Comprehensive genetic analyses of relapsed B-cell precursor acute lymphoblastic leukemia in children

The causes for individual relapse in children with B-cell precursor acute lymphoblastic leukemia （BCPALL）remain incompletely understood. Here, we performed comprehensive genetic analyses of 20 pediatric BCP-ALL paired diagnosis-relapse samples. Copy number variation analysis of IKZF1, a gene for which deletions are associated with increased relapse risk, revealed deletions at both diagnosis and at relapse （n=5）. Targeted next generation sequencing showed that RAS pathway genes including KRAS （n=4）, NRAS （n=2）and PTPN11 （n=2）were the most common mutations among the sequencing targets at diagnosis and/or relapse. In 7 of 20 cases （35%）, mutations in PTPN11, KRAS, TP53, CTCF, NCOR1, WHSC1, TUSC3, ERG and NT5C2 were detected only at relapse. Two cases with TP53 mutations showed fatal outcomes. In two of the four cases with high hyperdiploid BCP-ALL, associated with favorable prognosis, PTPN11 mutations were detected only at relapse. Targeted RNA sequencing identified a rare subtype of BCP-ALL with a NUP214-ABL1 fusion that could benefit from tyrosine kinase inhibitors. Together with recent reports that RAS mutations confer sensitivity to MEK inhibitors, these results suggest that comprehensive genetic analysis will contribute to the optimal treatment for relapsed BCP-ALL.