Imagine you’re organising a potluck dinner. You ask everyone to bring a dish to share. Ideally, you end up with a good selection of food: some sweet, some savoury. Everyone goes home happy, and you have some leftovers for the next day. You might also be unlucky: too many desserts, not enough vegetarian dishes. The vegetarian guests go hungry, and so does anyone with diabetes. Next time, you decide you will ask people to make a specific type of dish so that there’s enough for everyone.
What does this have to do with blood and the development of cancer? Well, your stem cells face the equivalent of this potluck problem when they’re making blood cells. Stem cells are the source of all blood cells, including stem cells themselves. Stem cells therefore have two tasks: making more stem cells (called self-renewal) and making other types of blood cells (called differentiation). Individual stem cells might do one or both of these at any time. In potluck terms, that’s like having some guests who’ve agreed to bring savoury dishes, some guests who’ve agreed to bring sweet dishes, and some guests who’ve agreed to bring one of each. Next time, they might volunteer to bring something different.
For stem cells, making blood is like trying to organise a potluck dinner…
We know that healthy stem cells act in this way thanks to recent work led by Mairi Shepherd, a PhD student in Bloodwise-funded researcher Dr David Kent’s lab at the University of Cambridge. Mairi, David and other members of the research team have been working on understanding the decisions that stem cells make in myeloproliferative neoplasms (MPN), a group of disorders in which genetic mistakes in healthy stem cells can make cancerous MPN stem cells. Their most recent research has just been published in the journal Blood.
How do MPN stem cells make so many more cells?
In order to answer this question, the researchers looked at what was happening inside individual stem cells.
“MPNs are typically caused by cells with mutations in a small handful of genes,” says David, “but this makes understanding what each gene mutation does on its own quite difficult, affecting our ability to target these mutations in therapeutic approaches.”
Mairi, David and the team created cells with different types of genetic mutations that are commonly found in the stem cells of people with MPN. One of these mutations is in a gene called JAK2, which doesn’t seem to be enough to start MPN by itself, but can collaborate with other gene mutations to cause MPN. The genetic change it most commonly collaborates with is in a gene called TET2. To build up a full picture of what each of these genetic changes does, the team compared healthy stem cells with stem cells carrying the JAK2 mutation, the TET2 mutation, or both together.
“The single cell approach allowed us to specifically identify which mutation resulted in a particular cancer cell characteristic,” said Mairi. “This means that we can now move forward to investigate the genes which drive increased division or increased stem cell activity in a more targeted manner.”
Mairi at work in the lab
Understanding increased differentiation
The team took individual healthy stem cells and stem cells with JAK2 mutations and grew them in the lab under conditions that would encourage them to divide and make more cells. Compared to healthy stem cells, JAK2 mutated cells did more differentiation and less self-renewal. On examining individual stem cells that were particularly prone to differentiation, the researchers found that several genes were not as active as they should be, which had knock-on effects on the ways that cells communicate within themselves and with other cells around them.
The JAK2 mutation only causes increased differentiation, meaning that by itself it can’t cause an MPN – without making large numbers of new MPN stem cells, the population of JAK2 mutated cells would simply divide quickly and then die out. Something else must be causing the new MPN stem cells to be made, and that’s where TET2 mutations come in…
The JAK2 mutation causes stem cells to split into lots of other kinds of blood cells, but that means they can’t renew themselves
Understanding increased self-renewal
In order to understand how TET2 contributes to MPN, the team transplanted stem cells from donor mice with either the JAK2 or TE2 mutation, or both, into other mice (‘recipients’), then waited 16 weeks to see whether there would be more donor cells than recipient cells present in the mice. If there were, that would mean the donor cells had been able to differentiate and self-renew faster than the recipient cells.
As you might expect, donor cells with a JAK2 mutation alone had all but disappeared after 16 weeks, because they tend to differentiate without making new MPN stem cells. By contrast, donor cells with a TET2 mutation were present in high quantities, as were donor cells with TET2 and JAK2 mutations together. Mice who had received donor cells with both mutations also had much higher quantities of red blood cells than mice who had received any other kind of donor cell, because these stem cells could produce lots of new MPN stem cells and lots of different kinds of mutated blood cells, leading to an MPN. It’s as if you had invited five people to a potluck dinner and each of them brought both sweet and savoury dishes, but in quantities enough for fifty – fine in the short term, but afterwards your fridge is full to overflowing.
Three of the genes that were identified in this study were overactive in stem cells that have increased differentiation and increased self-renewal. One of these (a gene called Bmi1) is a particularly interesting candidate since it is also associated with a worse outcome if it’s particularly active in chronic myeloid leukaemia, acute myeloid leukaemia, and myelodysplastic syndromes.
The research team with Mairi (second from left) and David (far right)
The finding that JAK2 can’t drive MPN on its own is interesting, because it is the only identified gene mutation for quite a few people with MPN. An obvious next question is what could be happening to drive MPN for these people. David has some ideas about what might be happening in this group of people: there could be other genetic errors that we don’t yet know about; there could be inherited risk factors that make their healthy stem cells self-renew and differentiate more slowly than other people’s, allowing MPN to gain a foothold; or there might be aspects of the environment immediately around MPN cells in the body that allow these cells to thrive.
David says, “Just because we have not yet identified what collaborates with JAK2 mutations in these patients does not mean that something isn’t doing the same job as a TET2 mutation. Researchers working on this have already identified a number of genetic mutations (e.g., Dnmt3a, Asxl1, and Ezh2 mutations) and a number of research groups including our own are investigating the impact of neighbouring cells that might help an MPN stem cell grow faster than its normal counterpart. At the end of the day, we hope that there might be a common thread between the different collaborating events such that we could identify a molecule they might all work through to cause an MPN – this would be an incredibly attractive target for MPN therapies.”
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