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| Item Type: | Article |
|---|---|
| Title: | Mutant CEBPA directly drives the expression of the targetable tumor-promoting factor CD73 in AML |
| Creators Name: | Jakobsen, J.S., Laursen, L.G., Schuster, M.B., Pundhir, S., Schoof, E., Ge, Y., d'Altri, T., Vitting-Seerup, K., Rapin, N., Gentil, C., Jendholm, J., Theilgaard-Mönch, K., Reckzeh, K., Bullinger, L., Döhner, K., Hokland, P., Fitzgibbon, J. and Porse, B.T. |
| Abstract: | The key myeloid transcription factor (TF), CEBPA, is frequently mutated in acute myeloid leukemia (AML), but the direct molecular effects of this leukemic driver mutation remain elusive. To investigate mutant AML, we performed microscale, in vivo chromatin immunoprecipitation sequencing and identified a set of aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. Comparing gene expression changes in human mutant AML and the corresponding mouse model, we identified , encoding CD73, as a cross-species AML gene with an upstream leukemic enhancer physically and functionally linked to the gene. Increased expression of CD73, mediated by the CEBPA-p30 isoform, sustained leukemic growth via the CD73/A2AR axis. Notably, targeting of this pathway enhanced survival of AML-transplanted mice. Our data thus indicate a first-in-class link between a cancer driver mutation in a TF and a druggable, direct transcriptional target. |
| Keywords: | 5'-Nucleotidase, Binding Sites, CCAAT-Enhancer-Binding Proteins, Genetic Enhancer Elements, Genetic Epigenesis, GPI-Linked Proteins, Gene Expression Profiling, Leukemic Gene Expression Regulation, Acute Myeloid Leukemia, Mutation, Nucleotide Motifs, Prognosis, Genetic Promoter Regions, Protein Binding, Protein Isoforms / Genetics, Animals, Mice |
| Source: | Science Advances |
| ISSN: | 2375-2548 |
| Publisher: | American Association for the Advancement of Science |
| Volume: | 5 |
| Number: | 7 |
| Page Range: | eaaw4304 |
| Date: | July 2019 |
| Official Publication: | https://doi.org/10.1126/sciadv.aaw4304 |
| PubMed: | View item in PubMed |
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