When is a leukaemia cell not like a leukaemia cell?

When it’s pretending to be a superhero and hiding in plain sight.

And that’s what Michael Ashby’s research is about. Not superhero disguises exactly, but it’s a good analogy for what he is looking at.

Dr Michael Ashby, haematologist at Alfred Health and one of our current PhD researchers, is focusing his research on acute myeloid leukaemia (AML). He is looking at what causes relapse in some patients but not in others, and whether there might be better ways to manage patients after they have had a stem cell transplant to help more have a successful outcome.

But before we get int to that, let’s take a step back. What actually is leukaemia and how does a stem cell transplant help?

Leukaemia and stem cell transplants

At its simplest, you can think of leukaemia as a disease in which the body produces too many white blood cells.

Your blood stem cells  create all the different types of cells you need in your blood, including the ones that fight disease and keep you healthy. The main cells involved in this process are white blood cells, or leukocytes.

You might think more white blood cells would be a good thing because white cells are the disease-fighting cells. More of them = more immunity, right?

Wrong.

The white blood cells in leukaemia are not healthy white blood cells, and they don’t fight disease properly. In fact, they are the disease.

When you have an allogeneic stem cell transplant, the aim is to replace your blood stem cells with someone else’s healthy blood stem cells. The transplant provides your body with a new immune system (from a donor) that can recognise leukaemia cells as bad guys.

But even after a successful transplant some of the old leukaemia cells can still return, this time wearing a disguise.

Sneaky leukaemia cells hiding in plain sight

This is where Michael’s research comes in.

One of the key areas of Michael’s work surrounds a process called methylation. Methylation is an “epigenetic” process that changes how cells behave, without changing their underlying DNA.

“It changes the way cells express themselves,” Michael explained. It involves the attachment of methyl groups to DNA. Where those methyl groups attach and the pattern in which they attach, determines which bits of the cell’s DNA turn on, and which stay turned off – effectively it determines how the whole cell can function.

And in the case of leukaemia cells, epigenetics helps act a bit like a disguise.

If you think of your immune system as a band of superheroes all wearing capes and masks, it’s as if the “bad guy” leukaemia cell has also grabbed itself a cape and mask and is pretending to be one of the good guys. It’s hiding in plain sight. The disguise is enough to fool the new immune system after a transplant. The new immune system doesn’t recognise that cell as a bad guy, and so it leaves that cell alone.

That bad cell – a leukaemia cell – then multiplies over and over again, which can lead to a situation that no one wants: relapse.

Michael’s research

Michael’s research seeks to understand why relapse happens in some patients after a stem cell transplant – and whether we can intervene with more targeted treatments.

“Not all transplants relapse the same,” Michael said. “But transplants are all managed in a similar way. We’re trying to prevent relapse, but we’re managing it all the same way. My [research] underpins that this is not necessarily the right thing to do.”

“These relapses are clearly different in the mechanisms behind them. We only treat them all the same because we lack any other options, because we don’t [yet] know any better, but hopefully by describing how some of these things are different, it might lead to more targeted or appropriate treatments in the future.”

To explore this, Michael has been looking at cells from people who have had stem cell transplants.

“I’m working with cells collected from a group of patients with acute myeloid leukaemia who have relapsed after treatment. We collect cells at diagnosis and relapse, for patients who have had chemotherapy and a transplant, and compare them to patients who have only had chemotherapy,” he said.

“This way we can compare if a stem cell transplant – and all the post-transplant treatment that goes with it – has an effect on DNA methylation.”

In other words, do these methylation changes play a part in helping those ‘bad guy’ cells grab themselves a cape and mask and put on a disguise.

What has he found?

Michael’s PhD research has several parts, but here’s what the early data shows:

As expected, there was not much variation in methylation among the group of patients who received chemotherapy only. Among the transplant group, however, some patients had only minor changes in methylation, while others had quite a lot of change in methylation.

So, what does this mean?

Michael’s next step is single cell sequencing. He will look at individual cells to see what is going on at a deeper level, looking in particular at the immune components of the cells of the donor, and any of the recipient cells that may have grown back.

“What we’re expecting to see is that the cells will be different in their immune component, the ones that relapse and the ones that don’t,” he explained.

“We don’t know what they will be, but we’re expecting that there will be subsets of cells that behave in certain ways. This will help us understand how they’re responding, or not responding, to treatment, again with a view to making that treatment more effective.”

“We’re hoping to gain understanding on what treatment might be more helpful post-transplant. We’ve got some good ideas, but at the moment it’s not been shown at a cellular level why or how treatments work.”

Single cell analysis is a complicated and expensive process, so at the moment Michael is doing a lot of work on how to best collect samples, how to prepare those samples for analysis, and how best to run these experiments

We wish Michael the best with the continuation of his work, and look forward to hearing what this next phase of his research reveals.