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Published on: March 17, 2020
RUNX inhibitor suppresses graft-versus-host disease through targeting RUNX-NFATC2 axis
Hirohito Kubota1, Tatsuya Masuda2, Mina Noura2
1Department of Pediatrics Graduate School of Medicine Kyoto University Sakyo-ku Kyoto Japan.
Abstract:
Patients with refractory graft-versus-host disease (GVHD) have a dismal prognosis. Therefore, novel therapeutic targets are still needed to be identified. Runt-related transcriptional factor (RUNX) family transcription factors are essential transcription factors that mediate the essential roles in effector T cells. However, whether RUNX targeting can suppress, and GVHD is yet unknown. Here, we showed that RUNX family members have a redundant role in directly transactivating NFATC2 expression in T cells. We also found that our novel RUNX inhibitor, Chb-M', which is the inhibitor that switches off the entire RUNX family by alkylating agent-conjugated pyrrole-imidazole (PI) polyamides, inhibited T-cell receptor mediated T cell proliferation and allogenic T cell response. These were designed to specifically bind to consensus RUNX-binding sequences (TGTGGT). Chb-M' also suppressed the expression of NFATC2 and pro-inflammatory cytokine genes in vitro. Using xenogeneic GVHD model, mice injected by Chb-M' showed almost no sign of GVHD. Especially, the CD4 T cell was decreased and GVHD-associated cytokines including tissue necrosis factor-α and granulocyte-macrophage colony-stimulating factor were reduced in the peripheral blood of Chb-M' injected mice. Taken together, our data demonstrates that RUNX family transcriptionally upregulates NFATC2 in T cells, and RUNX-NFATC2 axis can be a novel therapeutic target against GVHD.
Insights
Targeting the RUNX-NFATC2 axis with novel inhibitors like Chb-M' shows promise for treating refractory graft-versus-host disease (GVHD). This approach suppresses T cell responses and reduces GVHD severity in preclinical models.
Area of Science:
- Immunology
- Molecular Biology
- Hematology
Background:
- Refractory graft-versus-host disease (GVHD) presents a significant clinical challenge with limited therapeutic options.
- Runt-related transcriptional factors (RUNX) are crucial for effector T cell function, but their role in GVHD is not fully understood.
Purpose of the Study:
- To investigate the role of RUNX transcription factors in GVHD pathogenesis.
- To evaluate the therapeutic potential of targeting the RUNX family, specifically the RUNX-NFATC2 axis, for GVHD treatment.
Main Methods:
- Assessed the role of RUNX family members in transactivating NFATC2 expression in T cells.
- Utilized a novel RUNX inhibitor, Chb-M', designed to bind RUNX-binding sequences.
- Evaluated Chb-M' effects on T cell proliferation, cytokine production in vitro, and GVHD severity in a xenogeneic mouse model.
Main Results:
- RUNX family members redundantly regulate NFATC2 expression in T cells.
- Chb-M' inhibited T cell receptor-mediated T cell proliferation and suppressed NFATC2 and pro-inflammatory cytokine gene expression.
- Chb-M' treatment in a xenogeneic GVHD model significantly reduced GVHD signs, CD4 T cell populations, and key GVHD-associated cytokines.
Conclusions:
- The RUNX-NFATC2 axis is a critical pathway in T cells that drives GVHD.
- Targeting RUNX transcription factors with inhibitors like Chb-M' represents a promising novel therapeutic strategy for refractory GVHD.
