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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

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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