James Downing and colleagues report the discovery of recurrent driver mutations in non-Down syndrome acute megakaryoblastic leukemia (non-DS-AMKL), including a CBFA2T3-GLIS2 fusion present in 27% of pediatric cases (Cancer Cell 22, 683–697, 2012). The authors sequenced the transcriptomes of 14 pediatric AMKL cases and found 7 with a balanced inversion on chromosome 16 resulting in an in-frame fusion of CBFA2T3 and GLIS2. Follow-up analyses in a larger set of pediatric and adult AMKL cases showed that this fusion was recurrent, restricted to pediatric cases and associated with unfavorable outcome. The authors also identified a NUP98-KDM5A fusion in 8% of pediatric cases, as well as recurrent mutations in GATA1 and JAK kinase genes. To examine the biological effects of the CBFA2T3-GLIS2 fusion, the authors transduced mouse hematopoietic cells with a retrovirus encoding CBFA2T3-GLIS2 and found that the fusion conferred increased capacity for self-renewal, with evidence for differentiation along the megakaryocytic lineage. They further showed that these effects on self-renewal were likely mediated by upregulation of bone morphogenetic protein (BMP) signaling. These findings provide insights into the biology of AMKL and identify CBFA2T3-GLIS2 as a new clinical marker with prognostic significance for pediatric patients with AMKL.
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Vogan, K. Recurrent fusion in pediatric AMKL. Nat Genet 45, 11 (2013). https://doi.org/10.1038/ng.2512
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DOI: https://doi.org/10.1038/ng.2512