Rearrangement and Deletion of the PAX5 Gene in Pediatric Acute B-Cell Lineage Lymphoblastic Leukemia.

Pediatric acute lymphoblastic leukemia (ALL) is the most common malignant disease in children. The disease results from accumulation of mutations of tumor suppressor genes and oncogenes. Recently, higher resolution SNP-chips (50,000–500,000 probes) have been developed allowing us to identify genes involved at the start sites of deletions/duplications. This permitted us both to identify unbalanced translocations involving t(1;19)(q23;p13) (TCF3/PBX1) and t(12;21)(p13;q11) (ETV6/RUNX1), as well as, to find novel fusion genes involving PAX5 in B-cell lineage ALL. PAX5 gene was rearranged to a variety of partner genes including ETV6, FOXP1, AUTS2 and C20orf112. In each case, tthe C-terminal end of the PAX5 gene was replaced by the partner gene. The PAX5 fusion gene products suppressed transcriptional activity of PAX5 in a dominant negative fashion. We also found a point mutation of PAX5 at codon 26 (Val 26 Gly); and this mutated PAX5 had attenuated transcriptional activity. Expression of PAX5/C20orf112 fusion gene in a B-cell line suppressed endgenous expression of PAX5 target genes including BLK1 and CD19. Furthermore, deletion of PAX5 was common in B-cell lineage ALL (34/339 cases). PAX5 gene is localized on chromosome 9p and concurrent deletion of PAX5 and INK4A genes were frequently detected in B-cell linage ALL. PAX5 gene may behave as a tumor suppressor gene during early development of B-cells and its alteration by either fusion to another gene, point mutation, or deletion may be associated with leukemogenesis of B-cell lineage ALL.