Details

Autor(en) / Beteiligte

• 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

Titel

CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia

Ist Teil von

• Blood, 2020-07, Vol.136 (4), p.387-400

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. •NUP98-fusion proteins directly regulate leukemia-associated gene expression programs in AML.•CDK6 expression is under direct transcriptional control of NUP98-fusions, and NUP98-fusion AML is particularly sensitive to CDK6 inhibition. [Display omitted]