL, and was not limited to any particular genotype. All cell lines and primary blasts with E2A-PBX1 translocation and a portion of patients with other high risk genotypes, such as MLL rearrangement, expressed cell surface ROR1. Importantly, cell surface ROR1 expression was found in many of the pediatric B-ALL patients with multiply relapsed and refractory disease and normal karyotype or low risk cytogenetics, such as hyperdiploidy. Notably, cell surface ROR1 was virtually absent in normal adult and pediatric tissues.Conclusions and SignificanceCollectively, this study suggests that ROR1 merits preclinical and clinical investigations as a novel target for mAb-based therapies in pediatric B-ALL. We propose cell surface expression of ROR1 detected by flow cytometry as primary inclusion criterion for pediatric B-ALL patients in future clinical trials of ROR1-targeted therapies.
Highlights
Pediatric B-lineage acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer in the USA, accounting for,25% of all cancers
We propose cell surface expression of ROR1 detected by flow cytometry as primary inclusion criterion for pediatric B-ALL patients in future clinical trials of ROR1-targeted therapies
ROR1 mRNA isoform 1 was expressed in all 18 patients with E2A-PBX1 genotype
Summary
Pediatric B-ALL is the most common childhood cancer in the USA, accounting for ,25% of all cancers. Pediatric B-ALL generally arises from pre-B cells in bone marrow and has the general immunophenotype CD10+ CD19+, yet its genotypes differ widely [1]. Other common cases of pediatric B-ALL have hyperdiploid, hypodiploid, and complex genotypes. Cure rates for pediatric B-ALL are .80% with optimal use of chemotherapy based on risk-based stratification [2]. The survival for the 15–20% of children who relapse is short and survivors have significant risks of long-term toxicities from chemotherapy, including secondary cancers, cardiovascular disease, obesity, neurocognitive and psychosocial disorders, and sterility. Despite high cure rates for pediatric B-lineage acute lymphoblastic leukemia (B-ALL), short-term and longterm toxicities and chemoresistance are shortcomings of standard chemotherapy. Immunotherapy and chemoimmunotherapy based on monoclonal antibodies (mAbs) that target cell surface antigens with restricted expression in pediatric B-ALL may offer the potential to reduce toxicities and prevent or overcome chemoresistance. The receptor tyrosine kinase ROR1 has emerged as a candidate for mAb targeting in select B-cell malignancies
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