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Myeloproliferative neoplasms are hematological disorders characterized by increased production in one or more myeloid cell lines, associated with driver mutations in

Mutations in hydroxymethylbilane synthase (HMBS) cause acute intermittent porphyria (AIP), an autosomal dominant disease where typically only one HMBS allele is mutated. In AIP, the accumulation of porphyrin precursors triggers life-threatening neurovisceral attacks and at long-term, entails an increased risk of hepatocellular carcinoma, kidney failure, and hypertension. Today, the only cure is liver transplantation, and a need for effective mechanism-based therapies, such as pharmacological chaperones, is prevailing. These are small molecules that specifically stabilize a target protein. They may be developed into an oral treatment, which could work curatively during acute attacks, but also prophylactically in asymptomatic HMBS mutant carriers. With the use of a 10,000 compound library, we identified four binders that further increased the initially very high thermal stability of wild-type HMBS and protected the enzyme from trypsin digestion. The best hit and a selected analog increased steady-state levels and total HMBS activity in human hepatoma cells overexpressing HMBS, and in an Hmbs-deficient mouse model with a low-expressed wild-type-like allele, compared to untreated controls. Moreover, the concentration of porphyrin precursors decreased in liver of mice treated with the best hit. Our findings demonstrate the great potential of these hits for the development of a pharmacological chaperone-based corrective treatment of AIP by enhancing wild-type HMBS function independently of the patients’ specific mutation., Graphical Abstract, Individuals with acute intermittent porphyria (AIP) carry both normal and defected mutant variants of the enzyme hydroxymethylbilane synthase. With the use of pharmacological chaperones, Martinez and colleagues enhance the normal enzyme to compensate for mutants, representing a proof of concept for a novel therapeutic approach for AIP and dominantly inherited disorders in general.

BACKGROUND The relationship between the JAK2V617F mutation and myeloproliferative neoplasms was described in 2005, and has since paved the way for a new understanding of these diseases. The purpose of the study was to determine the prevalence of JAK2V617F in a Norwegian patient cohort assessed for myeloproliferative neoplasia, and to investigate potential clinical and biochemical differences between mutation-positive and mutation-negative patients. MATERIAL AND METHOD Since 2006, the Laboratory for Clinical Biochemistry at Haukeland University Hospital has been performing analyses for the JAK2V617F mutation in real time polymerase chain reactions (PCR). In the present study, we retrieved the results of all JAK2V617F mutation analyses performed in the period 2006 – 2012. The results were compared with clinical data from electronic patient records. RESULTS Of 803 patients who underwent analysis, 156 were found to have the mutation (19.4 %), while 216 were diagnosed as having a myeloproliferative disorder. Eighty-one of 108 patients diagnosed as having polycythaemia vera (75.0 %), 55 of 92 with essential thrombocytosis (59.8 %) and eight of 16 patients with myelofibrosis (50.0 %) had the mutation. Mutation-positive patients with polycythaemia vera had high levels of platelets and leukocytes. The age of onset of mutation-negative patients was lower, and they were more often smokers. Mutation-positive patients with essential thrombocytosis had high levels of haemoglobin, haematocrit and leukocytes. INTERPRETATION JAK2V617F is an essential diagnostic marker of myeloproliferative neoplasms and is associated with differences in the phenotypes of these disorders.

The relationship between the JAK2V617F mutation and myeloproliferative neoplasms was described in 2005, and has since paved the way for a new understanding of these diseases. The purpose of the study was to determine the prevalence of JAK2V617F in a Norwegian patient cohort assessed for myeloproliferative neoplasia, and to investigate potential clinical and biochemical differences between mutation-positive and mutation-negative patients.Since 2006, the Laboratory for Clinical Biochemistry at Haukeland University Hospital has been performing analyses for the JAK2V617F mutation in real time polymerase chain reactions (PCR). In the present study, we retrieved the results of all JAK2V617F mutation analyses performed in the period 2006 – 2012. The results were compared with clinical data from electronic patient records.Of 803 patients who underwent analysis, 156 were found to have the mutation (19.4 %), while 216 were diagnosed as having a myeloproliferative disorder. Eighty-one of 108 patients diagnosed as having polycythaemia vera (75.0 %), 55 of 92 with essential thrombocytosis (59.8 %) and eight of 16 patients with myelofibrosis (50.0 %) had the mutation. Mutation-positive patients with polycythaemia vera had high levels of platelets and leukocytes. The age of onset of mutation-negative patients was lower, and they were more often smokers. Mutation-positive patients with essential thrombocytosis had high levels of haemoglobin, haematocrit and leukocytes.JAK2V617F is an essential diagnostic marker of myeloproliferative neoplasms and is associated with differences in the phenotypes of these disorders.