Over the past few decades, there has been little progress in developing new therapies for follicular lymphoma, one of the most common forms of non-Hodgkin lymphoma. The disease, which involves the abnormal production of white blood cells called B cells, is often slow growing but is still considered incurable. It also has proven hard for researchers to study, due to a lack of cell lines and a good animal model.
Now Memorial Sloan Kettering researchers led by cancer biologist Hans-Guido Wendel, working in collaboration with the laboratory of Ari Melnick at Weill-Cornell Medical College, have made a surprising discovery about the molecular basis of follicular lymphoma. The most commonly mutated gene in this disease, KMT2D, does not cause cancer through the typical mechanisms, which act directly to drive uncontrolled cell growth. Instead it controls the activity of hundreds of other genes through a process called epigenetic regulation.
“This is the most important mutation in this incurable disease, and we figured out what it does,” says Dr. Wendel. “Understanding the molecular cause is an important step toward new and better therapies. For example, emerging drugs are able to target some of these signaling pathways and may be effective against these tumors.”
The discovery is published online in Nature Medicine.
A Mutation’s Ripple Effect
Epigenetics relates to a gene’s functioning being changed by factors unrelated to the sequence of its DNA. Epigenetic changes are a normal part of many biological processes, but they also can lead to cancer and other diseases.
KMT2D operates through an epigenetic mechanism called histone modification. Histones are proteins that DNA wraps around like yarn on a spool. In effect, if the DNA is wrapped too tightly, it is unable to unspool and the genes encoded on it cannot be expressed — they remain “off.” If it’s too loose, genes that should remain silent may be activated.
The tightness or looseness of the DNA — and resulting gene expression — is regulated by histone modifying enzymes, or HMEs, which “mark” a histone to alter it. The KMT2D gene produces an HME that uses this process to turn on an array of genes that manage B cell growth and prevent the cells from becoming malignant.
“We found that the KMT2D enzyme activates a large number of genes, many of which are essential to the normal production of B cells,” explains Ana Ortega-Molina, a postdoctoral research fellow in Dr. Wendel’s laboratory and one of the first authors of the study. “When the KMT2D gene is mutated, these other genes fail to switch on, and the B cells don’t receive the signal to stop dividing when they should. This results in the proliferation of abnormal B cells that leads to follicular lymphoma.”Back to top
A Better Tool Provides the Proof
KMT2D is one of the most frequently mutated genes across all cancer types. This is especially true for follicular lymphoma — at least 50 percent of tumors have KMT2D gene mutations.
The frequency of these mutations indicates that this is likely one of the key causes of the cancer and makes KMT2D an inviting target for study. However, until recently it was difficult to design a way to clarify its normal function — and to figure out how the breakdown of that function could cause the disease.
A key step forward was the Wendel lab’s development of a follicular lymphoma mouse model in 2011. This tool is now broadly used by scientists working on lymphoma and allows researchers to conduct experiments clarifying the function of specific genes mutated in follicular lymphoma cells and to test new therapies.
In the Nature Medicine study, Dr. Ortega-Molina used this model to test what happened when KMT2D activity is blocked. She found that loss of the enzyme’s function caused the mice to develop more advanced follicular lymphoma tumors even more rapidly, demonstrating a functional link between the gene mutation and the disease.
Genetic analysis of the tumors allowed her and her collaborators at Weill-Cornell to define exactly how the mutations lead to cancer and which genes are directly affected when KMT2D is mutated.
“Ana is the first person to show that KMT2D acts as a tumor suppressor through epigenetic regulation of critical growth and survival pathways in B cells,” Dr. Wendel says.
He adds that clarifying KMT2D’s role could guide new treatment strategies. “We know that mutation of KMT2D leads to loss of a specific mark on histone proteins,” he explains. “We also know which other genes are responsible for removing this mark as part of their normal function. We can speculate that inhibitors of these removal factors may restore the balance and could be effective against lymphomas caused by mutated KMT2D.”Back to top