Healthy cell function relies on well orchestrated gene activity. Via a fantastically complex network of interactions, around 30,000 genes cooperate to maintain this delicate balance in each of the 37.2 trillion cells in the human body.
Broadly speaking, cancer is a disruption of this balance by genetic changes, or mutations. Mutations can trigger over-activation of genes that normally instruct cells to divide, or inactivation of genes that suppress the development of cancer. When a mutated cell divides, it passes the mutation down to its daughter cells. This leads to the accumulation of non-functioning, abnormal cells that we recognise as cancer.
Our laboratory is focused on understanding how one particular cancer – chronic myeloid leukaemia or CML – works. Each year more than 700 patients in the UK – and over 100,000 worldwide – are diagnosed with CML. After recent advances, almost 90% of patients under the age of 65 now survive for more than five years.
But in the vast majority of patients CML is currently incurable and lifelong treatment means that patients must live with side effects and the chance of drug resistance arising. With increasing numbers of CML patients surviving (and treatment costing between £40,000 and £70,000 per patient a year), increasing strain is being placed on health services.
CML is perhaps unique in cancers in that a single mutation, named BCR-ABL, underlies the disease biology. This mutation originates in a single leukaemic stem cell, but is then propagated throughout the blood and bone marrow as leukaemia cells take over and block the healthy process of blood production. The presence of BCR-ABL affects the activity of thousands of genes, in turn preventing these cells from fulfilling their normal function as blood cells.
Drugs that specifically neutralise the aberrant effects of this mutation were introduced to the clinic from the early 2000s. These drugs have revolutionised CML patient care. Many are now able to live relatively normal lives with their leukaemia under good control.
But while these drugs kill the more mature daughter cells of the originally mutated leukaemia stem cell, they have not fully lived up to their initial billing as “magic bullets” in the fight against cancer. This is because the original “seed” population of leukaemic stem cells evade therapy, lying dormant in the bone marrow to stimulate new cancer growth when treatment is withdrawn.
To truly cure CML we must expose, understand the inner workings of, and uproot the leukaemia stem cells. And to do this, we need to learn more about them. How do they survive the treatment that so readily kills their more mature counterparts? Which overactive or inactivated genes protect them?
We believe that the answers to these questions lie in the analysis of biological “big data”.
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