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Gluten contributes to the development of a very rare blood cancer

With funding from Worldwide Cancer Research, scientists in The Netherlands have revealed how gluten plays a role in the development of a rare form of cancer, for a small group of people with coeliac disease.

The scientists at Leiden University Medical Center (LUMC) have shown that immune system cells, which react to gluten, produce chemicals called cytokines that can contribute to the development of a rare form of lymphoma (cancer of the white blood cells). The findings were published recently in the Proceedings of the National Academy of Sciences (PNAS). LUMC researcher and Worldwide Cancer Research scientist, Dr Jeroen van Bergen, explained “the immune system is seen as an ally in the battle against cancer, but that isn’t always the case.”

Refractory coeliac disease

For some people, eating grains such as wheat, barley and rye, which contain gluten, can cause chronic inflammation in the small intestine. This condition is known as coeliac disease, an autoimmune disease, where special immune system cells, called gluten-specific T cells, have an extraordinarily strong inflammatory reaction to the gluten. The cells produce chemicals known as cytokines which can then stimulate other immune system cells.

Coeliac patients usually manage to control their symptoms by following a gluten-free diet. However, a small percentage (2-5%) of coeliac disease patients diagnosed in adulthood does not respond to such a diet and have what is called refractory coeliac disease (RCD). As these people are only diagnosed as an adult they will have been eating gluten over many years before, by which time the inflammation and long term damage may already have been done and therefore changing their diet at this point does not help. In one type of refractory coeliac disease, called RCDII, immature white blood cells from the immune system (called lymphocytes) which are located in the wall of the small intestine, multiply in number in an uncontrolled manner. In about half of these patients, these cells develop into a malignant, incurable form of white blood cell cancer called enteropathy-associated T-cell lymphoma (EATL), a very rare type of lymphoma arising from the inflammation caused by the body’s reaction to gluten.

EATL is an aggressive lymphoma and the future for these patients is not very good, meaning new treatments are urgently needed.

Growth factors

Scientists have known for a long time that in order to grow and survive, the lymphoma cells are dependent on a cytokine called IL-15 which acts as a growth factor, encouraging cells to multiply. Now the researchers have shown that the proliferation can be stimulated just as effectively by three other cytokines, TNF, IL-2 and IL-21. These three cytokines are produced by the gluten-specific T cells, which react to gluten. The new findings thus provide a potential mechanism by which the immune response to gluten contributes to the growth of malignant cells in RCDII.

Targeted treatments

An important question now is to find out at which stage of lymphoma development these cytokines are involved. Dr van Bergen explained: “It is likely that at the time of lymphoma diagnosis, the patient has already experienced decades of intestinal inflammation. We need to determine the extent to which it would actually help to block these newly discovered growth factors with targeted drugs at the time of diagnosis? In the meantime, we have tested a large number of potential drugs in the laboratory, and two of them seem promising. But as I said, this is only interesting in terms of a new treatment if these growth factors still have a role to play in the growth and development of the lymphoma after diagnosis.”

Dr Lara Bennett, Science Communications Manager at Worldwide Cancer Research added “this is another great example of the importance of early-stage, discovery research, like that funded by Worldwide Cancer Research. This is a rare type of cancer but the findings could be of real benefit to this small but important group of patients with refractory coeliac disease in the future.”

These findings from the researchers in Leiden and Amsterdam were published in the leading journal PNAS.

The research was funded by a grant from Worldwide Cancer Research.

New insight into the cause of a rare blood cancer

With funding from Worldwide Cancer Research, Dr Golam Mohi and his colleagues have found that loss of activity of the EZH2 gene can allow the development of Myelofibrosis (MF) in mice. The findings reveal a new pathway which can now be studied to better understand the cause of MF and provide new therapeutic targets to block the progression of this rare form of blood cancer.

This work was recently published in the medical journal Blood, the most cited peer-reviewed publication in the field of hematology.

MF is a life-threatening, progressive blood cancer that affects both men and women.  It can occur at any age, but usually patients are over age 50 when they are diagnosed.  MF is characterized by abnormal scar tissue in the bone marrow which means the bone marrow cells can no longer produce red blood cells, leading to anaemia and enlargement of the spleen and liver. Other associated symptoms include tiredness, itching, bleeding and bone pain. There is no cure for MF, only treatments that help reduce symptoms of the disease and sadly, the overall survival for patients is less than 6 years.

“It is imperative to better understand the cause of the disease, so that more targeted therapies can be developed to help manage MF, and optimally, to prevent the disease from progressing,” said Dr Mohi, associate professor of pharmacology at Upstate Medical University in the USA.

Dr Mohi’s study stems from his previous investigations into the genetic mutation, known as JAK2V617F.  This mutation has been associated with three different blood conditions, collectively known as Myeloproliferative Neoplasms (MPNs) which can lead to MF. However, it remained unclear as to how this single gene mutation could give it was the focus of his current work.

“Previous evidence suggested that although JAK2V617F is sufficient to induce one of the MPNs, additional mutations might be required to progress to MF,” said r Mohi. “We found that a small group of MF patients with the JAK2 mutation were also found to have loss of activity mutations in EZH2. To prove there was a link, we used genetically engineered mouse models that have the JAK2V617F mutation and observed that loss of activity of EZH2 reduces the red blood cells, increases the platelet counts and rapidly induces MF. This suggests that loss of EZH2 cooperates with JAK2V617F in the development of MF.”

Dr Lara Bennett, Science Communication Manager at Worldwide Cancer Research said “Understanding MF at the molecular level is critical for the development of new therapies.  While this work is still very much in its early-stages, it is an important step forward for patients with this rare but devastating blood cancer.”

When asked about his support from Worldwide Cancer Research, Dr Mohi explained "Our ultimate goal is to find a cure for the deadly blood cancer MF. This research grant from Worldwide Cancer Research is extremely helpful in reaching that goal."

Press release written by Upstate Medical University press office and edited by Worldwide Cancer Research.