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  • 总部: 泰国曼谷市巴吞汪区仑披尼分区 普勒吉路齐隆巷5号.
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Other entities represented in this entry:MYELOFIBROSIS WITH MYELOID METAPLASIA, INCLUDED; MMM, INCLUDEDMany cases of myelofibrosis are associated with a somatic ...

Other entities represented in this entry:


Many cases of myelofibrosis are associated with a somatic mutation in the JAK2 gene (147796) on chromosome 9p, somatic mutation in the MPL gene (159530) on 1p34, or somatic mutation in the CALR gene (109091) on chromosome 19p13.

Somatic mutations in the TET2 gene (612839), the ASXL1 gene (612990), the SH2B3 gene (605093), the SF3B1 gene (605590), and the NFE2 gene (601490) have also been found in cases of myelofibrosis.

▼ Clinical Features

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.

▼ Clinical Management

Passamonti et al. (2014) reported a favorable response to treatment with the JAK2 inhibitor fedratinib in 2 unrelated patients with myelofibrosis due to CALR mutations. Cazzola and Kralovics (2014) responded that effective treatment with another JAK2 inhibitor, ruxolitinib, had been reported in myelofibrosis patients who did not have JAK2 mutations, consistent with the findings of Passamonti et al. (2014).

Cassinat et al. (2014) reported 2 patients with CALR mutations and essential thrombocythemia who responded well to peginterferon alfa-2a therapy.

▼ Molecular Genetics

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.

▼ Pathogenesis

Most patients with myeloproliferative neoplasms (MPNs) like myelofibrosis have an acquired mutation of JAK2 (V617F; 147796.0001) in hematopoietic stem cells (HSCs) that renders the kinase constitutively active, leading to uncontrolled cell expansion. Mendez-Ferrer et al. (2008) and Mendez-Ferrer et al. (2010) showed that bone marrow nestin (NES; 600915)-positive mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibers regulate normal HSCs. Arranz et al. (2014) demonstrated that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibers, supporting Schwann cells and nestin-positive MSCs, were consistently reduced in the bone marrow of MPN patients and mice expressing the human V617F mutation in the JAK2 gene in HSCs. Unexpectedly, MSC reduction was not due to differentiation but to bone marrow neural damage and Schwann cell death triggered by IL1B (147720) produced by mutant HSCs. In turn, in vivo depletion of nestin-positive cells or their production of CXCL12 (600835) expanded mutant HSC number and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with beta-3-adrenergic agonists that restored the sympathetic regulation of nestin-positive MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing the number of leukemic stem cells. Arranz et al. (2014) concluded that their results demonstrated that mutant-HSC-driven niche damage critically contributes to disease manifestations in MPNs, and identified niche-forming MSCs and their neural regulation as therapeutic targets.

▼ Animal Model

Kaufmann et al. (2012) found that mice with overexpression of the Nfe2 gene in hematopoietic cells developed features of myeloproliferative disorders, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. This phenotype was transplantable to secondary recipient mice. Cells from Nfe2 transgenic mice showed hypoacetylation of histone H3 (602810). Treatment of mice with a histone deacetylase inhibitor (HDAC-I) restored physiologic levels of histone H3 acetylation, decreased Nfe2 expression, and normalized platelet numbers. Similarly, patients with myeloproliferative disorders treated with an HDAC-I showed a decrease in NFE2 expression. These data established a role for aberrant NFE2 expression in the pathophysiology of myeloproliferative disorders.

Tags: 1p34.2, 9p24.1, 12q24.12, 19p13.13