Myeloproliferative disorders form a range of haematological malignant diseases, with three main members: polycythaemia vera, essential thrombocythaemia, and idiopathic myelofi- brosis. The disorders are characterised by overactive production of blood cells and can lead to thrombosis, haemorrhage or acute myeloid leukaemia. The absence of a definitive diagnostic test and the scarcity of randomised clinical trials make management of these diseases especially challenging.
Tony Green (Cambridge Institute for Medical Research, UK) and colleagues analysed a candidate gene called JAK2 in 140 patients with myeloproliferative disorders from haematological clinics in the UK. They also took control DNA samples from a population of patients with type 1 diabetes. A single point mutation was identified in the JAK2 gene in 71 (97%) of 73 patients with polycythaemia vera, 29 (57%) of 51 with essential thrombocythaemia, and eight (50%) of 16 with idiopathic myelofibrosis. The mutation was not detected in any of the controls.
Distinguishing myeloproliferative disorders from other blood disorders such as thrombocytosis can be difficult; the authors suggest the detection of the JAK2 mutation could become a widely used diagnostic test.
Professor Green concludes: For more than a quarter of a century, the myeloproliferative disorders have been known to be clonal haematological malignancies, but the identity of underlying target genes has remained elusive. We have shown that a single acquired point mutation in JAK2 is present in virtually all patients with polycythaemia vera and in about half of those with either essential thrombocythaemia or idiopathic myelofibrosis. It is also important to acknowledge the work of several other research groups who have similar data submitted for publication. These exciting results have important implications for the classification, diagnosis, and treatment of the myeloproliferative disorders and provide insight into their pathogenesis.
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In all species Reenan studied, the RNA region that regulates folding is located within an intron--a string of non-protein coding letters that cells cut out or "splice" from the molecule during processing. RNA recoding can't occur without introns, so cells must have a way of slowing down splicing long enough for editing enzymes to do their job. "The structures imply a really strong interaction between splicing and editing," according to Reenan, who notes that, "these complicated structures actually tie up--literally--splicing signals." By making small alterations in introns during evolution, different insects conserved the basic RNA code for making important proteins, but developed a way to tweak the resulting nerve cell protein's function in a species-specific manner. The species-specific editing may give insects different abilities by modifying behaviors.
According to Joanne Tornow, the National Science Foundation program manager who oversees Reenan's work, "These findings provide dramatic evidence that intron sequences, which were once thought to serve little purpose of their own, are functionally important in the accurate expression and regulation of these genes. What's more," she adds, "this work is revealing a new type of genetic code, which incorporates both sequence and structural signals." She anticipates this work, also funded in part by the National Institutes of Health, will "greatly increase our ability to interpret the information encoded in the genome."
Researchers still don't know why editing occurs, but posit that organisms use it to increase protein variety. RNA recoding lets cells generate an array of proteins from a single DNA sequence, each with a slightly different function. Producing different proteins in a cell at once could let organisms fine tune biological processes with extreme precision--a level of flexibility the DNA code doesn't afford. "Genetics is digital," says Reenan, adding "Editing changes digital to analog," letting cells "dial up" the exact amounts of altered proteins required at any given time or place.
No matter why organisms do it, one thing is clear--serious problems can occur when RNA editing goes awry. RNA recoding defects cause neurological problems in all of the animals examined to date.
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