Specific Gene Mutation Plays Key Role in Follicular Lymphoma Development

Specific Gene Mutation Plays Key Role in Follicular Lymphoma Development

In a recent study published in Nature Medicine, entitled “The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development“, researchers revealed the mechanisms by which mutations in the gene KMT2D participate in follicular lymphoma’s (FL) development.

FL is a form of blood cancer that occurs when white blood cells (lymphocytes) of the immune system multiply uncontrollably to induce tumors, with consequent enlargement of body parts like lymph nodes, spleen, and bone marrow. As a result, patients with FL may experience shortness of breath, fatigue, and weight loss. With regard to therapy, there is no consensus of the best treatment protocol for FL but considerations depend on factors like age, stage, and prognostic scores. In general, if no symptoms appear, FL patients could benefit from a watch and wait approach as early treatment does not provide survival benefit. However, if symptoms emerge, patients may be assisted with available therapies including chemotherapy drugs like R-CHOP or monoclonal antibody rituximab (Rituxan).  It is worth noting that FL constitutes around 22% of all cancers associated with same class of blood cell.

It is believed that FL is caused by genetic abnormalities where mutations in a gene named KMT2D occur in at least 50 percent of tumors. However, the normal function of KMT2D and the role of its mutations in disease development/progression are not fully understood. To clarify these questions, the team blocked the activity of KMT2D in a mouse model of FL, observing that loss of the enzyme’s function rapidly led to more advanced FL tumors.

To understand the mechanisms on KMT2D’s mutations along with its capacity to accelerate cancer growth, the researchers analyzed data obtained from genetics experiments. They found that mutation of KMT2D does not directly lead to uncontrollable cell growth of white blood cells, but instead it uses a process named epigenetic regulation to control the activity of a large number of other genes involved in cell growth. In this process, KMT2D gene mutations do not relate to its DNA sequence, instead they are caused by modifications in proteins named histones where DNA wraps around them like yarn on a spool. Consequently, if DNA is wrapped too tightly to the protein the gene could remain silent. Furthermore, because KMT2D is involved in an array of genes that manage normal growth of white blood cells, when a mutation occurs it results in abnormal function of other genes, leading to cell proliferation and FL development.

“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.”

In summary, these findings demonstrate the importance of KMT2D and the functional link between gene mutation and the FL disease. Surprisingly, KMT2D mutations do not directly induce uncontrolled growth of white blood cells, but rather control the activity of many other genes. As such, inhibiting these removal factors may restore the genetic balance and could be used in the future as an effective approach against FL caused by mutated KMT2D.

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Malika Ammam received her MS degree from the University of Pierre et Marie CURIE in July 2002 and her PhD from the University of Paris Sud XI, France in September 2005. From 2006 to 2007, she worked as a research fellow at the University of Kansas in collaboration with Pinnacle Technology Inc. (USA). From 2007 to 2010, she was a research associate at KU Leuven, Belgium. From 2010 to 2012, she worked at the University of Ontario Institute of Technology in collaboration with Alcohol Countermeasure Systems Corporation, Canada. She held a prestigious Rosalind Franklin fellowship and resigned in 2015. Now, she is a freelancer.

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