The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription.
Bibliographical noteFunding Information:
We thank Christof Fellmann and Johannes Zuber for shRNA sequence designs; Osama El Demerdash, Ying Jin, Yuan Hao, and Molly Hammell for assistance with genomic analysis; James Bradner and Jun Qi for providing JQ1; and Zihua Wang and Michael Wigler for assistance with deep sequencing. This work was supported by Cold Spring Harbor Laboratory NCI Cancer Center Support grant CA455087 for developmental funds and shared resource support. Additional funding was provided by the Alex’s Lemonade Stand Foundation and the V Foundation. J.-S.R. is supported by the Martin Sass Foundation and the Lauri Strauss Leukemia Foundation. L.J.-T. is supported by the Cold Spring Harbor Laboratory Women in Science Award and as an investigator of the Howard Hughes Medical Institute. C.R.V. is supported by a Burroughs-Wellcome Fund Career Award, NIH grant NCI RO1 CA174793, and a Leukemia & Lymphoma Society Scholar Award. This work was supported in part by a grant from Boehringer Ingelheim.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology