CBFA2T3‐GLIS2‐positive acute myeloid leukaemia. A peculiar paediatric entity

The scenario of paediatric acute myeloid leukaemia (AML), particularly non‐Down syndrome acute megakaryoblastic leukaemia (non‐DS‐AMKL), has been recently revolutionized by the advent of large‐scale, genomic sequencing technologies. In this changing landscape, a significantly relevant discovery has been represented by the identification of the CBFA2T3‐GLIS2 fusion gene, which is the result of a cryptic inversion of chromosome 16. It is the most frequent chimeric oncogene identified to date in non‐DS‐AMKL, although it seems not to be exclusively restricted to the French‐American‐British M7 subgroup. The CBFA2T3‐GLIS2 fusion gene characterizes a subtype of leukaemia that is specific to paediatrics, having never been identified in adults. It characterizes an extremely aggressive leukaemia, as the presence of this fusion is associated with a grim outcome in almost all of the case series reported, with overall survival rates ranging between 15% and 30%. Although the molecular basis that underlies this leukaemia subtype is still far from being completely elucidated, unique functional properties induced by CBFA2T3‐GLIS2 in the leukaemogenesis driving process have been recently identified. We here review the peculiarities of CBFA2T3‐GLIS2‐positive AML, describing its intriguing clinical and biological behaviour and providing some challenging targeting opportunities.