CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia
In: Blood, Jg. 136 (2019-09-10), Heft 4
Online
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Zugriff:
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.
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CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia
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Autor/in / Beteiligte Person: | Grebien, Florian ; Ha Thi Thanh Pham ; Petit, Arnaud ; Manhart, Gabriele ; Meisel, Roland ; Puissant, Alexandre ; Valent, Peter ; Schmoellerl, Johannes ; Schmidt, Luisa ; Troester, Selina ; Sagarajit, Mohanty ; Lapillonne, Hélène ; Itzykson, Raphael ; Inês Amorim Monteiro Barbosa ; Hoermann, Gregor ; Heuser, Michael ; Ebner, Jessica ; Duployez, Nicolas ; Brandstoetter, Tania ; Zuber, Johannes ; Aslan, Ezgi ; Eder, Thomas ; Moriggl, Richard ; Terlecki-Zaniewicz, Stefan ; Christa Van Der Veen ; Sexl, Veronika ; Maurer, Barbara |
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Zeitschrift: | Blood, Jg. 136 (2019-09-10), Heft 4 |
Veröffentlichung: | 2019 |
Medientyp: | unknown |
ISSN: | 1528-0020 (print) |
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