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Fighting AML by getting white blood cells to grow up

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15 Feb 2018

Professors Conny Bonifer and Peter Cockerill at the University of Birmingham may have found a way to restore healthy blood production in acute myeloid leukaemia (AML) by helping cells stuck in an immature state to develop into mature blood cells.

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Imagine the immune system of the human body as an army that fights off invading infectious organisms. White blood cells form a large part of this army, each specialising in a particular job. For example, basophils cause inflammation, which can help form a barrier around infections so they can’t spread to the rest of the body, while macrophages can ‘eat’ invading infections by engulfing them. Basophils and macrophages are specialised cells that both develop from other types of white blood cell called monocytes and granulocytes, which in turn come from multi-potent progenitor cells. Multi-potent progenitor cells are immature white blood cells, so they do not fight off infection – instead, their job is to make the cells that can fight.

A diagram which illustrates how a genetic mutation can cause acute myeloid leukaemia

A genetic change (mutation) causing AML can occur in multi-potent progenitor cells and stem cells or even later, affecting any cells that develop from them.

AML starts when a genetic error (called a mutation) occurs in a myeloid stem cell or a multi-potent progenitor cell. The bone marrow, which normally produces healthy myeloid cells, begins to make lots of myeloid cells that are unable to function properly, effectively stopping the normal development of blood cells. Soon, the defective myeloid cells begin to crowd out the healthy myeloid cells so the immune army becomes filled with cells that are unable to fight.

AML progresses very quickly and needs to be treated early to give the best chance of survival. However, the only treatment options available at the moment are chemotherapy and, if that fails, stem cell transplants. Unfortunately, because AML is largely a disease that affects older adults, many people who have it are too frail to undergo these harsh treatments. To make matters more complicated, there are several different types of genetic error that can cause AML, and each one causes the disease to behave in a different way.

Professors Conny Bonifer and Peter Cockerill are pictured in a laboratory wearing white lab coats

At the University of Birmingham, Professors Conny Bonifer and Peter Cockerill (pictured above) are leading a team of researchers who are improving our understanding of how genetic changes reprogram healthy white blood cells into AML cells. A large part of healthy blood cell development is tightly controlled through proteins called ‘transcription factors’, which regulate the activity of other genes and often work in networks. RUNX1 is a transcription factor, and we know in AML that the gene that makes this protein is altered, resulting in an ‘oncoprotein’ (cancer protein) that causes blood development genes to become active at the wrong time.

In AML, RUNX1 switches off a gene called CEBPA, which makes another transcription factor protein called C/EBPα that plays an important role in the development of white blood cells (basophils, neutrophils and phagocytes) from myeloid blasts. The result is that myeloid blasts are stuck at one point in development and keep growing – this is the core problem of AML. Switching C/EBPα back on can therefore help start healthy blood cell development back up again. However, it’s not clear how switching on C/EBPα does this, which means its potential as a treatment is limited because it may not work for every genetic error that leads to AML.

Dr Paulynn Chin pictured working in a laboratory
Dr Paulynn Chin, one of the members of the research team.

Recently, Professors Cockerill and Bonifer and their team have been testing what happens when they artificially switched on C/EBPα in lab-grown cells with two AML types caused by different genetic errors. These two types of AML maintain themselves through different genetic pathways, so testing them on both is a good way to assess whether switching on C/EBPα is likely to be a treatment that can be used in several types of AML, or if it will only work for some types. Most importantly, they examined precisely what happens to global gene expression (how active each gene is) within AML cells once this protein is switched on.

Excitingly, the team found that switching on C/EBPα seems have the same two effects in both types of AML. These two effects were to activate genes that are responsible for helping multi-potent progenitor cells to differentiate into granulocytes and monocytes and to deactivate genes which help maintain leukaemia. Analysing all the genes that respond to C/EBPα, they also showed that the original oncoprotein (the mutated RUNX1 protein) causing the disease was still there, but C/EBPα was capable of overriding its harmful activity.

Professor Bonifer explains: “In AML, we know that multi-potent progenitor cells shift from developing into mature blood cells towards staying at one stage of development. Our work sheds light on a fundamental mechanism of how oncoproteins keep leukaemic cells in their harmful state. Our work now shows that this balance can be shifted and AML cells could be forced to make healthy mature blood cells. Our team has now identified the pathways that need to be activated to do this.”

Although it is early work, this research is adding to our knowledge of how AML develops, and is revealing ways in which we could restore healthy blood cell development. By allowing the blood cells to develop normally again, it could be possible to bring back a healthy army of fighting fit immune cells in people with AML.

On average, 7 people will be told that they have AML today. Sadly, many of those people will not survive beyond five years. With your help, our researchers can continue to find ways to help more people survive AML. Find out more about our fundraising. 

If you need support, or would like to know more about AML, our Support Line is open Monday-Friday 10am-4pm on 0808 2080 888. Read our patient information.


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