CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
23 07 2020
23 07 2020
Historique:
received:
10
09
2019
accepted:
08
04
2020
pubmed:
29
4
2020
medline:
26
2
2021
entrez:
29
4
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32344427
pii: S0006-4971(20)61858-4
doi: 10.1182/blood.2019003267
pmc: PMC7115844
mid: EMS86766
doi:
Substances chimiques
Nuclear Pore Complex Proteins
0
Nup98 protein, human
0
Oncogene Proteins, Fusion
0
CDK6 protein, human
EC 2.7.11.22
Cdk6 protein, mouse
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
387-400Subventions
Organisme : European Research Council
ID : 636855
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 by The American Society of Hematology.
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