PAX5 Mutations Occur Frequently in Adult B-Cell Acute Lymphoblastic Leukemia (B-ALL) and Is Significantly Associated with BCR-ABL1 Fusion Gene.

Abstract PAX5 is a transcription factor central to B-cell differentiation, frequently mutated in pediatric B-ALL (38.9% in 192 B-ALL, Nature,2007;446:758). PAX5 mutations consist in whole or partial gene deletions or amplifications, fusion gene or point mutations. Adult B-ALL differs in many regards from pediatric B-ALL as demonstrated by differences in prognosis and genetic abnormalities (ETV6-RUNX1 almost absent from adult; BCR-ABL1 rare in children). We screened the occurrence of PAX5 mutations in a series of 119 adult patients with B-lineage ALL prospectively treated in the GRAALL-2003 (pediatric-like protocol for BCR-ABL1 negative patients) or GRAAPH-2003 (imatinib-containing protocol for BCR-ABL1 positive patients), with a median follow-up of 667 days. PAX5 copy number was evaluated using quantitative PCR of each exon performed in hexaplicate (10 exons). PAX5 point mutations of the paired and transactivation domains (exons 2, 3, 7, 8 and 9) were evaluated by sequence analysis. PAX5 rearrangement was evaluated by caryotype and FISH analysis. Globally, PAX5 mutations were identified in 35 cases (30%). Isolated complete deletion of 1 allele was found in 13 cases (11%). Hypomorphic PAX5 alleles were detected in 22 cases (19%) consisting either of partial deletion (13 cases), partial amplification (1), point mutations (7 cases, frequently associated with complete deletion of the remaining allele in 5 cases) or fusion gene (1 PAX5-ELN). In addition, 2 cases of whole PAX5 amplification were found (2%). The remaining 82 cases had two normal PAX5 alleles (68%). BCR-ABL1 fusion gene was significantly associated with PAX5 mutations (Pearson Chi2, p=0.045) occurring in 40% of patients with PAX5 mutations and 18.3% without. PAX5 mutations were rare in the early stages of B-ALL as estimated by the immunological EGIL classification (only 2/35 PAX5 mutant cases [5.7%] vs. 16/82 [19.5%] in normal PAX5 B-ALL cases blocked at the B-I stage). Frequencies of CD10+ and CD20+ blasts were significantly higher in PAX5 mutant cases (Mann-Whitney, p=0.022 and p=0.038, respectively). As PAX5 is essential to the immunoglobulin heavy chain DHJH to VHDHJH transition, we analyzed IGH rearrangement. No difference was detected regarding the frequency of IGH rearrangement (78% in normal vs. 74% in mutants) or the rearranged VH. Survival was not significantly different between the two groups of patients (log rank, p=0.45). In conclusion, PAX5 mutations were a frequent event in adult B-ALL, associated with BCR-ABL1 fusion gene but were not associated with a significant clinical evolution.