RUNX inhibitor suppresses graft-versus-host disease through targeting RUNX-NFATC2 axis

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.