Copy Number Alterations of PAX5, CDKN2A/B Genes Rather Than IKZF1 gene Are Associated with Pathogenesis of Childhood ALL in Korean Assessed by Multiplex Ligation-Dependent Probe Amplification

Recent genomic studies have analyzed genetic alterations and gene expression in childhood acute lymphoblastic leukemia (ALL), and detected multiple new submicroscopic genetic abnormalities in key cellular pathways, and also identified new prognostic markers and therapeutic targets. More than 50 recurring genetic alterations have been identified, and these genes are known to play key or putative roles in lymphoid development and leukemogenesis. Multiplex Ligation-dependent Probe Amplification (MLPA) is a rapid multiplex PCR based technique that allows the comparative quantification of multiple sites. However, there have been no reports on the MLPA based copy number alterations (CNA) of childhood ALL in Asian countries. The aim of this study is to reveal the CNA of genes involved in lymphoid differentiation and cell cycle control in Korean children with ALL.

Reference ranges for individual MLPA probes were established from a group of 30 healthy control subjects. The MLPA assay was performed for 121 children with ALL in Korea to target those genes including the lymphoid differentiation genes (BTG1, EBF1, IKZF1, and PAX); cell cycle control genes (CDKN2A/B and RB1); transcriptional factors regulating genes (ETV6); and those deleted from the PAR1 region (IL3RA, CRLF2 and CSF2RA). We also evaluated the prognostic impact of these abnormalities.

Out of the 121 patients analyzed in our study, 96 (79%) displayed CNA in at least one gene: PAX5, 49 (40%); CDKN2A, 42 (35%); CDKN2B, 35 (29%); IKZF1, 22 (18%); ETV6, 22 (18%); EBF1, 16 (13%); RB1, 16 (13%); BTG1, 14 (12%); CRLF2, 12 (10%); IL3RA, 12 (10%); CSF2RA, 11 (9%). Thirteen of 121 (11%) patients relapsed. There was no significant correlation between these CNA and the recurrence of ALL.

These results suggest that CNA of PAX5, CDKN2A/B may play an important role in the pathogenesis of childhood ALL in Korea, contrasting to those findings from western countries showing a significant correlation between IKZF1 and childhood ALL. Several factors should be considered to explain a discrepancy between our results and the previous studies, which include different genotype frequencies in polymorphisms and varied susceptibility to ALL in different ethnic groups. Further studies incorporating larger number of cases and analyzing other possible genes are warranted in childhood ALL.

No relevant conflicts of interest to declare.