Genomic landscape of pediatric B-other acute lymphoblastic leukemia in a consecutive European cohort

Abstract

Novel biological subtypes and clinically important genetic aberrations (druggable lesions, prognostic factors) have been described in B-other acute lymphoblastic leukemia (ALL) during the last decade; however, due to a lack of studies on unselected cohorts, their population frequency and mutual associations still have to be established. We studied 110 consecutively diagnosed and uniformly treated childhood B-other patients using single nucleotide polymorphism arrays and whole exome/transcriptome sequencing. The frequency of <i>DUX4</i>-rearranged, <i>BCR-ABL1</i>-like, <i>ZNF384</i>-rearranged, <i>ETV6-RUNX1</i>-like, iAMP21 and <i>MEF2D</i>-rearranged subtypes was 27%, 15%, 5%, 5%, 4%, and 2%, respectively; 43% of cases were not classified into any of these subtypes (B-rest). We found worse early response to treatment in <i>DUX4</i>-rearranged leukemia and a strong association of <i>ZNF384</i>-rearranged leukemia with B-myeloid immunophenotype. Of the druggable lesions, JAK/STAT-class and RAS/RAF/MAPK-class aberrations were found in 21% and 43% of patients, respectively; an ABL-class aberration was found in one patient. A recently described negative prognostic factor, <i>IKZF1^plus</i> , was found in 14% of patients and was enriched in (but not exclusive for) <i>BCR-ABL1</i>-like subtype. <i>PAX5</i> fusions (including 4 novel), intragenic amplifications and P80R mutations were mutually exclusive and only occurred in the B-rest subset, altogether accounting for 20% of the B-other group. <i>PAX5</i> P80R was associated with a specific gene expression signature, potentially defining a novel leukemia subtype. Our study shows unbiased European population-based frequencies of novel ALL subtypes, recurrent (cyto)genetic aberrations and their mutual associations. This study also strengthens and widens the current knowledge of B-other ALL and provides an objective basis for optimization of current genetic diagnostics.