Targeting RUNX3 as a novel treatment for hemophagocytic lymphohistiocytosis

The National Institute of Allergy and Infectious Diseases awarded the University of Texas Health Science Center at Tyler $223,500 on July 20, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate RUNX3 as a novel therapeutic target for primary hemophagocytic lymphohistiocytosis.

The research addresses the treatment of PHLH, a life-threatening genetic inborn error of immunity triggered by viral infection that causes uncontrolled CD8+ T-cell activation, interferon-driven cytokine storms, and hemophagocytosis. Despite existing immunosuppressive, chemotherapeutic, and anti-interferon therapies, up to 40 percent of PHLH patients die from uncontrolled disease or treatment complications. The work examines RUNX3's role as a critical regulator of CD8+ T-cell activation and interferon production, with preliminary data indicating that RUNX3 preferentially mediates interferon production from CD8+ T cells in response to IL-12 and IL-18 stimulation. The research team will explore whether targeting RUNX3 offers a more effective treatment approach with reduced toxicity for PHLH patients.

The award is classified as a Project Grant with a performance period from July 20, 2026, through June 30, 2028. Work is performed in Tyler, Texas. The University of Texas System is the parent organization.

Abstract

Primary hemophagocytic lymphohistiocytosis (phlh) is a life-threatening genetic disease (inborn error of immunity) caused by biallelic mutations in genes involved in the cytotoxic machinery of cytotoxic CD8+ t and NK cells. When triggered by a viral infection, the impaired cytotoxic functions result in the exuberant activation and expansion of IFN-producing CD8+ t cells, leading to a self-perpetuating IFN-driven cytokine storm and hemophagocytosis. Phlh commonly occurs in early childhood and is often triggered by viral infection, although pathogens are diverse (viral, bacterial and fungal) and influenced by geographic regions. Despite use of the conventional immunosuppressive and chemotherapeutic regimens and the recently developed anti-IFN therapies, up to 40% of phlh patients DIE due to uncontrolled disease and/or the complications of its treatment. Hence, there is a pressing need to develop novel and more effective therapies with less toxicity to ultimately improve outcomes for phlh patients. This R21 proposal will address this important issue by targeting RUNX3 (a critical regulator of CD8+ t cells) for the treatment of phlh. We and other groups have demonstrated that RUNX3 is essential for the activation and expansion of CD8+ cytotoxic t cells and the cell expression of IFN in response to the infections of lymphocytic choriomeningitis virus (lcmv) or influenza a virus (IAV). We also found that an inducible general RUNX3 KO did not significantly alter IAV clearance in mice but tended to improve animal survival outcomes following IAV infection, although the numbers of lung CD8+ cytotoxic t cells were markedly reduced. Our new preliminary data show that RUNX3 preferentially mediates IFN production from t cells, especially CD8+ t cells by IL-12 plus IL-18 that are two potent inducers of IFN production. Moreover, RUNX3 regulates IL-12/IL- 18-mediated production of IFN in mice with endotoxin lipopolysaccharide (LPS) challenge. As a result, RUNX3 KO markedly suppressed the IFN-central cytokine storm and mortality in mice challenged with a lethal dose of LPS. These preliminary data prompt US to test the hypothesis that targeting RUNX3 could be an effective therapeutic strategy for phlh. We will test this novel hypothesis with the following two sub-aims. 1) determine the role of RUNX3 in phlh using a lcmv-infected PRF1−/−; RUNX3-KO mouse model; 2) determine the effect of RUNX3 KO after the onset of phlh on host immune responses. The proposed studies have not been explored previously and will offer proof of concept that targeting RUNX3 is a tolerable and effective therapeutic strategy for phlh, a life-threatening hyperinflammatory disease, thereby will advance the field. If successful, this proposal will attract future development of RUNX3 selective inhibitors to treat this often-fatal HLH disease.