In one of the most common forms of lymphoma, the immune system's B cells that ordinarily fight disease genetically mutate and grow out of control — they no longer fight infection, die off, then accumulate — forming tumors that spread throughout the body. 

For years, Joel Pomerantz, Ph.D., associate professor of physiology, pharmacology and therapeutics at the Johns Hopkins University School of Medicine, has been investigating one of the primary drivers of diffuse large B-cell lymphoma: CARD11, an immune signaling protein that mutates in this cancer.

"In different lymphomas, CARD11 is mutated in a way that inappropriately activates B cells, which contributes to the disease," says Pomerantz.

Recently, his pursuit of CARD11 research has yielded a promising new potential target for autoimmune disease, leukemias and lymphomas treatments: QRICH1, a protein that binds to CARD11.

Now, Pomerantz says, his team of researchers has pinpointed a surprising pathway driven by a CARD11 mutation that helps ensure the survival of immune B cells, and which could be targeted by future drugs to prevent or slow the spread of diffuse large B-cell lymphoma, one of the most aggressive and common subtypes of the disease.

A report of the National Institutes of Health-funded research, led by Pomerantz, was published Nov. 26 in Cell Reports.

The study, conducted with genetically engineered mice, focused on the CARD11 protein, which ordinarily helps the immune system's protective T and B cells function. Mutations in the CARD11 protein are thought to contribute to the spread of certain types of lymphomas, including diffuse large B-cell lymphoma.

The findings indicate that a specific mutation of CARD11, the so-called C49Y mutant, turns on the noncanonical NF-κB pathway, an immune response pathway that is critical to helping B cells survive but that has not previously been linked to CARD11, Pomerantz says. The scientists were surprised to find that other well-known signaling pathways that ordinarily help the immune system respond to immediate threats did not seem to be affected by the CARD11 mutation.

"Based on our findings, we suspect the noncanonical NF-κB pathway could be important in many different types of lymphomas," Pomerantz says.

In experiments, scientists observed mice that were genetically engineered to continuously express the CARD11 C49Y variant. Using a variety of techniques, they determined B cells in the C49Y mice survived longer periods on their own when compared to normal mice, and contained higher levels of a protein, p100, associated with the noncanonical NF-κB pathway, a pathway that normally helps to ensure B cell survival.

Additionally, the scientists say, the C49Y mice had a 14-fold increase in the level of a particular subset of B cells called marginal zone B cells, when compared to normal mice, and also had visibly enlarged spleens.

"The pathway affected by this mutation is likely important in many different types of lymphomas and could be targeted by drugs in the future to help treat these cancers," Pomerantz says.

Funding support for this research was provided by the National Institutes of Health (RO1AI148143) and from the Johns Hopkins University School of Medicine Department of Biological Chemistry.

In addition to Pomerantz, Johns Hopkins scientists who contributed to this work include Anushka Ghosh, Tyler Jones, Sophie Mackinnon, Shelby Hutcherson, Julia Tritapoe, Piyusha Mongia, Neha Shah, Emma Mehlhop and Nicole Carter.