The key to understanding how more aggressive lymphomas emerge and resist current therapies may lie in mutations that disrupt a critical natural selection process among antibody-producing B cells, according to a multi-institutional preclinical study led by Weill Cornell Medicine investigators.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma, with at least 40 percent of cases not responding to treatment. Patients with mutations in B cell translocation gene 1 (BTG1) The gene, which is primarily found in B-cell lymphomas, has a particularly poor outcome.
The new study, published Jan. 19 in the journal Science, shows that BTG1 acts as an “evolutionary” checkpoint for important B cells that governs the process of natural B-cell selection, said lead study author Dr. Ari M. Melnyk, GPRO family professor. in Hematology/Oncology and is a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. To generate powerful antibodies against novel infectious agents such as COVID-19, B cells go through a process of cyclic growth, genetic mutation of antibodies and extremely rapid cell division. Thousands of these mutant B cells vigorously compete for access to a much smaller number of immune T cells. These T cells select only a few B cells for survival, based on their ability to bind to antigens and molecules foreign to viruses and other microorganisms that trigger an immune response.
“This intense competition between individual B cells differs from the more altruistic and cooperative cell behavior found in all other tissues in humans, and is very similar to how single-celled organisms compete with one another,” explained Dr. Melnyk.
Interaction with T cells is essential for B cell survival because it stimulates transient expression of a powerful cell growth regulator called MYC, which fuels the cells’ metabolism to generate the building blocks needed for the subsequent bursts of cell division.
BTG1 acts as a gatekeeper to ensure that only a select few B cells survive this process of competitive natural selection, while also reining in competition, by preventing inappropriate fueling by MYC. To achieve this delicate balance, BTG1 controls the rate of MYC protein expression in B cells. BTG1 Mutations occur in about 70 percent of the most aggressive forms of DLBCL and aberrate this process, allowing for faster induction of MYC protein expression in B cells. “The effect is minimal from a molecular point of view,” said Dr. Melnyk. “It represents about a 10 percent increase in the rate at which the MYC protein is produced.”
However, this small effect enables BTG1-mutant B cells to outcompete and control the immune response by competing with healthy B cells during T-cell-driven natural selection. This effect enables B cells to undergo more mutation cycles, which puts them at risk of damaging other genes and eventually becoming cancerous.
In this study, BTG1 “A mutation that accelerated the formation of lymphomas and led to highly aggressive cancers that spread throughout the body in mice, which is reminiscent of what happens in patients,” said Dr. “Therefore, this tiny 10 percent effect provides, over time, an important ‘fitness’ gain and leads to very aggressive disease.”
The study also shows how sensitive evolution is, explained Dr Melnyk, to small influences that can dramatically increase cell fitness in the context of competition. In addition, this change in natural selection for B cells is strikingly similar to the process of super competition in organ development in insect and animal embryos. There, too, small differences in MYC expression allow the supercompetitive cells to fully dominate the formation of new tissues.
“Lymphomas are strange and malignant tumors because they arise from the immune system that is supposed to protect us from cancer,” said Dr. Melnyk. “Because we currently do not have therapies that work for these patients, understanding the processes involved in developing the worst and most lethal form of DLBCL is the first step toward intervention.”
“Scientists working together in teams are driving the fastest research breakthroughs,” he added, pointing to important contributions to this study from Dr. Gabriel Victora, a primary immunologist at The Rockefeller University and Dr. Michael Meyer Hermann, a mathematician at the Helmholz Center for Infection Research in Germany.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborations with external organizations to advance scientific innovation and provide expert guidance. The Foundation publishes these disclosures to ensure transparency. For this information, see profile for Dr. Melnik.