IRF8 expression

We demonstrate that IRF8 is expressed in a significant subset of tested neoplasms of histiocytic and dendritic cell lineage. While we confirmed that IRF8 is useful to identify monoblasts, these results highlight that IRF8 cannot be reliably used to distinguish histiocytic sarcomas from myeloid neoplasms of monocytic lineages, and caution is advised interpreting IRF8 staining in that setting.

However, a panel combining IRF8, CD123, and CD20, with at least 1 positive marker was more accurate than any individual marker by receiver operating characteristic curve analysis. Our study provides a rationale for potentially including IRF8 as part of an immunohistochemical panel composed of other currently available markers used to differentiate LEP from SPTCL.

RAS mutations also decrease efficacy of the BCL2 inhibitor venetoclax now widely used in AML, suggesting an anti-apoptotic influence of MAPK signaling...Using GSEA we found that gilteritinib stimulated adaptive interferon/inflammatory gene signatures at 16h drug treatment, but this response was restrained by addition of SEL120...We speculate this latter effect may in part alter an AML cell's differentiation state to sensitize cells to apoptosis, though further study to explore this hypothesis is needed. Our in vitro and in vivo efficacy data further validated combined FLT3i/CDK8i as a promising investigational strategy to pre-empt or overcome MAPK-mediated FLT3 TKI resistance.

Altogether, our results highlight the inflammatory status of the DLBCL microenvironment orchestrated by macrophages. More work is needed to understand the complexity and potential therapeutic implications of inflammasomes in DLBCL.

Using a xenograft mouse model, we discovered the antiproliferative effect of losing IRF8 in vivo. In conclusion, this study found that IRF8 may play a prognostic factor and therapeutic target in AML.

Targeting the FTO-IRF8 axis is used as a proof of concept therapy; inhibition of FTO's demethylase activity drastically alleviates the proliferation of leukemic cells and prolongs the survival of T-ALL mice by restoring IRF8 expression. This study elucidates the pathogenesis of T-ALL from the perspective of epitranscriptomics and provides new insight into the genetic mechanisms and targeted therapy of T-ALL.

Furthermore, the TAM-IRF8 signature co-segregated with CTL exhaustion signatures across multiple cancer types. Thus, CTL exhaustion is promoted by TAMs via IRF8.

PD-L1 was expressed in human osteosarcoma tissues, and its expression was moderately correlated with that of ICSBP in osteosarcoma patients. ICSBP regulates PD-L1 expression in osteosarcoma cells, and PD-L1 knockdown combined with doxorubicin treatment could represent a strategy for controlling osteosarcoma expressing ICSBP.

Conclusions Our studies suggest that eliminating STAT3 checkpoint allows for TLR9-mediated reprogramming of leukemic cells into antigen-presenting cells capable of stimulating adaptive T cell immune responses against AML. Furthermore, these findings support further development of CpG-STAT3 inhibitors as a new bi-functional agent for AML immunotherapy.