Leukaemia & Lymphoma Research scientists have helped decipher the origins of a rare but aggressive form of childhood leukaemia, which could one day improve the way doctors monitor and treat the disease.
The researchers have homed in on the disastrous genetic faults that drive a particular type of acute lymphoblastic leukaemia (ALL) in children. They discovered that people born with a distinct abnormality of their chromosomes – the structures of genetic information in cells – have a 2,700-fold increased risk of developing this blood cancer compared to the general population.
These patients carry an unusual chromosome that is created from two separate chromosomes snapping and fusing together. This structure is highly prone to a catastrophic event that shatters the genetic material, before the fragments are then pieced together in a disorderly way. When this massive genetic assault occurs in immature white blood cells, it can form a rampant leukaemia that grows quickly out of control.
Reconstructing cancer's history
Humans usually have 23 pairs of chromosomes, housing the vast majority of genes that are the recipe book for a healthy working cell. Scientists already knew that in the cancerous cells of a small number of ALL patients, the 21st chromosome contained many repeated sections – a bit like duplicating some of the ingredients in a recipe. These patients, whose leukaemia we call iAMP21 ALL, need more intensive treatment and generally do not survive as long as other ALL patients.
The collaborative team led by Newcastle and Cambridge researchers used cutting-edge DNA analysis methods to interrogate iAMP21 ALL in nine patients in unprecedented detail. They report in the leading journal Nature how they were able to unravel the pattern and sequence of errors across the leukaemia cells’ entire genetic material, or 'genome'. In effect, looking back through time to build a picture of the cell’s life history.
As Leukaemia & Lymphoma Research scientist Professor Christine Harrison, co-leader of the team based at Newcastle University, says:
Leukaemia's 'catastrophic' beginnings
The genetic detectives identified four of the nine patients as having a special chromosomal rearrangement, called a Robertsonian translocation. This is where chromosomes 15 and 21 break and swap bits of their genetic material, creating a 'cut-and-shut' chromosome. In the receipt book analogy, this is like swapping pages of one recipe with the pages of another.
Clearly, when the instructions are so messed up, thing can go awry.
The scientists believe that because the new cut-and-shut chromosome has two centre points instead of one (like two Xs stuck together), something can go very wrong when the cell divides. As the cell splits and the genetic material tries to distribute evenly between the two new daughter cells, the abnormal chromosome gets pulled apart from two points rather than one. They think it's this irregular event that can lead to the catastrophic shattering of the chromosome. The cell's DNA repair machinery is then only able to stitch the chromosome together in a highly flawed order (see image), akin to ripping up some of the recipe book’s pages and cobbling them back together with sticky tape.
So it's a spiral of genetic wreckage after genetic wreckage.
In the five other iAMP21 ALL patients, the cancer was triggered by the two pairs of chromosome 21 becoming fused together, head-to-head.
This is then again usually followed by chromosomal shattering.
This disastrous fragmentation, called 'chromothripsis', was discovered only three years ago and it forces us to rethink how cancers can start. Whilst
we have traditionally thought of cancers being born from the slow and progressive accumulation of genetic faults, often over many years, these new discoveries show that it can be kick-started by a one-off act of large-scale genetic vandalism. It may go someway to explain why these particular cases of cancer can affect the very young.
As Dr Peter Campbell, co-leader of the study based at the Wellcome Trust Sanger Institute in Cambridge, says: "What is striking about our findings is that this type of leukaemia could develop incredibly quickly – potentially in just a few rounds of cell division." And noting the next phase of research to nail the mechanism of cancer initiation: "We now want to understand why the abnormally fused chromosomes are so susceptible to this catastrophic shattering."
What would also be fascinating, as well as useful in the management of this disease, is to understand how the abnormal chromosome came into existence in the first place. I’ve written before about finding the causes of the causes – the environmental or physiological influences that induce certain cancer-causing genetic mistakes. With this knowledge, perhaps one day we could devise ways to prevent it from occurring in the first place, or at least reduce the likelihood.
Homing in on cancer's culprit
But the researchers didn't stop there. They knew that only if the shattered chromosome boosted the cell's ability to survive and grow, would a cancer form – otherwise, the damage would be too much to bear and the cell would die.
So, focusing on the cells that had become cancerous, they zoomed in on the areas of the chromosome that were fused together, to see which genes were nearby. They found a number that are already known to be associated with other blood cancers.
This not only suggests we may, at some point, be able to accurately predict which cells in crisis are likely to become cancerous, but also raises the possibility that therapies targeting these faults developed for other diseases may be useful for these patients. Doctors may, as some point in the future, be able to pick out high-risk individuals who carry the Robertsonian chromosome, closely monitoring them to see whether leukaemia develops. If it does, then they could have the exact drugs to treat their specific disease.
But it is worth emphasising that Robertsonian translocation is rare. The investigators estimate that only one or two in 200,000 people are born with this particular abnormality and it’s responsible for only two percent of childhood ALL cases (fewer than 10 cases in the UK each year). Nevertheless, if we reach a future where everyone’s genome is sequenced from birth, it would be possible to pinpoint high-risk individuals and screen them regularly to catch the disease at its inception.
Leading the way in cancer research
The researchers note that, despite the run-up of genetic events seeming random and chaotic at first glance, the end result was quite consistent across the patients studied – they all ended up with a new chromosome 21 in which the numbers and arrangement of genes are optimised to drive leukaemia.
Yilong Li of the Wellcome Trust Sanger Institute, principal author of the report, says: "This is a remarkable cancer – for patients with iAMP 21 ALL we see the same part of the genome struck by massive chromosomal rearrangement". And, whilst the insights into childhood leukaemia are stunning, Dr Li also notes the implications for blood cancers and beyond. "The method we’ve developed can now be used to investigate genetic changes in all cancer types."
This groundbreaking discovery boosts our fundamental understanding of childhood leukaemia. It demonstrates a general trend in cancer research and one blood cancer research is at the forefront – we’re subdividing once single diseases into a raft of individual conditions, often by the genetic root cause. This growing body of knowledge is allowing us to distinguish blood cancers on an increasingly personalised level, and will be the key to individualising patient care and beating each and every person’s blood cancer.
Li Y, Schwab C, et al. Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia. Nature (2014) doi:10.1038/nature13115. Published online 23 March 2014