Rapid growth of blood cancer driven by a single genetic 'hit'

Researchers from the Wellcome Sanger Institute and their collaborators used whole genome sequencing to study when BCR::ABL1 -- an abnormal fusion of the different genes called BCR and ABL1, which is known to cause chronic myeloid leukaemia. The team investigated when BCR::ABL1 first arises in a blood cell and how quickly these cells with this genetic change then multiply and expand to lead to a diagnosis of a type of leukaemia.

The research, published today (9 April) in Nature, contributes to the scientific understanding of how strong this abnormal fusion gene is in its ability to drive cancer.

Chronic myeloid leukaemia (CML) is a cancer of the bone marrow and blood. CML is caused by a rearrangement of genetic material between two chromosomes. In those with CML, part of the ABL1 gene from chromosome 9 is fused with the BCR gene from chromosome 22. This creates an abnormal fusion gene called BCR::ABL1 on chromosome 22, also known as the Philadelphia chromosome.

However, despite its well-understood role in CML, little is known about the evolution of this fusion gene, the rate at which cells with BCR::ABL1 start to multiply, and how this contributes to disease progression.

In a new study, researchers from the Sanger Institute used DNA sequencing to analyse over 1,000 whole genomes of single blood cells from nine people with CML, ranging from 22 to 81 years of age. The researchers then used the genetic changes identified in these genomes to study how the cells were ancestrally related to one another. This is akin to creating family trees of cells -- known as phylogenetic trees -- which allowed the team to look back in the past to explore how the tumour cells grew over time and exactly when the abnormal fusion of the two genes occurred to start off the cancer growth.

The phylogenetic trees from CML patients showed that the BCR::ABL1 fusion gene typically appeared three to 14 years before diagnosis. Once this fusion occurred, the tumour clones -- tumour cells that are genetically identical -- grew very quickly, sometimes in excess of 100,000 per cent growth annually, suggesting the fusion gene has a uniquely strong ability to drive the disease. Interestingly, this rapid growth is substantially faster than the growth rates of other blood cancers and solid tumours, which tend to develop more slowly with multiple genetic changes accumulating over many decades. Not only was the rapid growth of the tumour compared to other cancers unusual, but that this growth was driven by just one single genetic variation, whereas most other cancers require multiple genetic changes to accumulate before the cancer arises.

The researchers also discovered that age impacts tumour growth rates, with younger patients showing much higher rates at which cancerous cells with the fusion gene multiply compared to older patients. The study also found that patients with faster-growing CML were less likely to respond well to tyrosine kinase inhibitors (TKIs) -- the standard treatment for CML. With one in five patients not responding to TKIs, this study has implications for considering cancer cell growth rates in a clinical setting. However, the researchers note that further studies in larger patient cohorts are needed to validate this.

To investigate whether people could carry BCR::ABL1 without showing symptoms, the researchers also analysed sequencing data and health records from over 200,000 participants from the USA-based "All of Us" cohort. They showed that almost all individuals with BCR::ABL1 were later diagnosed with a blood disorder, and so they suggest that expansion of BCR::ABL1 clones without developing subsequent symptoms is unlikely.

Overall, the results show the uniquely strong ability of the BCR::ABL1 fusion gene to drive growth of cancerous cells in CML, and that variation in these growth rates between patients may be useful in the future clinical setting to better predict patient responses to treatment.

Dr Aleksandra Kamizela, co-first author of the study, resident doctor at the Lister Hospital, Stevenage and soon Addenbrooke's Hospital, Cambridge, said: "In a clinical setting, healthcare professionals will perform a reverse transcription polymerase chain reaction (RT-PCR) test, a type of blood test, to measure a patient's response to CML treatment. However, they are not able to routinely see differences in the genetic cause of CML in patients at the DNA level, which we have been able to highlight in our study. Our findings also provide a rationale to look at the rate of cancer growth more closely in future studies in order to understand if we can use such information in a clinical setting."

Dr Jyoti Nangalia, senior author of the study, haematologist at the University of Cambridge and Group Leader at the Wellcome Sanger Institute, said: "What our study suggests is that chronic myeloid leukaemia is an outlier compared to other cancers -- both solid tumours and other blood cancers. We have shown that chronic myeloid leukaemia cells undergo incredibly rapid growth within a few years to a decade before diagnosis, whereas for most cancers, the timeline from start to clinical presentation is several decades. This work paves the way to understanding how we might optimise treatment for those patients that currently respond poorly to treatment."