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Gene Expression Profiling Identifies BAX- as a Novel Tumor Antigen in Acute Lymphoblastic Leukemia

Departments of ¹ Medical Oncology, ² Pediatric Oncology, and ³ Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School; ⁴ Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts; ⁵ Unit of Tumor Biology, Institute of Molecular Medicine, University of Lisbon, Portugal; and ⁶ Department of Pediatric Oncology/Hematology, Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, the Netherlands

Requests for reprints: Angelo A. Cardoso, Department of Medical Oncology, Dana-Farber Cancer Institute, Room D-540B, 44 Binney Street, Boston, MA 02115. Phone: 617-632-6706; Fax: 617-632-4369; E-mail: cardoso{at}mbcrr.harvard.edu.

The identification of new tumor-associated antigens (TAA) is critical for the development of effective immunotherapeutic strategies, particularly in diseases like B-cell acute lymphoblastic leukemia (B-ALL), where few target epitopes are known. To accelerate the identification of novel TAA in B-ALL, we used a combination of expression profiling and reverse immunology. We compared gene expression profiles of primary B-ALL cells with their normal counterparts, B-cell precursors. Genes differentially expressed by B-ALL cells included many previously identified as TAA in other malignancies. Within this set of overexpressed genes, we focused on those that may be functionally important to the cancer cell. The apoptosis-related molecule, BAX, was highly correlated with the ALL class distinction. Therefore, we evaluated BAX and its isoforms as potential TAA. Peptides from the isoform BAX- bound with high affinity to HLA-A*0201 and HLA-DR1. CD8⁺ CTLs specific for BAX- epitopes or their heteroclitic peptides could be expanded from normal donors. BAX-–specific T cells lysed peptide-pulsed targets and BAX-–expressing leukemia cells in a MHC-restricted fashion. Moreover, primary B-ALL cells were recognized by BAX-–specific CTL, indicating that this antigen is naturally processed and presented by tumor cells. This study suggests that (a) BAX- may serve as a widely expressed TAA in B-ALL and (b) gene expression profiling can be a generalizable tool to identify immunologic targets for cancer immunotherapy.