Blood cancer’s genetic warning signs may appear years early

Published in Cancer Discovery, the study was led by researchers at the Wellcome Sanger Institute and their collaborators. The team combined genetic analysis with detailed clinical records to investigate how chronic blood cancers can develop over several decades. The findings were also presented at the American Association of Cancer Research (AACR) Conference in San Diego.

How Chronic Blood Cancers Develop

Myeloproliferative neoplasms (MPNs) are a group of rare, long-lasting blood cancers that begin in the bone marrow, where blood cells are produced. In people with MPNs, the bone marrow makes certain blood cells in an uncontrolled way.

Around 40,000 people in the UK are living with MPNs, and approximately 4,000 new cases are diagnosed each year.^[1] These cancers often progress slowly. They can begin with mutations, or changes in DNA, that arise very early in life, followed by additional mutations that accumulate over several decades.^[2]

Most MPNs are associated with mutations in the JAK2, CALR or MPL genes. However, around 10 percent of patients do not have any of these common genetic changes.

In these cases, doctors may diagnose cancer largely by examining the appearance of cells in the bone marrow. As a result, some patients could receive cancer treatment, including chemotherapy, without definitive genetic evidence that they have an underlying blood cancer.

Why Some Cases Worsen

The course of chronic blood cancer varies widely between patients. Some people feel well for years and need only mild treatment while their disease remains stable. Others eventually develop more serious conditions, including leukemia or myelofibrosis, which causes scarring in the bone marrow.

Doctors cannot always determine in advance whose disease will remain stable and whose will progress. The researchers therefore investigated whether genetic changes could reveal which patients were at greater risk. They also examined whether people who lacked the common MPN mutations truly had blood cancer.

The team followed 30 patients with chronic blood cancers, primarily MPNs. They combined whole-genome sequencing with extensive clinical information, including nearly 8,000 blood test results, treatment records and disease data.^[3]

More than 450 samples were examined through repeated genomic testing. Some patients were monitored through routine clinical care for as long as 25 years.

Building Family Trees of Blood Cells

The long follow-up period connected genomic research at the Sanger Institute with routine patient care at Cambridge University Hospitals NHS Foundation Trust. This allowed the scientists to observe how blood cell populations changed over time and provided a broader view of how cancers evolve.

Using DNA taken from blood cells, the researchers created genetic 'family trees'. These reconstructions allowed them to trace the origins of cancer clones, groups of genetically identical cells that later contributed to disease progression.

The analysis revealed distinct patterns of evolution among patients with MPNs.

People whose disease remained clinically stable tended to have genetically 'steady' blood cell populations that acquired few or no additional mutations. By contrast, patients whose disease progressed developed new DNA changes over time.

The results suggest that progression in chronic blood cancers may be biologically 'encoded' years before a patient's condition visibly deteriorates. Mutations linked to future progression may be detectable long before symptoms worsen or standard clinical tests reveal a major change.

Some Diagnoses May Reflect Normal Aging

The researchers also examined patients who lacked mutations in JAK2, CALR or MPL.

They reconstructed 'family trees' from around 200 blood cell genomes belonging to these patients. Instead of finding patterns typical of cancer, the scientists observed changes that were more consistent with normal aging.

This finding challenges the assumption that everyone with certain unusual bone marrow features has a true blood cancer. Some people currently placed in this disease category may instead have biological characteristics that are different from those seen in genuine MPNs.

The results suggest that doctors may need to reconsider how these patients are diagnosed and managed. They also support new British Society for Haematology guidelines for investigating people without JAK2, CALR or MPL mutations.^[4,5]

These guidelines recommend that some patients initially be described as having thrombocytosis without JAK2, CALR or MPL mutations, rather than being immediately diagnosed with blood cancer. Thrombocytosis means a high platelet count without clear genetic evidence of cancer.

Toward Regular Genomic Monitoring

The study highlights several possible clinical benefits of using genomic information more routinely in cancer care. Genetic testing could help doctors distinguish stable disease from cancers that are likely to progress, refine uncertain diagnoses and guide the development of more precise treatments.

In the future, regular genomic tests could allow clinicians to identify high-risk patients years before their disease worsens. That could create opportunities to intervene earlier while avoiding unnecessary treatment for people whose blood changes may not be cancerous.

Dr. Daniel Leongamornlert, first author at the Wellcome Sanger Institute, said: "We followed patients with myeloproliferative neoplasms over many years and used genome sequencing and clinical history to trace how blood cell populations changed over time. By reconstructing the ancestry of cells, we were able to see different evolutionary patterns between patients who had stable disease compared to others who progressed."

Dr. Dani Skirrow, Research Information Manager at Cancer Research UK, who part-funded the study, said: "We're in a golden age of research where advances in technology mean we can rapidly read DNA to find the errors in the code that can lead to cancer. Collaboratively, our researchers have read huge amounts of DNA to build up a detailed picture of how certain blood cancers can start, grow and behave, revealing some changes that could help us predict cancer years in advance. This type of discovery research is essential to improve how we monitor people at risk of blood cancer, and to help us find better ways to prevent, detect and treat the disease so people can live longer, better lives."

Dr. Jyoti Nangalia, senior author at the Wellcome Sanger Institute and Honorary Consultant Haematologist at Cambridge University Hospitals NHS Foundation Trust, said: "These are patients we have cared for and followed in our clinic for over 15 years. It can be incredibly difficult to predict how their cancers might change over time. By combining long-term clinical care with regular genomic analysis, we've been able to watch how the genetic code of their disease evolves in advance of clinical changes. The patterns we have found will help doctors develop better monitoring strategies, refine diagnosis and lead to better patient outcomes in the long run."

One Patient's Decades-Long Experience

Alan Everitt, 77, has received care at Cambridge University Hospitals NHS Foundation Trust for more than three decades. He was diagnosed in 1992 with essential thrombocythemia (ET), a rare form of MPN that causes the body to produce too many platelets, the blood cells involved in clotting.

His condition later progressed to myelofibrosis, which causes scar tissue to develop in the bone marrow. He has also experienced recurrent skin cancers.

Alan Everitt, from Hardwick, Cambridgeshire, said: "It's been reassuring to be cared for over so many years by both the hematology and plastic surgery teams at Addenbrooke's Hospital in Cambridge. I have always felt well supported and I'm grateful for the care and feedback at every step. Living with a blood cancer for such a long time has come with many challenges, and I hope that taking part in this research will help make a difference for future patients whose cancer is likely to progress over time, as mine has."

Notes:

1. Blood Cancer UK. Myeloproliferative neoplasms (MPN). Available at: https://bloodcancer.org.uk/understanding-blood-cancer/myeloproliferative-neoplasms/ (Last accessed: April 2026)
2. N. Williams et al. (2022). 'Life histories of myeloproliferative neoplasms inferred from phylogenies.' Nature. DOI: 10.1038/s41586-021-04312-6
3. Blood and bone marrow samples were obtained from patients recruited at Cambridge University Hospitals NHS Foundation Trust. Clinical data regarding the patients including blood counts and treatment history were collected using the electronic health record (EHR) systems. Whole blood and skin biopsies were obtained during routine clinical visits with buccal swab or T-cell samples from patients for matched 'normal' material.
4. A. Godfrey et al. (2026). 'Investigation and management of thrombocytosis without JAK2, CALR or MPL mutations: A British Society for Haematology Guideline'. British Journal of Haematology. DOI: 10.1111/bjh.70260
5. New British Society for Haematology guidelines recommend describing some patients as having thrombocytosis without JAK2, CALR or MPL mutations -- meaning a high platelet count without clear genetic evidence of cancer -- rather than initially diagnosing them with a blood cancer.

This research was supported in part by Wellcome and Cancer Research UK.