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New drug target identified for X-linked lymphoproliferative disease

An international research collaboration with St. Jude Children’s Research Hospital reveals how impairment of a crucial signaling enzyme in humans may translate to the development of new therapeutics for an often-fatal immunodeficiency disease

Memphis, Tennessee, January 13, 2016

Kim Nichols, M.D.

Kim Nichols, M.D., a member of the St. Jude Department of Oncology 

An international team of scientists including researchers at St. Jude Children’s Research Hospital have identified a crucial signaling enzyme as a possible therapeutic target for the treatment of a hereditary immune disease. X-linked lymphoproliferative disease is a life-threatening condition that has few treatment options. Affected individuals are vulnerable to massive accumulation and activation of white blood cells known as T cells if they also become infected with Epstein-Barr virus, the virus that causes infectious mononucleosis. Without treatment, this accumulation of activated T cells leads to severe organ damage and, in many cases, death. The study appears online today in Science Translational Medicine.

Scientists have known for some time that X-linked lymphoproliferative disease is a hereditary disorder caused by germline mutations in the SH2D1A gene. When this gene is affected, defects occur in a specific adaptor molecule known as SAP (Signaling Lymphocytic Activation Molecule-associated protein). This protein plays important roles in the signaling events related to receptors on the surface of T cells. Without an effective SAP adaptor molecule, normal cell death processes (apoptosis) are impaired and an enzyme known as diacylglycerol kinase alpha is activated. The research team questioned whether the over-activation of diacylglycerol kinase alpha might contribute to the reduced apoptosis of X-linked lymphoproliferative disease T cells and the accumulation of T cells that occurs following infection with Epstein-Barr virus.

The researchers showed that inhibition of diacylglycerol kinase alpha using specific drugs restored the sensitivity of X-linked lymphoproliferative T cells to cell death. The scientists observed similar results when they looked at the effects of “knocking out” the same enzyme in cultured X-linked lymphoproliferative T cells using inhibitory RNA molecules. Consistent with these observations, pharmacologic inhibition of diacylglycerol kinase alpha also curtailed the expansion of T cells in virus-infected mice that serve as model organisms to study X-linked lymphoproliferative disease. 

“Patients with X-linked lymphoproliferative disease are prone to severe Epstein-Barr virus infection due to a weakened immune system,” said Kim Nichols, M.D., a member of the St. Jude Department of Oncology and one of the study’s lead authors. Nichols identified the SH2D1A gene in 1998, and her laboratory has been studying how SAP regulates immune cell development and function for more than 15 years. “Infection with Epstein-Barr virus can have potentially fatal consequences for these patients,” she said. “This severe disease is a double-edged sword. On the one hand, the immune system is significantly weakened. However, detrimental side effects occur due to the expansion and hyper-activation of T cells. Together with our collaborators in Europe and other institutions in the United States, we wanted to establish the biochemical mechanism underlying these changes so that we could develop better treatments for X-linked lymphoproliferative disease patients experiencing hyper-inflammation.”

“Our findings suggest that inhibition of diacylglycerol kinase alpha could reverse some of the life-threatening effects linked to Epstein-Barr virus infection of patients with X-linked lymphoproliferative disease,” Nichols said.

T cells from patients with X-linked lymphoproliferative disease are hard to obtain in sufficient quantities to permit many experiments, and such experiments in the laboratory do not fully model human symptoms. The St. Jude researchers therefore turned to a model system that replicates the conditions of the disease in genetically modified mice. Mice deficient in SAP, when challenged with lymphocytic choriomeningitis virus, show similar symptoms to patients with X-linked lymphoproliferative disease, including an abnormal accumulation and activation of T cells. Collectively, the data from cultured human T cells and SAP-deficient mice show that inhibition of diacylglycerol kinase alpha helped restore the natural balance of the immune system.

“These results are very exciting and provide proof-of-principle that treatment with an inhibitor of diacylglycerol kinase alpha could help patients with the symptoms experienced after Epstein-Barr virus infection,” Nichols said. “However, this work is still at an early preclinical stage of investigation. We have identified a new target for X-linked lymphoproliferative disease, but further work is needed to identify and advance the best drug candidate from preclinical testing to a viable treatment option for patients.”

The study’s other authors are  Elisa Ruffo, Valeria Malacarne, Sasha E. Larsen, Rupali Das, Laura Patrussi, Christoph Wülfing, Christoph Biskup, Senta M. Kapnick, Katherine Verbist, Paige Tedrick, Pamela L. Schwartzberg, Cosima T. Baldari, Ignacio Rubio, Andrew L. Snow, Gianluca Baldanzi, Andrea Graziani.

This research was supported by funding from XLP Research Trust; the Sean Fischel Fund for HLH (hemophagocytic lymphohistiocytosis) research; the National Institutes of Health (grant 1R01GM105821); USUHS; Telethon;  AIRC (Associazione Italiana per la Ricerca sul Cancro); the University of Piemonte Orientale (Young AQ19 Investigators); the Compagnia di San Paolo; and ALSAC.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude shares the discoveries it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. To learn more, visit or follow St. Jude on social media at @stjuderesearch.