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Gewählte Publikation:

Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2020

AutorInnen: Schmoellerl, J; Barbosa, IAM; Eder, T; Brandstoetter, T; Schmidt, L; Maurer, B; Troester, S; Pham, HTT; Sagarajit, M; Ebner, J; Manhart, G; Aslan, E; Terlecki-Zaniewicz, S; Van der Veen, C; Hoermann, G; Duployez, N; Petit, A; Lapillonne, H; Puissant, A; Itzykson, R; Moriggl, R; Heuser, M; Meisel, R; Valent, P; Sexl, V; Zuber, J; Grebien, F

Titel: CDK6 is an essential direct target of NUP98-fusion proteins in acute myeloid leukemia.

Quelle: Blood. 2020; 136(4):387-400



Autor/innen der Vetmeduni Vienna:

Brandstötter Tania
Ebner Jessica
Eder Thomas
Grebien Florian
Manhart Gabriele
Maurer Barbara
Moriggl Richard
Pham Ha
Schmidt Luisa
Schmöllerl Johannes
Sexl Veronika
Tröster Selina

Beteiligte Vetmed-Organisationseinheiten
Institut für Tierzucht und Genetik, Abteilung für Funktionelle Krebsgenomik
Institut für Medizinische Biochemie
Institut für Pharmakologie und Toxikologie


Zugehörige(s) Projekt(e): Common Oncogenic Mechanisms in Multi-Partner Translocation Families in Acute Myeloid Leukemia


Abstract:
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.© 2020 by The American Society of Hematology.


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