Dr Ichiro TANIUCHI RIKEN Center for Integrative Medical Sciences Japan Link to biosketch

Abstract

The Runx Transcription Factor family proteins function as a heterodimer with a common partner Cbfb and are essential for development of hematopoietic cells. In mammals, there are three Runx proteins, Runx1, Runx2 and Runx3. While Runx1 is essential for early hematopoiesis, Runx3 regulates the differentiation of unique immune cells with cytolytic activity such as cytotoxic T cells and natural killer (NK) cells. Besides regulation of immune cell development, Runx proteins shape the tissue environment in part by suppressing chemokine CCL5 and enhancing anti-tumor immunity¹

It has been shown that dysregulation of RUNX3 is associated with tumorigenesis. Among the cancer-related variations in the human RUNX3 gene, we are currently focusing on the RUNX3^R122C mis-sense variant in collaboration with Prof. Ito’s group at NUS. The RUNX3^R122C variant, which was originally isolated from gastric cancer cells², supported tumor growth when induced in a cancer cell line, while wild-type RUNX3 suppressed it. Interestingly, the mouse strain harboring the mutation corresponding to human RUNX3^R122C variant developed hyperplasia and proliferative changes in the gastric epithelial cells³. In the immune system of Runx3^R122C/R122C mutant mice, although primary development of CD8⁺ cytotoxic T cells was not affected, development of skin dendritic epidermal T cells and Langerhans cells was severely impaired. In the B16 melanoma metastasis model, which is primarily NK-cell responsive model, Runx3^R122C/R122C mutant mice strongly reduced metastatic lesions and this was consistent with the upregulation of genes that function in cytolytic activity in Runx3^R122C/R122C lung-resident NK cells in their steady-state. In addition, we found that the anti-tumor activity of CD8⁺ cytotoxic T cells was enhanced by the Runx3^R122C mutation. Our chromatin immune-precipitation (ChIP)-seq assay in CD8⁺T cells showed that Runx3R122 mutant protein is recruited to aberrant genomic regions where ETS transcription family motifs are enriched. This mechanistically suggests that the RUNX3^R122C mis-sense variant alters the affinity with RUNX3 interacting partner proteins and re-writes a developmental program of immune cells toward acquiring strong anti-tumor activity. Thus, RUNX3^R122C might act as a double-edged sword, inducing precancerous changes in the epithelium whilst the cytolytic immune cells efficiently respond and eradicate non-self/abnormal cells.

References
[1] Seo W, et. al., Runx-mediated regulation of CCL5 via antagonizing two enhancers influences immune cell function and anti-tumor immunity. Nat Commun. 11:1562, 2020.
[2] Li et al., Causal Relationship between the Loss of RUNX3Expression and Gastric Cancer. Cell 109:113, 2002.
[3] Douchi et al., A point mutation R122C in RUNX3 promotes the expansion of isthmus stem cells and inhibits their differentiation in the stomach. Cell Mol Gastroenterol Hepatol.13:1317, 2022.