Healthy stem cells produce billions of different cells every day, and these go on to perform a wide range of functions in our bodies. But this production line can be hijacked, as is the case in certain types of cancer. One such cancer is Acute Myeloid Leukaemia (AML). Zahra Aboukhalil, a DPhil student in the Vyas lab, is trying to find out how this hijacking takes place in AML. In this piece, for which she was awarded the Moorbath Domus prize by Linacre College, she tells us more about her project and how it could help develop improved treatments.
Not all cells are equal. While many cells in the body are busy performing a specific function, such as sensing the world around us or protecting us from infection, other cells are responsible for maintaining the production of new cells. This happens in a series of steps, and at the top of this hierarchy are stem cells, the master regulators. Stem cells have the unique ability of both producing more of themselves (self-renew) and generating a multitude of other cell types. This means that, throughout our lives, the body continues to have the ability to produce more cells. A small group of stem cells keep the production line active.
Cancer hijacks this well-refined system and disrupts the production of healthy cells. It also establishes its own hierarchy by generating cancer stem cells. These cells have the power to indefinitely produce cancerous cells and generate new cancer stem cells. As many treatments do not specifically target cancer stem cells, treatment success can be limited. By evading treatment detection, cancer stem cells can lurk in the background, awaiting the opportunity to re-establish their reign.
A classic example of a healthy stem cell hierarchy is the production of the cells in the blood and immune systems, which is driven by haematopoietic stem cells (HSCs). HSCs manage an exceptional production line that generates all the cells circulating in our blood. This tightly controlled process produces billions of new blood cells every single day. Immune and blood cells are produced through intermediate (progenitor) cells, which act as the primary workforce in the production line. These progenitor cells have a decreased ability to self-renew and are more restricted in the different types of cell they can produce.
Acute myeloid leukaemia (AML), the most common acute adult blood cancer, is capable of crippling this healthy production of immune and blood cells. Like a production line with a failure midway, generation of the final product of immune and blood cells is halted, due to a build-up of faulty progenitor cells. AML establishes this malfunction by diverting the cells along its own cancerous production line. Controlling this cancerous system is the leukaemia stem cell (LSC).
Intriguingly, our lab at the MRC Weatherall Institute of Molecular Medicine has shown that in most cases of AML, rather than completely impersonating the healthy HSC, the LSC resembles the healthy, progenitor cells. But despite its likeness to progenitor cells, the LSC re-activates the ability to self-renew, allowing it to generate not only leukaemic cells, but also additional LSCs. To eradicate leukaemia, we must target the LSC and to achieve this goal it is essential that we develop a thorough understanding of these cells.
A fundamental step towards understanding any cell’s behaviour is investigating its genes. All our cells contain the same DNA, which is made up of functional units known as genes. The extent to which these genes are used determines a cell’s function and role. A molecule called RNA is the messenger that allows the DNA to be read and used by the cell. The RNA produced by a cell represents the genes the cell is using and thus reveals information about how the cell functions. By decoding a cell’s RNA we can expose its unique fingerprint.
© Zahra Aboukhalil (right) with members of the Vyas lab
As part of my PhD project, our lab has applied this powerful technique to blood cells and has identified the fingerprints of healthy HSCs and progenitor cells. We have also completed the decoding of the LSC’s RNA, in order to compare it with healthy cells. I seek to identify the genes that are key to the survival and function of the LSC. My ultimate aim is to understand what empowers the LSC to maintain leukaemia. This knowledge will help develop new, specific, treatments targeting the LSC, striving to shut off the leukaemic production line from the top.
Leukaemia is a prime example of how a cancer can mimic healthy cells to its advantage. Healthy stem cells carry out the extraordinary feat of producing billions of different cells of diverse types through a tightly regulated hierarchy of cells. This system is usurped in cancer and a cancerous hierarchy is established. Ultimately, by understanding and targeting the fundamental features of the cancer stem cell, we can progress towards truly eliminating the disease.