The research from Prof Green and a second paper from Dr Kraloviks in Vienna was published in December 2013, in the New England Journal of Medicine.
Myeloproliferative disorders (MPDs), which affect an estimated 50,000 people annually in the UK, cause the over-production of blood cells such as red cells (known as polycythaemia vera) or platelets (known as essential thrombocythaemia), and can also cause scarring of the bone marrow (called myelofibrosis). These changes result in an increased incidence of blood clots which can be devastating when strokes or heart attacks occur. Although many patients can live for years with few or no symptoms, in some patients these disorders can become more aggressive with time and may even develop into acute leukaemia.
In 2005 scientists identified abnormalities in the JAK2 gene in patients with MPDs. Since the discovery, blood testing for JAK2 has become a routine part of the diagnostic work-up of patients with suspected MPDs. However, whilst the vast majority of patients with polycythaemia vera are positive for the JAK2 test and can be readily diagnosed, only about half of patients with essential thrombocythaemia or myelofibrosis have a positive test. Diagnosing these patients is currently time consuming and requires multiple, often invasive tests, such as a bone marrow biopsy.
In a recent study led by Professor Tony Green from the University of Cambridge, and Dr Peter Campbell from the Wellcome Trust Sanger Institute, researchers identified a new gene called CALR that was found to be abnormal in 40% of MPD patients. In particular, this was found in the majority of patients with essential thrombocythaemia or myelofibrosis that were negative for the JAK2 test.
Professor Tony Green said: “Diagnosing these chronic blood cancers is currently difficult and requires multiple tests, some of which are invasive and painful. Now, most patients with a suspected myeloproliferative disorder will be able to be given a diagnosis after a simple blood test.”
For the research, the scientists sequenced the DNA of patients with MPDs from Addenbrooke’s Hospital and Guy’s and St Thomas’ Hospitals that had given their consent for research blood samples to be taken. By analysing the DNA sequence, they were able to identify mutations in the gene CALR in patients. Additionally, they found that patients with the CALR mutation – unlike those with the JAK2 mutation – had higher platelet counts and lower haemoglobin levels.
Dr Jyoti Nangalia, who discovered the mutations in CALR said: “Not only will the identification of CALR lead to a new, less invasive test, we also hope that it can lead to new treatments – just as the discovery of JAK2 did. The CALR gene is involved in a cell function – aiding with the folding of proteins made by the cell - which was not implicated in these disorders before, so our research raises as many questions as it does answers.”
Based on these findings a blood test is being developed which will transform the way MPDs will now be diagnosed. The test is currently a research tool but is anticipated to be available in a number of hospitals in 2014.
Dr Peter Campbell said: “There is now a sense of completeness with these disorders – the vast majority of our patients can now have a definitive genetic diagnosis made. In the next year or two, we will see these genetic technologies increasingly used in the diagnosis of all cancers, especially blood cancers.”
Further details can be found at the New England Journal of Medicine in the paper entitled “Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2” by Nangalia J, Massie C, et al.
genetic karyotyping and attending MPN London
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