RUNX1 encodes a Runt-related transcription factor that is critical for hematopoiesis. In this study, through a combinatorial molecular approach, we characterized a novel t(5;21)(q13;q22) translocation involving RUNX1 that was acquired during the progression of myelodysplastic syndrome to acute myeloid leukemia (AML) in a pediatric patient. We found that this translocation did not generate RUNX1 fusion but aberrantly upregulated RUNX1. This upregulation was attributed to the disruption of long-range chromatin interactions between the RUNX1 P2 promoter and a silencer in the first intron of the gene. Characterization of the silencer revealed a role of SNAG repressors and their corepressor LSD1/KDM1A in mediating the effect. Our findings suggest that chromosomal rearrangements may activate RUNX1 by perturbing its transcriptional control to contribute to AML pathogenesis, in keeping with an emerging oncogenic role of RUNX1 in leukemia.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0881-2) contains supplementary material, which is available to authorized users.
Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacological profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models. Integration with genomic data uncovered new gene-drug associations, suggesting actionable therapeutic vulnerabilities. Transcriptome profiling further identified gene expression signatures associated with on- and off-target drug responses. We also demonstrated the feasibility of drug screening-guided treatment for children with high-risk AML, with two evaluable cases achieving remission. Collectively, this study offers a high-dimensional gene-drug-clinical dataset that could be leveraged to research the unique biology of pediatric AML, and sets the stage for realizing functional precision medicine for clinical management of the disease.
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