Bromodomain protein BRD4 is an epigenetic activator of B7-H6 expression in acute myeloid leukemia

Abstract

B7-H6, a ligand for the NK activating receptor NKp30, has been identified as a biomarker of poor prognosis in several solid cancers. However, little is known about the role of B7-H6 and the mechanisms that control its expression in acute myeloid leukemia (AML). Epigenome modulation, including epigenomic reader dysregulation, is one of the hallmarks of AML. Bromodomain-containing protein 4 (BRD4), the best-known member of the BET family of epigenetic readers, is overexpressed in AML cells and regulates the transcription of genes involved in the pathogenesis of AML, as MYC oncogene. Here, we analyze the role of BRD4 in regulating B7-H6 in AML cells. Results demonstrated that the specific inhibition of BRD4 drastically reduces the expression of B7-H6 in AML cells. Histone acetylation mediated by CBP30/P300 facilitates the binding of BRD4 to the B7-H6 promoter, which recruits the P -TEFb elongation factor that phosphorylates RNA polymerase II, thereby activating B7-H6 transcription. BRD4 also co-bounded with JMJD6 at the distal enhancer of the B7-H6 gene. Metabolic modulation with metformin modifies the acetylation pattern in the B7-H6 promoter, impairing BRD4 binding, thereby inhibiting B7-H6 expression. B7-H6 knockdown induces the apoptosis in HEL-R cell line. Moreover, a high level of B7-H6 expression in AML patients is related to increased BRD4 levels, myelodysplastic-derived AML, and del5q, the two latter being associated with poor prognosis. Our data show that BRD4 is a positive regulator of the pro-tumorigenic molecule B7-H6 and that the blockage of the B7-H6 is a potential therapeutic target for the treatment of AML.

B7H6 Serves as a Negative Prognostic Marker and an Immune Modulator in Human Pancreatic Cancer

“…B7H6, a new newly discovered member of the B7 family, has been found in many tumors but not in normal tissues. Moreover, expression of B7H6 in tumors correlates with tumor progression and poor patient survival-except in gastric carcinoma (14)(15)(16)(17)(18)(19)(20)(21)(22). To date, no studies of the clinical significance of B7H6 expression in human PC have been reported.…”

“…There are two forms of B7H6-cell-surface B7H6 and soluble B7H6 (sB7H6)-and both have been detected in primary tumors and the tumor microenvironment, including in glioma, neuroblastoma, breast cancer, non-small cell lung cancer, hepatocellular carcinoma, gastric carcinoma, ovarian cancer, leukemia, and lymphoma-though rarely in normal tissues (14)(15)(16)(17)(18)(19)(20)(21)(22). Cell-surface B7H6 associates with cell damage, and it triggers innate immunity when it binds to NKp30 on NK cells (23).…”

Chemotherapy resistance in acute myeloid leukemia is associated with decreased anti-tumor immune response through MHC molecule and B7 family members

“…Moreover, high co-expression of immune checkpoints in blast cells of AML patients correlated with poor outcome FLT3 mut , RUNX1 mut , or TET2 mut [ 17 ]. Overexpression of B7-H6, a ligand for the NK activating receptor NKp30, is correlated with the clinical characteristics of poor prognosis in some AML patients [ 18 ]. B7-H7 serves as a potential prognostic indicator, associating with tumor immunity in human pan-cancer, including AML [ 19 ].…”

B7H6 silencing increases chemosensitivity to dacarbazine and suppresses cell survival and migration in cutaneous melanoma

“…This checkpoint molecule is a type I membrane protein with a 51 kDa molecular weight and 454 amino acids [18]. By binding to its receptor on natural killer cells (NKp30), this molecule produces cytotoxic chemokines and activates innate immune responses [17,19,20]. Even though the B7H6 is overexpressed in a variety of tumor cells, the expression of this molecule is low or negligible in normal tissues [17,19,20].…”