Unknown

Dataset Information

0

CDK6 is an essential direct target of NUP98 fusion proteins 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.

SUBMITTER: Schmoellerl J 

PROVIDER: S-EPMC7115844 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

altmetric image

Publications


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-fus  ...[more]

Similar Datasets

2020-05-08 | GSE134784 | GEO
| PRJNA556414 | ENA
| S-EPMC7600396 | biostudies-literature
| S-EPMC8791568 | biostudies-literature
2017-07-10 | PXD001828 | Pride
| S-EPMC5239466 | biostudies-literature
2008-04-01 | GSE10909 | GEO
| S-EPMC60524 | biostudies-literature
| S-EPMC3567982 | biostudies-literature
| S-EPMC7535657 | biostudies-literature