Coraline Mlynarczyk / Melnick Lab

This image depicts mouse lymphoma B cells stained disseminated in soft tissue under a 40x objective lens. The sample is stained with two dyes called hematoxylin and eosin to help identify the pattern, structure and shape of the cells.

February 22, 2023

Weill Cornell Researchers Identify Lymphoma Mutation That Disrupts Critical B-Cell Selection Process

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Researchers of the Melnick Lab, led by Prof. Ari Melnick, medicine, recently published a study identifying a key mutation that disrupts the B-cell natural selection process during immune response, leading to the rise of aggressive diffuse large B-cell lymphoma within the body. 

DLBCL is a type of cancer found in the lymphatic system, which plays an important role in the body’s germ-fighting immune system. DLBCL can expand rapidly and is difficult to eliminate, with at least 40 percent of patients not responding to treatment. 

The root cause for DLBCL lies within mutated B-cells, which are white blood cells that produce protective proteins called antibodies. Thousands of B-cells develop in a specialized structure of lymphoid organs called the germinal center, where they undergo a cyclical process of mutation and rapid growth. B-cells compete for selection by a smaller number of T-cells — white blood cells that recognize foreign particles called antigens. Selected B-cells then receive signals that enable them to differentiate and help initiate immune response. 

The germinal center is one of the unique places in the body where intense competition between cells occurs, since most human tissues require cooperative and altruistic cell behavior to function. This volatile process leads to rapid accumulation of abnormal mutations. 

According to Dr. Coraline Mlynarczyk, medicine, co-author of the study and research associate of the Melnick Lab, lymphomas arise because B-cells are subjected to high pressure to mutate, divide and be selected by T-cells. If mutations occur in unexpected locations, B-cells can gain abnormal survival advantage. 

To identify the mechanisms behind B-cell growth, the researchers examined mutations in the B-cell translocation gene 1, which are found exclusively in aggressive B-cell tumors. They found that this gene encodes for a checkpoint protein that governs B-cell natural selection and ensures that only a few selected B-cells survive competition. It also controls the expression of MYC, a powerful regulator that fuels cell growth. In cells with BTG1 mutations, MYC expression is inappropriately enhanced. 

“We examine genes that are found to be altered in B-cell lymphomas, and this allows us to learn about their function during immune activation,” Mlynarczyk said. “In the case of BTG1 mutations, we found that mutant cells can produce MYC more rapidly.” 

Mlynarczyk and her team found that cells with BTG1 mutations respond faster to T-cell selection signals every cycle until they can outcompete other cells. The researchers studied this super-competition phenomenon in mice, which were created to express the same mutant form of BTG1 most frequently found in patients. 

To achieve these results, the team collaborated with researchers from across the country, including researchers from Rockefeller University and the Memorial Sloan Kettering Cancer Center. The scientists at Rockefeller had deep expertise in the specifics of how immune responses work, and the teams at Cornell and MSKCC were focused on the biochemical mechanisms of the process, according to Melnick, the study’s senior author.

Looking back, Mlynarczyk and Melnick reflected on the difficulties and triumphs they faced for seven years working on this research. Mlynarczyk noted that it was particularly challenging to understand the subtle effects of MYC enrichment. 

The Melnick lab now aims to study the mechanistic pathways of checkpoint security, cell signaling and fitness acquisition to ultimately inform novel therapeutic strategies. 

“Within all these different mechanisms that intersect with each other, you begin to see a pattern. This complicated picture comes together to give you a feel for the biological mechanisms that have to be perverted to target the tumors,” Melnick said. “After the past ten years, we’re now starting to see the puzzle, but there’s still a lot to learn to get to the ultimate medical goal —  to cure the patients.”