| Autor: |
Schmoellerl, Johannes, Barbosa, Inês Amorim Monteiro, Eder, Thomas, Brandstoetter, Tania, Schmidt, Luisa, Maurer, Barbara, Troester, Selina, Pham, Ha Thi Thanh, Sagarajit, Mohanty, Ebner, Jessica, Manhart, Gabriele, Aslan, Ezgi, Terlecki-Zaniewicz, Stefan, Van der Veen, Christa, Hoermann, Gregor, Duployez, Nicolas, Petit, Arnaud, Lapillonne, Helene, Puissant, Alexandre, Itzykson, Raphael, Moriggl, Richard, Heuser, Michael, Meisel, Roland, Valent, Peter, Sexl, Veronika, Zuber, Johannes, Grebien, Florian |
| Zdroj: |
Blood; July 2020, Vol. 136 Issue: 4 p387-400, 14p |
| Abstrakt: |
Fusion proteins involving Nucleoporin 98(NUP98) are recurrently found in acute myeloid leukemia (AML) and are associated with poor prognosis. Lack of mechanistic insight into NUP98-fusion–dependent oncogenic transformation has so far precluded the development of rational targeted therapies. We reasoned that different NUP98-fusion proteins deregulate a common set of transcriptional targets that might be exploitable for therapy. To decipher transcriptional programs controlled by diverse NUP98-fusion proteins, we developed mouse models for regulatable expression of NUP98/NSD1, NUP98/JARID1A, and NUP98/DDX10. By integrating chromatin occupancy profiles of NUP98-fusion proteins with transcriptome profiling upon acute fusion protein inactivation in vivo, we defined the core set of direct transcriptional targets of NUP98-fusion proteins. Among those, CDK6 was highly expressed in murine and human AML samples. Loss of CDK6 severely attenuated NUP98-fusion–driven leukemogenesis, and NUP98-fusion AML was sensitive to pharmacologic CDK6 inhibition in vitro and in vivo. These findings identify CDK6 as a conserved, critical direct target of NUP98-fusion proteins, proposing CDK4/CDK6 inhibitors as a new rational treatment option for AML patients with NUP98-fusions. |
| Databáze: |
Supplemental Index |
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