Sieff and Malleson (1980) described a brother and sister who developed fulminant fatal myeloproliferative disease at 7 and 8 weeks of age. The bone marrow showed reduced hemopoiesis with generalized fibrosis. Although clinically resembling familial hemophagocytic reticulosis, the ... Sieff and Malleson (1980) described a brother and sister who developed fulminant fatal myeloproliferative disease at 7 and 8 weeks of age. The bone marrow showed reduced hemopoiesis with generalized fibrosis. Although clinically resembling familial hemophagocytic reticulosis, the disorder did not show the characteristic hemophagocytosis as a prominent feature. The parents were not related. Bonduel et al. (1998) reported 2 sisters, born of nonconsanguineous parents, with idiopathic myelofibrosis and multiple hemangiomas. The older sister presented at 4 years of age with pallor, weakness, and purpura; the younger sister was hospitalized at 7 months of age because of fever and splenomegaly. Multiple small hemangiomas were pictured on the neck and back of the older sister.
Baxter et al. (2005) and Kralovics et al. (2005) found that 50% (8 of 16) and 57% (13 of 23) of patients with idiopathic myelofibrosis, respectively, carried a somatic mutation in the JAK2 gene (V617F; 147796.0001).
... Baxter et al. (2005) and Kralovics et al. (2005) found that 50% (8 of 16) and 57% (13 of 23) of patients with idiopathic myelofibrosis, respectively, carried a somatic mutation in the JAK2 gene (V617F; 147796.0001). Pikman et al. (2006) identified a somatic mutation in the MPL gene (W515L; 159530.0011) in 4 (9%) of 45 patients with myelofibrosis with myeloid metaplasia (MMM). Two of the patients also had leukocytosis and thrombocytosis at the time of disease presentation. Functional expression studies showed that this was an activating mutation conferring cytokine-independent growth and hypersensitivity to thrombopoietin (THPO; 600044) in cell culture. Pardanani et al. (2006) identified somatic mutations in the MPL gene (W515L and W515K; 159530.0011) in 9 patients with myelofibrosis with myeloid metaplasia. Some of these patients were also heterozygous for the JAK2 V617F mutation. Delhommeau et al. (2009) analyzed the TET2 gene (612839) in bone marrow cells from 320 patients with myeloid cancers and identified TET2 defects in 4 patients with primary myelofibrosis, 3 of whom also displayed the JAK2 V617F mutation. Jutzi et al. (2013) identified 7 different somatic insertion or deletion mutations in the NFE2 gene (601490) in 8 patients with myeloproliferative disorders, including 3 with polycythemia vera (PV; 263300) and 5 with myelofibrosis, either primary or secondary. In vitro studies showed that the mutant truncated NFE2 proteins were unable to bind DNA and had lost reporter gene activity. However, coexpression of mutant NFE2 constructs with wildtype NFE2 resulted in significantly enhanced transcriptional activity. Analysis of patient cells showed low levels of the mutant truncated protein, but increased levels of the wildtype NFE2 protein compared to control cells, likely due to both increased mRNA and increased stability of the wildtype protein. All 7 patients tested also carried a JAK2 V617F mutation (147796.0001). Hematopoietic cell colonies grown from 3 patients showed that the NFE2 mutation was acquired subsequent to the JAK2 mutation, and further cellular studies indicated that an NFE2 mutation conferred a proliferative advantage of cells compared to cells carrying only the JAK2 mutation. Cells carrying mutant NFE2 displayed an increase in the proportion of cells in the S phase, consistent with enhanced cell division and proliferation, and this was associated with higher levels of cell cycle regulators. These findings were replicated in mice carrying NFE2 mutations, who developed thrombocytosis, erythrocytosis, and neutrophilia.