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Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). Using RNA sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a subtype characterized by recurrent  IGH-DUX4  or  ERG-DUX4  fusions, representing 4% of cases, leading to overexpression of  DUX4  and frequently co-occurring with intragenic  ERG  deletions. Furthermore, we identify a subtype characterized by an  ETV6-RUNX1 -like gene-expression profile and coexisting  ETV6  and  IKZF1  alterations. Thus, this study provides a detailed overview of fusion genes in paediatric BCP ALL and adds new pathogenetic insights, which may improve risk stratification and provide therapeutic options for this disease.

Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia