Finding the Trigger That Sets Off Growth of Hodgkin Lymphoma Cells

Recovery rates for Hodgkin lymphoma are relatively high—more than 90% of those with localized cancer are cured, as are 80% with advanced disease. But this good news is offset by the long-term effects of chemotherapy, which can lead to heart and lung problems, infertility, or secondary cancers.

Since many patients with Hodgkin lymphoma are older teens or young adults, the effects of chemotherapy last for decades. Thus, there is interest in finding less toxic ways to treat this disease, which accounts for about 8100 new cases a year, according to the American Cancer Society.

“We therefore need to develop new therapeutic approaches to help prevent such problems,” Claus Scheidereit, head of the research group on Signal Transduction in Tumor Cells at the Max Delbruck Center (MDC), said in a statement.

Scheidereit’s group worked with others at MDC and Charite University of Medicine in Berlin, led by Stephan Mathas, DMed, resulting in a paper in Blood that identifies a potential target for new therapies. Their discovery starts with something the research community has known for a while: the protein complex NF-κB, which controls DNA transcription and cell survival, exists in the nuclei of Hodgkin cells and plays a critical role in this cancer.

But what sets NF-κB in motion?

Normally, the transcription factor NF-κB lives in a cell’s cytoplasm and only temporarily migrates to the nucleus to control gene expression; something happens in Hodgkin lymphoma to cause NF-κB to stay in the nucleus and cause lymphoma cells to grow unchecked, releasing signals that draw white blood cells into the lymph nodes.

The paper in Blood focuses on a series of tests to determine which molecules produced by Hodgkin cells activated NF-κB. Through this process, “We identified one single factor that is secreted by Hodgkin’s cells and activates NF-κB; a signaling molecule called lymphotoxin-alpha, or LTA for short,” said Eva Kaergel, a research assistant and co-author of the study.

Tissue sample analyses confirmed that lymph nodes from Hodgkin patients produce high levels of LTA, and other tests shows that inhibiting LTA blocked NF-κB activity in the Hodgkin cells.

The Scheidereit team not only showed the importance of LTA in triggering NF-κB, they also showed how it set off the signals that elevated white blood cells in the lymphatic system and set the stage for cancer to spread. Separately, the experiments suggest that LTA can be turned on and turned off, which offers promise for alternatives to chemotherapy.

“Our work suggests that LTA could be a good target for diversifying the existing treatment strategies for Hodgkin’s lymphoma,” Scheidereit said.

Reference

von Hoff L, Kargel E, Franke V, et al. Autocrine LTA signaling drives NF-κB and JAK-STAT activity and myeloid gene expression in Hodgkin lymphoma. Blood. 2019;133:1489-1494. doi: 10.1182/blood-2018-08-871293.