background Polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are clonal myeloproliferative disorders arising from a multipotent progenitor. The loss of heterozygosity (LOH) on the short arm of chromosome 9 (9pLOH) in myeloproliferative disorders suggests that 9p harbors a mutation that contributes to the cause of clonal expansion of hematopoietic cells in these diseases. methods We performed microsatellite mapping of the 9pLOH region and DNA sequencing in 244 patients with myeloproliferative disorders (128 with polycythemia vera, 93 with essential thrombocythemia, and 23 with idiopathic myelofibrosis). results Microsatellite mapping identified a 9pLOH region that included the Janus kinase 2 ( JAK2 )

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A Gain-of-Function Mutation of JAK2 in Myeloproliferative Disorders

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)71142-9.pdf

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines(1,2). The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly(3). Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines(4,5). Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (>80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.

A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera

New therapeutic strategies have emerged along with our understanding that disturbances of iron homeostasis, impaired proliferation of erythroid progenitor cells, and blunted erythropoietin response occur in anemia of chronic disease. This review discusses advances in our knowledge of the causes and management of the condition.

https://www.nejm.org/doi/pdf/10.1056/NEJMra041809

Anemia of Chronic Disease

Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.

https://www.exphem.org/article/S0301-472X(10)00488-1/pdf

Disease burden at the progenitor level is a feature of primary myelofibrosis: a multivariable analysis of 164 JAK2 V617F-positive myeloproliferative neoplasm patients.

Hepatitis-related hepatic erythropoietin production.

The erythropoietic mouse spleen-a model system of development.

In one patient generalized hemorrhage associated with hypofibrinogenemia and elevated fibrinogen-fibrin degradation products occurred two hours after the intra-amniotic injection of hypertonic saline. Serial coagulation studies were then performed on 12 patients undergoing abortion by intra-amniotic injection of 20 per cent sodium chloride, and six patients during normal labor and delivery. During normal delivery there was only a slight elevation of fibrinogen-fibrin degradation products. After injection of hypertonic saline solution, fibrinogen and platelets decreased significantly, and fibrinogen-fibrin degradation products increased.

https://www.nejm.org/doi/pdf/10.1056/NEJM197208172870702?listPDF=true

Defibrinogenation after intra-amniotic injection of hypertonic saline.

C-Mpl and PRV-1 expression was measured in a cohort of 48 patients with essential thrombocythemia (ET). A retrospective analysis was conducted to asses whether the presence of one or both markers correlates with a higher risk of developing thromboembolic complications. In this cohort, PRV-1 overexpression was associated with a significantly increased risk of thrombosis, whereas decreased c-Mpl expression was not. The results of this retrospective analysis must now be corroborated in a large, prospective trial of newly diagnosed patients.

Thrombotic and bleeding complications in four subpopulations of patients with essential thrombocythemia defined by c-Mpl protein expression and PRV-1 mRNA levels.

Jerry L. Spivak

Papers

Disease burden at the progenitor level is a feature of primary myelofibrosis: a multivariable analysis of 164 JAK2 V617F-positive myeloproliferative neoplasm patients.

Hepatitis-related hepatic erythropoietin production.

The erythropoietic mouse spleen-a model system of development.

Defibrinogenation after intra-amniotic injection of hypertonic saline.

Thrombotic and bleeding complications in four subpopulations of patients with essential thrombocythemia defined by c-Mpl protein expression and PRV-1 mRNA levels.