Researchers at the University of Wisconsin School of Medicine and Public Health have found a molecular regulator that controls cell life in diffuse large B cell lymphoma, the most common, aggressive form of lymphoma.

The regulator, a gene called STAT3, which controls the rate of transcription of genetic information from DNA to messenger RNA, is switched on in activated B cell-like subtype of diffuse large B cell lymphoma. Activation of STAT3, and its kinase JAK1, an enzyme, is caused by proteins called cytokines that cancer cells produce due to their genetic alterations.

The regulator’s discovery was described in a study recently published in the journal, Proceedings of the National Academy of the Sciences of the United States or America.

This type of lymphoma is a subgroup of the disease with a current cure rate of less than 50 percent.

In activated B cell-like diffuse large B cell lymphoma, STAT3 expression and function are required for cancer cell survival and proliferation, but the underlying mechanisms are not fully understood, according to Lixin Rui, PhD, an assistant professor of medicine at the UW School of Medicine and Public Health, who led the study.

“For the last two decades, STAT3 has been one of the most intensively studied genes,” he said. “STAT3 regulates gene expression necessary for normal immune response, but is deregulated in many diseases including cancer.”

Li Lu, PhD, a postdoc studying under Rui, integrated cancer genomic assays and identified several survival pathways that STAT3 promotes. From this work, the most surprising finding was that STAT3 can dampen interferon signaling, a “death” pathway that is driven by the same genetic cause for STAT3 activation in cancer cells, Rui said.

Based on this unexpected finding, Fen Zhu, a graduate student in the Rui lab, tested a hypothesis that inhibition of STAT3 by RNA interference enhances anti-tumor efficacy of lenalidomide, a clinical immunomodulatory drug that can trigger interferon production.

Zhu’s research showed that a greater toxicity of lenalidomide was observed in cancer cells when STAT3 was genetically inhibited, Rui said.

Yangguang Li, PhD, a former postdoc in the Rui lab, confirmed this synergistic anti-tumor effect using ruxolitinib, a JAK1 and JAK2 inhibitor widely used in clinical settings.

“We were very fortunate to be able to collaborate with Dr. Thomas Waldmann, at the National Cancer Institute, to incorporate animal models in this study,” Rui said.

Meili Zhang, PhD, in the Waldmann lab demonstrated that the ruxolitinib and lenalidomide combination achieved a nearly complete inhibition of tumor growth in mice, according to Rui.

“We hope that the study provides a mechanistic rationale for clinical trials to evaluate ruxolitinib or a specific JAK1 inhibitor combined with lenalidomide in the disease,” he said.

The study was supported by funding from the National Cancer Institute R01grant, the UW-Madison T32 Hematology Training Award and the UW-Madison Forward Lymphoma Fund.