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A potential new drug target for a deadly form of leukaemia

Acute myeloid leukaemia (AML) is a relatively rare form of leukaemia with around 350,000 people worldwide diagnosed each year. Although rare, survival rates are low, with only around 15% of people surviving the disease for more than 5 years after diagnosis.

Professor Suzanne Cory based at The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, is studying the role of MNT, an antagonist of the protein MYC, to explore its role in enabling AML cells to stay alive in the body. By unravelling the molecular connections that link MNT to cancer, they hope to discover a new target for drug development for AML.

Understanding why children with Down Syndrome are at risk of leukaemia

Down Syndrome is a genetic disorder caused by an additional copy of the chromosome 21. The disorder is estimated to effect 1 in every 1000 live births worldwide. Children with Down Syndrome are at greater risk of developing blood cancers, but the underlying biological mechanisms for this are unclear. In particular, the incidence of a type of blood cancer called acute megakaryoblastic leukaemia (AMKL) is 500 times more prevalent in children with Down Syndrome.

Dr Andrea Ditadi and his team based at Fondazione Centro San Raffaele, Milan, Italy, propose to uncover this mystery by carrying out in-depth studies on pluripotent stem cells – the cells that “give birth” to all the cell types in our body. By studying these cells they want to find out how the cells of the blood system develop in Down Syndrome and use this to identify the cells responsible for AMKL development. This fundamental understanding of the biology behind this phenomenon will ultimately lead to new ways to diagnose and treat AMKL.

Developing targeted immunotherapy for leukaemia

There are nearly 440,000 new cases of leukaemia diagnosed worldwide each year and less than half of these people will survive for 10 years or more after their diagnosis. The current therapies for leukaemia are often very successful at treating patients, but many people go on to develop the disease again further down the line.

Dr Giulia Casorati based at Fondazione Centro San Raffaele in Milan, Italy, has recently discovered a new immunotherapy technique that forces cells of the immune system to recognise, attack and destroy leukaemia cells. Dr Casorati and her team now want to see if they can develop this technique further by focusing their attention on a powerful immune cell called a Natural Killer T-cell. Their project aims to genetically engineer Natural Killer T-cells so that they recognise leukaemia cells and test their cancer killing ability in the lab. They hope that their technique will one day be turned into a new treatment for leukaemia.

Visualising molecular messengers in chronic lymphocytic leukaemia

There are around 440,000 new cases of leukaemia diagnosed worldwide each year and around a quarter of these are a type called chronic lymphocytic leukaemia (CLL). CLL is a cancer of a type of white blood called a B-lymphocyte. The surface of a B-lymphocyte is coated with a unique protein called a “B-cell receptor”, which act as a messenger, carrying molecular information from the outside of the cell to the inside. Once inside, the molecular message instructs the cell what to do by activating or deactivating genes. In CLL, the B-cell receptors are overactive causing uncontrolled growth and division of the lymphocytes.

Blocking the molecular signals transmitted into the cell from B-cell receptors is a promising therapeutic strategy for treating CLL patients, but the drugs that have designed to do this don’t work for every patient and can have unwanted side effects. Dr Massimo Degano, based at Fondazione Centro San Raffaele in Milan, is studying the varied molecular structures of B-cell receptors to understand why this is the case.

Using sophisticated chemical techniques, the team will work out the 3-dimensional structure of the different types of B-cell receptor, before using this information to identify drugs that can interact with the B-cell receptor and stop it working in CLL.

Unravelling the interplay between two proteins in B-cell lymphoma

Many types of cancer are driven by too much of a protein called “Myc” being produced by the cells. This protein acts like a molecular switch, turning on and off many different genes that control cell growth and division.

Thanks to our supporters, Dr Arianna Sabò at the European Institute of Oncology in Milan recently discovered that the tumorigenic activity of Myc required a specific enzyme found in cells. Importantly, this means that this enzyme could be a useful target for treating cancers that produce too much Myc.

Dr Sabò and her team now want to take this research to the next level by dissecting exactly how this enzyme cross-talks with Myc, with the hope of revealing insight into new therapeutic strategies. Dr Sabò is initially investigating this in a type of blood cancer called B-cell lymphoma, but the findings could have benefit for many other cancer types.

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.