New approach to treating anaemia in blood cancer
Researchers have found that when mistakes happen in a gene responsible for translating DNA to protein, it can lead to the development of a type of blood cancer called myelodysplastic syndrome (MDS). Find out more about this exciting research here.
When a cell wants to make a protein from a gene, the genetic code is translated into an intermediate gene product called RNA. This undergoes extensive editing before it makes a normal functioning protein. But what happens when this goes wrong?
In a study supported by Bloodwise, Professor Jackie Boultwood and Dr Andrea Pellagatti have found that when mistakes are made in the gene product, it can lead to the development of a type of blood cancer called myelodysplastic syndrome (MDS).
I caught up with the team to find out more.
What is MDS?
MDS happens because normal blood production in the bone marrow breaks down, leading to reduced numbers of blood cells. Low numbers of red blood cells can cause anaemia, and a lack of white blood cells lead to infections. Over time the bone marrow also becomes crowded with defective cells called blasts. MDS develops differently in people but in up to 40% of cases, it can progress into leukaemia.
Blood smear from a person with myelodysplastic syndrome (MDS). Credit: AFIP CC BY 2.0.
Influencing the outcome of MDS
Researchers led by Professor Jacqueline Boultwood and Dr Andrea Pellagatti at the University of Oxford studied people with MDS who had genetic changes in a gene called U2AF1. These people have more severe anaemia, a worse outcome, and a higher risk of developing leukaemia. So why does this happen? It turns out that it’s all to do with how the information from the gene product is translated into protein.
Making proteins from DNA
Genes are DNA sequences that code for a protein. Most genes that code for proteins are regularly interrupted by non-coding stretches of DNA. The coding regions of a gene are called exons and the intervening non-coding regions are called introns.
When the cell wants to make a protein, the DNA of the gene needs to be copied into RNA – an intermediate genetic product between DNA and the protein. But the non-coding parts of the gene product needs to removed and the coding parts stuck together again before a protein can be made. This process is called RNA splicing. A gene can make more than one protein by deciding what exons (coding regions) to include and exclude in the final gene product. The different forms of gene product are called ‘RNA isoforms’.
DNA is made from exons (coding regions) and introns (non-coding regions). The spliceosome removes the introns, and can edit the RNA so different forms (isoforms) can be made, which in turn allows a gene to make different proteins (protein isoforms).
Gene product editing is carried out by a large molecular machine called a spliceosome, and one of the key genes that control how this behaves is called U2AF1. When the spliceosome is faulty and starts making mistakes, it can lead to the development of cancer.
When U2AF1 turns bad
Wanting to find out more about how U2AF1 influences the outcome of MDS, the Oxford research team used a powerful technique called ‘RNA sequencing’. This allowed them to scan thousands of genes at the same time, to find which gene products become defective when the U2AF1 mutation was present in the bone marrow cells of people with MDS.
The U2FA1 gene. Credit: Emw CC BY 2.0.
They found that some abnormal gene products, such as H2AFY and STRAP, were responsible for reducing the production of red blood cells and a type of white blood cell seen in people with MDS.
Gaining back control
When researchers normalised the levels of the H2AFY and STRAP gene products using ‘RNA isoform modulation’, a technique which restores the balance of the different types of gene products, normal red blood cell production was restored in patient cells grown in the lab.
Correcting the levels of the faulty gene products suggests that we could rescue normal red blood cell production in people with MDS who have U2AF1 gene changes. And this opens up the prospect of using drugs that control splicing as a therapeutic approach to reduce the anaemia in people living with MDS.
Red blood cells. Credit: Wellcome Images.
Where to next?
Professor Boultwood says: “MDS affects around 2,000 people in the UK every year and can be treated in different ways - from palliative care to bone marrow transplantation. But this is not good enough, and it is vital that we search for newer and better ways to treat people living with MDS.”
Professor Jackie Boultwood.
Dr Pellagatti tells me: “The identification of the key gene products that are abnormal in people with MDS is crucial for understanding how these spliceosome mutations contribute to disease development. Our knowledge surrounding how this family of genes can cause blood cancer is growing, and it’s really exciting that we can start to think about correcting these effects. RNA isoform modulation approaches are already being used to successfully treat other conditions, such as spinal muscular atrophy, so we are hopeful that this strategy will work for MDS.”
Their findings have been recently published in the Journal of Clinical Investigation.