Findings from a new study, , demonstrate that inhibiting bromodomain and extra-terminal (BET) protein OPN-51107 (OPN5) in chronic lymphocytic leukemia (CLL) reduces leukemic cell burden and restores T-cell functions by decreasing immune inhibitory receptor (IR) expression and enhancing cytokine production. The research also suggests a reversal of T-cell exhaustion, indicated by changes in gene expression and chromatin accessibility.1
The study findings demonstrate that OPN5 treatment significantly reduces the presence of leukemic cells in the peripheral blood of CLL models. Mice treated with OPN5 for 21 days showed a decrease in CD19+/CD5+ peripheral blood lymphocytes (PBLs) from 71.8% in the control group to just 11.2% in the OPN5-treated group.The study identified 244 DEGs in the spleens of OPN5-treated mice. Findings include the upregulation of genes associated with T-cell activation, such as Cd3e, Cd8a, and inducible T-cell costimulator ligand (ICOSL). Conversely, genes involved in T-cell suppression, like Ctla4 and Cd274 (PD-L1), were downregulated.
BET proteins are known to influence chromatin structure.2 Chromatin accessibility analysis using ATAC sequencing revealed that OPN5 treatment also led to changes in chromatin accessibility. Genes involved in T-cell activation, such as TCF7 and CXCR5, showed increased accessibility, while those associated with terminal exhaustion, including CD101 and BATF3, displayed reduced accessibility.
The authors point out that although both OPN5 and chemotherapy treatments, such as fludarabine, reduce leukemic B-cell burden, only BET inhibition with OPN5 alleviated T-cell dysfunction in vivo, enriched for naïve CD5+ T cells, reduced IR expression, and altered the transcription factor profile of splenic CD8+ cells."Despite impressive single-agent activity in CLL, BET [inhibition] may be most effective in combinatory treatment regimens. Preclinical studies have shown that BET [inhibition] synergizes with other small molecule inhibitors, such as venetoclax and [ibrutinib], in B-cell non-Hodgkin lymphoma," the authors concluded.References
1. Smith AL, Skupa SA, Eiken AP, et al. BET inhibition reforms the immune microenvironment and alleviates T cell dysfunction in chronic lymphocytic leukemia. JCI Insight.🐠 Published online May 22, 2024. doi:10.1172/jci.insight.🌌177054
2. Cheung KL, Kim C, Zhou MM. The functions of BET proteins in gene transcription of biology and diseases. Front Mol Biosci. Published online Sept🍎ember 3, 2021. doi:10.3389/fmolb.💫2021.728777