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Putting leukaemia stem cells into reverse

Posted Dec 14 2010 12:00am
A white blood cell

A white blood cell, courtesy of the LRI Electron Microscopy Unit

Stem cells are ‘starter’ cells that produce all the organs and tissues of the body. As a baby grows in the womb, its stem cells churn out brand new specialised cells that will form an entire body, from lungs, liver and brain to head, shoulders, knees and toes. And as adults, we still have stem cells that replenish our skin, gut and other tissues as they get worn out.

But stem cells have a rogue counterpart – cancer stem cells, which we’ve written about several times on the blog . They’re the ‘immortal’ cells that appear to lie at the heart of many cancers, including some bowel, breast and prostate cancers, and leukaemia.

Cancer stem cells appear to be more resistant to radiotherapy and chemotherapy than the cells making up the ‘bulk’ of the tumour, so understanding how these rogue stem cells originate – and how we can kill them – will be a big step forward.

Although the existence of stem cells in some cancers is a hotly debated topic, the evidence for them is strongest in leukaemia – cancer of the white blood cells that form part of the immune system. Significant progress in this area has been made this week by scientists funded by Cancer Research UK along with the AICR and the Kay Kendall Leukaemia fund.

Led by Professor Eric So from King’s College London, the team have discovered the molecule responsible for driving the development of leukaemia stem cells. And  – more importantly – shown that switching it off can ‘reverse’ the rogue cells back towards good behaviour.

When good cells go bad

The research, published in the prestigious journal Cancer Cell , focuses on stem cells from leukaemias driven by faults in a gene called MLL . These are particularly aggressive cancers, which account for around 70 per cent of childhood leukaemias, and roughly one in ten acute adult leukaemias.

To start with, the researchers wanted to identify the key differences between MLL leukaemia stem cells and “pre-leukaemic” stem cells – stem cells that have started to show signs of ‘going rogue’ but may actually not develop into cancer. To do this, they analysed the activity patterns of thousands of genes in each type of stem cell, and compared the two.

Unsurprisingly (as both types of cells are very similar) the team found very little difference between them. But a few genes did seem to behave differently in the advanced cancer stem cells  – and all of them were members of a biological pathway known as Wnt (pronounced “wint”). Like a molecular relay race, the components of this pathway pass messages between themselves through the cell, eventually switching on genes that make the cell grow and divide.

One of the main players in this pathway is a molecule called beta-catenin, which helps to shuttle messages from outside a cell to the inside. The scientists noticed that the levels of beta-catenin were unusually high in the advanced leukaemic stem cells compared to the pre-leukaemic ones, suggesting that the Wnt pathway was playing an important role in the switch from a pre-leukaemic state to full-on cancerous behaviour.

Proving a role for beta-catenin

The next step was to prove that beta-catenin is a crucial part of this process. To do this, the researchers used a genetic engineering technique to remove the beta-catenin gene from bone marrow cells of mice that carried a faulty MLL gene (and were therefore highly susceptible to developing leukaemia). They discovered that the modified cells couldn’t develop into leukaemia stem cells so the mice remained leukaemia-free, strongly fingering beta-catenin for a major role in the development of the disease.

Further experiments provided more evidence.  The scientists used a technique called RNA interference to ‘switch off’ beta-catenin in mouse and human leukaemia stem cells, testing both cells grown in the lab, and cancer cells taken directly from people with the disease. The results were striking – switching off beta-catenin stopped the cancer stem cells from multiplying, and in some cases turned them back towards a pre-leukaemic state.

There was also an added bonus. ‘Bulk’ leukaemia cells and pre-leukaemic stem cells with faulty MLL have recently been shown to be sensitive to drugs called GSK3 inhibitors, sparking suggestions that they might be useful for treating the disease.

But MLL leukaemia stem cells stubbornly resist the drugs, limiting their potential effectiveness.   The researchers found that switching off beta-catenin in MLL stem cells could make them susceptible to GSK3 inhibitors, providing a possible way to increase the effectiveness of these drugs for treating leukaemia.

Where next?

Taken as a whole, the results show that blocking, reducing or switching off beta-catenin could be a potentially powerful way to treat MLL-related leukaemia – one of the most aggressive forms of the disease. Beta-catenin is an even more attractive drug target because it’s not needed by healthy bone blood stem cells, suggesting that blocking it would only damage leukaemia stem cells, rather than healthy ones.

At the moment, beta-catenin-blocking drugs are being developed in various labs around the world , although they’re yet to be tested in clinical trials. For now, Professor So and his colleagues continue to investigate the role of beta-catenin and Wnt signalling in the development of leukaemia, with the hope of identifying further targets for future drugs and finding out if this important molecule is involved in other types of cancer as well.

Kat 

Reference

Yeung, J. et al. (2010). β-Catenin Mediates the Establishment and Drug Resistance of MLL Leukemic Stem Cells Cancer Cell, 18 (6), 606-618 DOI: 10.1016/j.ccr.2010.10.032

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