Insights into Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency

Yizhe Sun; Janet Chou; Kevin D. Dong; Steven P. Gygi; Benjamin E. Gewurz

doi:10.1172/jci.insight.193787

Insights into Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency

Yizhe Sun,¹ Janet Chou,² Kevin D. Dong,³ Steven P. Gygi,³ and Benjamin E. Gewurz¹

Published July 17, 2025 - More info

View PDF

Abstract

X-linked Lymphoproliferative Syndromes (XLP), arising from mutations in SH2D1A or XIAP genes, are characterized by fulminant Epstein-Barr Virus (EBV) infection. Lymphomas occur frequently in XLP-1 and in other congenital conditions with heightened EBV susceptibility, but not in XLP-2. Why XLP-2 patients are apparently protected from EBV-driven lymphomagenesis remains a key open question. To gain insights, newly EBV-infected versus receptor-stimulated primary B-cells from XLP-2 patients or with XIAP CRISPR editing were compared to healthy controls. XIAP perturbation impeded outgrowth of newly EBV-infected B-cells, but not that of CD40 ligand and interleukin-21 stimulated B-cells. XLP-2 deficient B-cells showed significantly lower EBV transformation efficiency than healthy controls. Interestingly, EBV-immortalized lymphoblastoid cell proliferation was not impaired by XIAP knockout, implicating an XIAP role in early EBV B-cell transformation. Mechanistically, nascent EBV infection activated p53-mediated apoptosis signaling, which was counteracted by XIAP in control cells. With XIAP deficiency, EBV markedly elevated apoptosis rates over the first two weeks of infection. Interferon-gamma, whose levels are increased with severe XLP2 EBV infection, markedly increased newly EBV-infected B-cell apoptosis. These findings underscored XIAP's crucial role in support of the earliest stages of EBV-mediated B-cell immortalization and provide insights into the curious absence of EBV+ lymphoma in XLP-2 patients.

Insights into Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency

Yizhe Sun,¹ Janet Chou,² Kevin D. Dong,³ Steven P. Gygi,³ and Benjamin E. Gewurz¹

Article tools

Metrics

Go to

Insights into Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency

Yizhe Sun,1 Janet Chou,2 Kevin D. Dong,3 Steven P. Gygi,3 and Benjamin E. Gewurz1

Article tools

Metrics

Go to

Sign up for email alerts

Yizhe Sun,¹ Janet Chou,² Kevin D. Dong,³ Steven P. Gygi,³ and Benjamin E. Gewurz¹