Abstract
ABSTRACT
The mammalian BRG-/BRM-associated factor (BAF) chromatin remodeling complexes are crucial regulators of hematopoietic stem and progenitor cell (HSPC) fate. Expression of the ncBAF subcomponent, BRD9, is altered in both normal aging and myeloid malignancies. We find that in adult human HSPC, BRD9 regulates the differentiation of myeloid progenitors. Upon degradation of BRD9 in these cells, ncBAF is displaced from the chromatin, leading in turn to enhanced recruitment of cBAF to bona fide CEBPA target sites. With the shift from ncBAF to cBAF, HSPC differentiation results in increased generation of myeloid-derived suppressor cells (MDSC) that secrete elevated levels of IL-8. Soluble factors from these myeloid cells, which have lost BRD9, enhance the stemness of breast cancer cells in vitro. In contrast, bromodomain inhibition of BRD9 results in minimal alterations of ncBAF binding and myeloid differentiation, indicating that BRD9 acts as a barrier to human MDSC differentiation in a bromodomain-independent manner.
Statement of significance
In this study, we show that BRD9 regulates the differentiation of immunosuppressive myeloid cells in a bromodomain-independent manner and demonstrate that complete degradation of BRD9 results in increased T cell suppression and aggressiveness of breast cancer cells.
KEY POINTS
BRD9 suppresses the development of myeloid-derived suppressor cells in a bromodomain-independent manner
Loss of BRD9 results in increased cBAF recruitment to CEBPA target sites and enhanced myeloid differentiation