How do senescent stromal cells subvert the treatment response in acute lymphoblastic leukaemia?

Blood cancers form due to a fault in the genetic make-up of the blood manufacturing cells in the bone marrow. However, cancer cells do not occur in isolation. 'Ageing' of surrounding bone marrow cells, a process called senescence, affects the onset and progress of the disease. We have recently published work showing that premature cellular senescence in bone marrow support cells (called stromal cells) caused by certain chemotherapy drugs commonly used to treat blood cancers play a major part in preventing the complete clearance of leukaemia cells - in essence, the support cells donate "energy" to the blood cancer cells by giving them mitochondria, the power generators of the cell, via small, temporary, bridge-like connections formed between the cells.

The underpinning for this current application is the new data we have obtained which shows that the genetic damage in the leukaemia cells themselves can generate these senescent support cells. Of particular interest is the fact the type of genetic damage that causes leukaemia in children (which is typically curable) is much less likely to cause this senescence problem than the genetic damage which causes leukaemia in older adults (which is rarely curable).

With a growing ageing population, blood cancers in older persons are on the rise. We believe our work can help us to understand why blood cancers rise wiht age and to find less damaging and more successful ways to treat older people with leukaemia.

We are a team of two laboratories, one with a background in aging and the other with a background in blood cancer which have come together to work on this project. We propose to study senescent bone marrow support cells with an exciting technology which can characterise normal and abnormal gene activity in a single cell rather than from a collection of cells, as would be the case in a tissue biopsy.

Single cell approaches are very important in blood cancer research since we know that only a minor group/subpopulation of blood cells usually causes and maintains a disease. Senescence can spread through secreted factors to other, neighbouring cells. We aim to understand the different ways in which this spread of senescence can occur in detail and would like to study the consequences of different types of bone marrow senescence in blood cancer.

For example, we want to know how the senescent bone marrow support cells can protect blood cancer cells from being targeted by chemotherapy. To gain a better understanding of the different ways senescence can spread to other cells, we will characterise how senescent bone marrow cells communicate with blood cancer cells in a cell culture dish. We aim to investigate the importance of this cell-to-cell communication in a variety of senescence 'model' systems both in a cell culture dish, but also in a variety of ageing/ senescence mouse models.

We will use some primary human tissue samples which patients with the disease in question have donated, with consent.

Once we have established the different ways in which senescence can be propagated to other cells, we will probe our system with commonly-used drugs which also have senolytic capacity, namely those which can eliminate senescent bone marrow cells in a cell culture dish and in mouse model. We will study the impact on of these drugs on the response to chemotherapy. Some of these drugs are already safely and commonly used in completely different diseases and may find new purpose in this approach.