Abstract
PAX5 is a member of the paired box (PAX) family of transcription factors involved in B-cell development. PAX5(P80R) has recently been described as a distinct genetic B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) subtype with a favorable prognosis in adults. In contrast, an unfavorable outcome has been observed in children. Our aim was to determine the frequency of PAX5(P80R) in childhood BCP-ALL treated according to the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 protocol and to evaluate its clinical significance within this study cohort. The analyses included 1237 patients with ALL treated in the AIEOP-BFM ALL 2000 trial with complete information for copy number variations (CNVs) of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, and ERG. A customized TaqMan genotyping assay was used to screen for PAX5(P80R) . Sanger sequencing was used to confirm PAX5(P80R) -positive results as well as to screen for second variants in PAX5. Agilent CGH + SNP arrays (e-Array design 85 320; Agilent Technologies) were performed in PAX5(P80R) -positive patients to verify additional CNVs. Almost 2% (20/1028) of our BCP-ALL cohort were PAX5(P80R) -positive. White blood cell counts higher than 50 000/μl as well as male sex were significantly (P < .05) associated with PAX5(P80R) . Most of the PAX5(P80R) -positive cases were 10 years of age or older. PAX5(P80R) -positive samples were enriched for deletions affecting PAX5, IKZF1, CDKN2A, and CDKN2B. Compared to PAX5(P80R) -wildtype BCP-ALL, PAX5(P80R) -positive patients showed a significantly reduced 5-year overall survival (P = .042). Further studies should evaluate the interaction of PAX5(P80R) with other genetic aberrations to further stratify intermediate risk pediatric BCP-ALL.