ClinVar Genomic variation as it relates to human health

Polycythemia Vera, Thrombocythemia, Myelofibrosis, or Erythrocytosis In 71 (97%) of 73 patients with polycythemia vera (PV; 263300), 29 (57%) of 51 with essential thrombocythemia (THCYT3; 614521), and 8 (50%) of 16 with idiopathic myelofibrosis (254450), Baxter et al. (2005) identified a somatic G-to-T transversion in the JAK2 gene, resulting in a val617-to-phe (V617F) substitution in the negative regulatory JH2 domain. The mutation was predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as the result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. In all 51 patients with loss-of-heterozygosity (LOH) of chromosome 9p, Kralovics et al. (2005) identified a somatic V617F mutation. Of 193 patients without 9p LOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65% (83 of 128) among patients with polycythemia vera, 57% (13 of 23) among patients with idiopathic myelofibrosis, and 23% (21 of 93) among patients with essential thrombocythemia. James et al. (2005) identified a somatic V617F mutation in 40 of 45 patients with polycythemia vera. They found that the mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. Jamieson et al. (2006) identified the V617F mutation in peripheral blood and bone marrow cells in 14 of 16 PV patients. In all PV peripheral blood samples analyzed, there were increased numbers of hematopoietic stem cells compared to controls. The V617F mutation was detected in hematopoietic stem cells of all 6 PV samples examined further, and those stem cells showed skewed differentiation towards the erythroid lineage. However, the mutation was also identified in most myeloid precursor cells examined, indicating that the mutation was clonally transmitted to all stem cell progeny. Aberrant erythroid potential of PV stem cells was potently inhibited by the JAK2 inhibitor AG490. An acquired V617F mutation in JAK2 occurs in most patients with polycythemia vera, but is seen in only half those with essential thrombocythemia and idiopathic myelofibrosis. Campbell et al. (2005) attempted to determine whether essential thrombocythemia patients with the mutation are biologically distinct from those without, and why the same mutation is associated with different disease phenotypes. The mutation-positive patients had lower serum erythropoietin and ferritin concentrations than did mutation-negative patients. Mutation-negative patients did, nonetheless, show many clinical and laboratory features characteristic of a myeloproliferative disorder. These V617F-positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide, than those without the JAK2 mutation. Thus, Campbell et al. (2005) concluded that V617F-positive essential thrombocythemia and polycythemia vera form a biologic continuum, with the degree of erythrocytosis determined by physiologic or genetic modifiers. Most patients with myeloproliferative neoplasms (MPNs) like myelofibrosis have the acquired V617F mutation of JAK2 in hematopoietic stem cells (HSCs), which 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. Ortmann et al. (2015) determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 (612839) mutation was acquired first (hereafter referred to as 'TET2-first patients'), patients in whom the JAK2 mutation was acquired first (JAK2-first patients) had a greater likelihood of presenting with polycythemia vera (263300) than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from upregulating genes associated with proliferation. Ortmann et al. (2015) concluded that the order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. Acute Myelogeneous Leukemia Lee et al. (2006) identified heterozygosity for the V617F mutation in bone marrow aspirates from 2 of 113 patients with acute myelogenous leukemia (AML; 601626). Neither patient had a history of previous hematologic disorders and or evidence of erythroid lineage proliferation on bone marrow biopsy. Susceptibility to Pregnancy Loss Mercier et al. (2007) screened for the JAK2 V617F mutation in 3,496 pairs of women enrolled in a matched case-control study of unexplained pregnancy loss (see RPRGL1, 614389) and found that the mutation was significantly associated with the risk of fetal loss (OR, 4.63; p = 0.002) and embryonic loss (OR, 7.20; p = 0.009). The mutation was more frequent in women with embryonic loss than in those with fetal loss (p less than 0.001); clinical examination and complete blood count were normal in all women with the mutation. The increased risks were independent of those associated with the 1691A mutation in the factor V Leiden gene (612309.0001) and the 20210A mutation in the prothrombin gene (176930.0009). Dahabreh et al. (2008) screened 389 women with a history of at least 3 consecutive early or 1 late pregnancy loss but did not find the JAK2 V617F mutation in any case; the authors concluded that latent maternal JAK2 V617F-positive myeloproliferative neoplasm is an unlikely cause of miscarriage. Budd-Chiari Syndrome Chung et al. (2006) described Budd-Chiari syndrome (600880) in a 46-year-old woman who was well until the onset of increasing abdominal distention over a period of several days. She was found to have a combination of the V617F mutation and the factor V Leiden mutation (612309.0001). This somatic JAK2 mutation was found by Patel et al. (2006) in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder. Sozer et al. (2009) identified somatic homozygous V617F mutations in liver venule endothelial and hematopoietic cells from 2 unrelated PV patients who developed Budd-Chiari syndrome. However, analysis of endothelial cells from a third PV patient with Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis without PV showed only wildtype JAK2. Endothelial and hematopoietic cells are believed to come from a common progenitor called the hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive endothelial cells and hematopoietic cells from patients with PV who developed Budd-Chiari syndrome indicates that endothelial cells are involved by the PV malignant process, and suggested that the disease might originate from a common cell of origin in some patients. (less)

Polycythemia Vera, Thrombocythemia, Myelofibrosis, or Erythrocytosis In 71 (97%) of 73 patients with polycythemia vera (PV; 263300), 29 (57%) of 51 with essential thrombocythemia (THCYT3; 614521), and 8 (50%) of 16 with idiopathic myelofibrosis (254450), Baxter et al. (2005) identified a somatic G-to-T transversion in the JAK2 gene, resulting in a val617-to-phe (V617F) substitution in the negative regulatory JH2 domain. The mutation was predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as the result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. In all 51 patients with loss-of-heterozygosity (LOH) of chromosome 9p, Kralovics et al. (2005) identified a somatic V617F mutation. Of 193 patients without 9p LOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65% (83 of 128) among patients with polycythemia vera, 57% (13 of 23) among patients with idiopathic myelofibrosis, and 23% (21 of 93) among patients with essential thrombocythemia. James et al. (2005) identified a somatic V617F mutation in 40 of 45 patients with polycythemia vera. They found that the mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. Jamieson et al. (2006) identified the V617F mutation in peripheral blood and bone marrow cells in 14 of 16 PV patients. In all PV peripheral blood samples analyzed, there were increased numbers of hematopoietic stem cells compared to controls. The V617F mutation was detected in hematopoietic stem cells of all 6 PV samples examined further, and those stem cells showed skewed differentiation towards the erythroid lineage. However, the mutation was also identified in most myeloid precursor cells examined, indicating that the mutation was clonally transmitted to all stem cell progeny. Aberrant erythroid potential of PV stem cells was potently inhibited by the JAK2 inhibitor AG490. An acquired V617F mutation in JAK2 occurs in most patients with polycythemia vera, but is seen in only half those with essential thrombocythemia and idiopathic myelofibrosis. Campbell et al. (2005) attempted to determine whether essential thrombocythemia patients with the mutation are biologically distinct from those without, and why the same mutation is associated with different disease phenotypes. The mutation-positive patients had lower serum erythropoietin and ferritin concentrations than did mutation-negative patients. Mutation-negative patients did, nonetheless, show many clinical and laboratory features characteristic of a myeloproliferative disorder. These V617F-positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide, than those without the JAK2 mutation. Thus, Campbell et al. (2005) concluded that V617F-positive essential thrombocythemia and polycythemia vera form a biologic continuum, with the degree of erythrocytosis determined by physiologic or genetic modifiers. Most patients with myeloproliferative neoplasms (MPNs) like myelofibrosis have the acquired V617F mutation of JAK2 in hematopoietic stem cells (HSCs), which 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. Ortmann et al. (2015) determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 (612839) mutation was acquired first (hereafter referred to as 'TET2-first patients'), patients in whom the JAK2 mutation was acquired first (JAK2-first patients) had a greater likelihood of presenting with polycythemia vera (263300) than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from upregulating genes associated with proliferation. Ortmann et al. (2015) concluded that the order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. Acute Myelogeneous Leukemia Lee et al. (2006) identified heterozygosity for the V617F mutation in bone marrow aspirates from 2 of 113 patients with acute myelogenous leukemia (AML; 601626). Neither patient had a history of previous hematologic disorders and or evidence of erythroid lineage proliferation on bone marrow biopsy. Susceptibility to Pregnancy Loss Mercier et al. (2007) screened for the JAK2 V617F mutation in 3,496 pairs of women enrolled in a matched case-control study of unexplained pregnancy loss (see RPRGL1, 614389) and found that the mutation was significantly associated with the risk of fetal loss (OR, 4.63; p = 0.002) and embryonic loss (OR, 7.20; p = 0.009). The mutation was more frequent in women with embryonic loss than in those with fetal loss (p less than 0.001); clinical examination and complete blood count were normal in all women with the mutation. The increased risks were independent of those associated with the 1691A mutation in the factor V Leiden gene (612309.0001) and the 20210A mutation in the prothrombin gene (176930.0009). Dahabreh et al. (2008) screened 389 women with a history of at least 3 consecutive early or 1 late pregnancy loss but did not find the JAK2 V617F mutation in any case; the authors concluded that latent maternal JAK2 V617F-positive myeloproliferative neoplasm is an unlikely cause of miscarriage. Budd-Chiari Syndrome Chung et al. (2006) described Budd-Chiari syndrome (600880) in a 46-year-old woman who was well until the onset of increasing abdominal distention over a period of several days. She was found to have a combination of the V617F mutation and the factor V Leiden mutation (612309.0001). This somatic JAK2 mutation was found by Patel et al. (2006) in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder. Sozer et al. (2009) identified somatic homozygous V617F mutations in liver venule endothelial and hematopoietic cells from 2 unrelated PV patients who developed Budd-Chiari syndrome. However, analysis of endothelial cells from a third PV patient with Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis without PV showed only wildtype JAK2. Endothelial and hematopoietic cells are believed to come from a common progenitor called the hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive endothelial cells and hematopoietic cells from patients with PV who developed Budd-Chiari syndrome indicates that endothelial cells are involved by the PV malignant process, and suggested that the disease might originate from a common cell of origin in some patients. (less)

Polycythemia Vera, Thrombocythemia, Myelofibrosis, or Erythrocytosis In 71 (97%) of 73 patients with polycythemia vera (PV; 263300), 29 (57%) of 51 with essential thrombocythemia (THCYT3; 614521), and 8 (50%) of 16 with idiopathic myelofibrosis (254450), Baxter et al. (2005) identified a somatic G-to-T transversion in the JAK2 gene, resulting in a val617-to-phe (V617F) substitution in the negative regulatory JH2 domain. The mutation was predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as the result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. In all 51 patients with loss-of-heterozygosity (LOH) of chromosome 9p, Kralovics et al. (2005) identified a somatic V617F mutation. Of 193 patients without 9p LOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65% (83 of 128) among patients with polycythemia vera, 57% (13 of 23) among patients with idiopathic myelofibrosis, and 23% (21 of 93) among patients with essential thrombocythemia. James et al. (2005) identified a somatic V617F mutation in 40 of 45 patients with polycythemia vera. They found that the mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. Jamieson et al. (2006) identified the V617F mutation in peripheral blood and bone marrow cells in 14 of 16 PV patients. In all PV peripheral blood samples analyzed, there were increased numbers of hematopoietic stem cells compared to controls. The V617F mutation was detected in hematopoietic stem cells of all 6 PV samples examined further, and those stem cells showed skewed differentiation towards the erythroid lineage. However, the mutation was also identified in most myeloid precursor cells examined, indicating that the mutation was clonally transmitted to all stem cell progeny. Aberrant erythroid potential of PV stem cells was potently inhibited by the JAK2 inhibitor AG490. An acquired V617F mutation in JAK2 occurs in most patients with polycythemia vera, but is seen in only half those with essential thrombocythemia and idiopathic myelofibrosis. Campbell et al. (2005) attempted to determine whether essential thrombocythemia patients with the mutation are biologically distinct from those without, and why the same mutation is associated with different disease phenotypes. The mutation-positive patients had lower serum erythropoietin and ferritin concentrations than did mutation-negative patients. Mutation-negative patients did, nonetheless, show many clinical and laboratory features characteristic of a myeloproliferative disorder. These V617F-positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide, than those without the JAK2 mutation. Thus, Campbell et al. (2005) concluded that V617F-positive essential thrombocythemia and polycythemia vera form a biologic continuum, with the degree of erythrocytosis determined by physiologic or genetic modifiers. Most patients with myeloproliferative neoplasms (MPNs) like myelofibrosis have the acquired V617F mutation of JAK2 in hematopoietic stem cells (HSCs), which 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. Ortmann et al. (2015) determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 (612839) mutation was acquired first (hereafter referred to as 'TET2-first patients'), patients in whom the JAK2 mutation was acquired first (JAK2-first patients) had a greater likelihood of presenting with polycythemia vera (263300) than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from upregulating genes associated with proliferation. Ortmann et al. (2015) concluded that the order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. Acute Myelogeneous Leukemia Lee et al. (2006) identified heterozygosity for the V617F mutation in bone marrow aspirates from 2 of 113 patients with acute myelogenous leukemia (AML; 601626). Neither patient had a history of previous hematologic disorders and or evidence of erythroid lineage proliferation on bone marrow biopsy. Susceptibility to Pregnancy Loss Mercier et al. (2007) screened for the JAK2 V617F mutation in 3,496 pairs of women enrolled in a matched case-control study of unexplained pregnancy loss (see RPRGL1, 614389) and found that the mutation was significantly associated with the risk of fetal loss (OR, 4.63; p = 0.002) and embryonic loss (OR, 7.20; p = 0.009). The mutation was more frequent in women with embryonic loss than in those with fetal loss (p less than 0.001); clinical examination and complete blood count were normal in all women with the mutation. The increased risks were independent of those associated with the 1691A mutation in the factor V Leiden gene (612309.0001) and the 20210A mutation in the prothrombin gene (176930.0009). Dahabreh et al. (2008) screened 389 women with a history of at least 3 consecutive early or 1 late pregnancy loss but did not find the JAK2 V617F mutation in any case; the authors concluded that latent maternal JAK2 V617F-positive myeloproliferative neoplasm is an unlikely cause of miscarriage. Budd-Chiari Syndrome Chung et al. (2006) described Budd-Chiari syndrome (600880) in a 46-year-old woman who was well until the onset of increasing abdominal distention over a period of several days. She was found to have a combination of the V617F mutation and the factor V Leiden mutation (612309.0001). This somatic JAK2 mutation was found by Patel et al. (2006) in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder. Sozer et al. (2009) identified somatic homozygous V617F mutations in liver venule endothelial and hematopoietic cells from 2 unrelated PV patients who developed Budd-Chiari syndrome. However, analysis of endothelial cells from a third PV patient with Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis without PV showed only wildtype JAK2. Endothelial and hematopoietic cells are believed to come from a common progenitor called the hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive endothelial cells and hematopoietic cells from patients with PV who developed Budd-Chiari syndrome indicates that endothelial cells are involved by the PV malignant process, and suggested that the disease might originate from a common cell of origin in some patients. (less)

Polycythemia Vera, Thrombocythemia, Myelofibrosis, or Erythrocytosis In 71 (97%) of 73 patients with polycythemia vera (PV; 263300), 29 (57%) of 51 with essential thrombocythemia (THCYT3; 614521), and 8 (50%) of 16 with idiopathic myelofibrosis (254450), Baxter et al. (2005) identified a somatic G-to-T transversion in the JAK2 gene, resulting in a val617-to-phe (V617F) substitution in the negative regulatory JH2 domain. The mutation was predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as the result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. In all 51 patients with loss-of-heterozygosity (LOH) of chromosome 9p, Kralovics et al. (2005) identified a somatic V617F mutation. Of 193 patients without 9p LOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65% (83 of 128) among patients with polycythemia vera, 57% (13 of 23) among patients with idiopathic myelofibrosis, and 23% (21 of 93) among patients with essential thrombocythemia. James et al. (2005) identified a somatic V617F mutation in 40 of 45 patients with polycythemia vera. They found that the mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. Jamieson et al. (2006) identified the V617F mutation in peripheral blood and bone marrow cells in 14 of 16 PV patients. In all PV peripheral blood samples analyzed, there were increased numbers of hematopoietic stem cells compared to controls. The V617F mutation was detected in hematopoietic stem cells of all 6 PV samples examined further, and those stem cells showed skewed differentiation towards the erythroid lineage. However, the mutation was also identified in most myeloid precursor cells examined, indicating that the mutation was clonally transmitted to all stem cell progeny. Aberrant erythroid potential of PV stem cells was potently inhibited by the JAK2 inhibitor AG490. An acquired V617F mutation in JAK2 occurs in most patients with polycythemia vera, but is seen in only half those with essential thrombocythemia and idiopathic myelofibrosis. Campbell et al. (2005) attempted to determine whether essential thrombocythemia patients with the mutation are biologically distinct from those without, and why the same mutation is associated with different disease phenotypes. The mutation-positive patients had lower serum erythropoietin and ferritin concentrations than did mutation-negative patients. Mutation-negative patients did, nonetheless, show many clinical and laboratory features characteristic of a myeloproliferative disorder. These V617F-positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide, than those without the JAK2 mutation. Thus, Campbell et al. (2005) concluded that V617F-positive essential thrombocythemia and polycythemia vera form a biologic continuum, with the degree of erythrocytosis determined by physiologic or genetic modifiers. Most patients with myeloproliferative neoplasms (MPNs) like myelofibrosis have the acquired V617F mutation of JAK2 in hematopoietic stem cells (HSCs), which 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. Ortmann et al. (2015) determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 (612839) mutation was acquired first (hereafter referred to as 'TET2-first patients'), patients in whom the JAK2 mutation was acquired first (JAK2-first patients) had a greater likelihood of presenting with polycythemia vera (263300) than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from upregulating genes associated with proliferation. Ortmann et al. (2015) concluded that the order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. Acute Myelogeneous Leukemia Lee et al. (2006) identified heterozygosity for the V617F mutation in bone marrow aspirates from 2 of 113 patients with acute myelogenous leukemia (AML; 601626). Neither patient had a history of previous hematologic disorders and or evidence of erythroid lineage proliferation on bone marrow biopsy. Susceptibility to Pregnancy Loss Mercier et al. (2007) screened for the JAK2 V617F mutation in 3,496 pairs of women enrolled in a matched case-control study of unexplained pregnancy loss (see RPRGL1, 614389) and found that the mutation was significantly associated with the risk of fetal loss (OR, 4.63; p = 0.002) and embryonic loss (OR, 7.20; p = 0.009). The mutation was more frequent in women with embryonic loss than in those with fetal loss (p less than 0.001); clinical examination and complete blood count were normal in all women with the mutation. The increased risks were independent of those associated with the 1691A mutation in the factor V Leiden gene (612309.0001) and the 20210A mutation in the prothrombin gene (176930.0009). Dahabreh et al. (2008) screened 389 women with a history of at least 3 consecutive early or 1 late pregnancy loss but did not find the JAK2 V617F mutation in any case; the authors concluded that latent maternal JAK2 V617F-positive myeloproliferative neoplasm is an unlikely cause of miscarriage. Budd-Chiari Syndrome Chung et al. (2006) described Budd-Chiari syndrome (600880) in a 46-year-old woman who was well until the onset of increasing abdominal distention over a period of several days. She was found to have a combination of the V617F mutation and the factor V Leiden mutation (612309.0001). This somatic JAK2 mutation was found by Patel et al. (2006) in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder. Sozer et al. (2009) identified somatic homozygous V617F mutations in liver venule endothelial and hematopoietic cells from 2 unrelated PV patients who developed Budd-Chiari syndrome. However, analysis of endothelial cells from a third PV patient with Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis without PV showed only wildtype JAK2. Endothelial and hematopoietic cells are believed to come from a common progenitor called the hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive endothelial cells and hematopoietic cells from patients with PV who developed Budd-Chiari syndrome indicates that endothelial cells are involved by the PV malignant process, and suggested that the disease might originate from a common cell of origin in some patients. 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Polycythemia Vera, Thrombocythemia, Myelofibrosis, or Erythrocytosis In 71 (97%) of 73 patients with polycythemia vera (PV; 263300), 29 (57%) of 51 with essential thrombocythemia (THCYT3; 614521), and 8 (50%) of 16 with idiopathic myelofibrosis (254450), Baxter et al. (2005) identified a somatic G-to-T transversion in the JAK2 gene, resulting in a val617-to-phe (V617F) substitution in the negative regulatory JH2 domain. The mutation was predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as the result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. In all 51 patients with loss-of-heterozygosity (LOH) of chromosome 9p, Kralovics et al. (2005) identified a somatic V617F mutation. Of 193 patients without 9p LOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65% (83 of 128) among patients with polycythemia vera, 57% (13 of 23) among patients with idiopathic myelofibrosis, and 23% (21 of 93) among patients with essential thrombocythemia. James et al. (2005) identified a somatic V617F mutation in 40 of 45 patients with polycythemia vera. They found that the mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. Jamieson et al. (2006) identified the V617F mutation in peripheral blood and bone marrow cells in 14 of 16 PV patients. In all PV peripheral blood samples analyzed, there were increased numbers of hematopoietic stem cells compared to controls. The V617F mutation was detected in hematopoietic stem cells of all 6 PV samples examined further, and those stem cells showed skewed differentiation towards the erythroid lineage. However, the mutation was also identified in most myeloid precursor cells examined, indicating that the mutation was clonally transmitted to all stem cell progeny. Aberrant erythroid potential of PV stem cells was potently inhibited by the JAK2 inhibitor AG490. An acquired V617F mutation in JAK2 occurs in most patients with polycythemia vera, but is seen in only half those with essential thrombocythemia and idiopathic myelofibrosis. Campbell et al. (2005) attempted to determine whether essential thrombocythemia patients with the mutation are biologically distinct from those without, and why the same mutation is associated with different disease phenotypes. The mutation-positive patients had lower serum erythropoietin and ferritin concentrations than did mutation-negative patients. Mutation-negative patients did, nonetheless, show many clinical and laboratory features characteristic of a myeloproliferative disorder. These V617F-positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide, than those without the JAK2 mutation. Thus, Campbell et al. (2005) concluded that V617F-positive essential thrombocythemia and polycythemia vera form a biologic continuum, with the degree of erythrocytosis determined by physiologic or genetic modifiers. Most patients with myeloproliferative neoplasms (MPNs) like myelofibrosis have the acquired V617F mutation of JAK2 in hematopoietic stem cells (HSCs), which 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. Ortmann et al. (2015) determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 (612839) mutation was acquired first (hereafter referred to as 'TET2-first patients'), patients in whom the JAK2 mutation was acquired first (JAK2-first patients) had a greater likelihood of presenting with polycythemia vera (263300) than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from upregulating genes associated with proliferation. Ortmann et al. (2015) concluded that the order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. Acute Myelogeneous Leukemia Lee et al. (2006) identified heterozygosity for the V617F mutation in bone marrow aspirates from 2 of 113 patients with acute myelogenous leukemia (AML; 601626). Neither patient had a history of previous hematologic disorders and or evidence of erythroid lineage proliferation on bone marrow biopsy. Susceptibility to Pregnancy Loss Mercier et al. (2007) screened for the JAK2 V617F mutation in 3,496 pairs of women enrolled in a matched case-control study of unexplained pregnancy loss (see RPRGL1, 614389) and found that the mutation was significantly associated with the risk of fetal loss (OR, 4.63; p = 0.002) and embryonic loss (OR, 7.20; p = 0.009). The mutation was more frequent in women with embryonic loss than in those with fetal loss (p less than 0.001); clinical examination and complete blood count were normal in all women with the mutation. The increased risks were independent of those associated with the 1691A mutation in the factor V Leiden gene (612309.0001) and the 20210A mutation in the prothrombin gene (176930.0009). Dahabreh et al. (2008) screened 389 women with a history of at least 3 consecutive early or 1 late pregnancy loss but did not find the JAK2 V617F mutation in any case; the authors concluded that latent maternal JAK2 V617F-positive myeloproliferative neoplasm is an unlikely cause of miscarriage. Budd-Chiari Syndrome Chung et al. (2006) described Budd-Chiari syndrome (600880) in a 46-year-old woman who was well until the onset of increasing abdominal distention over a period of several days. She was found to have a combination of the V617F mutation and the factor V Leiden mutation (612309.0001). This somatic JAK2 mutation was found by Patel et al. (2006) in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder. Sozer et al. (2009) identified somatic homozygous V617F mutations in liver venule endothelial and hematopoietic cells from 2 unrelated PV patients who developed Budd-Chiari syndrome. However, analysis of endothelial cells from a third PV patient with Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis without PV showed only wildtype JAK2. Endothelial and hematopoietic cells are believed to come from a common progenitor called the hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive endothelial cells and hematopoietic cells from patients with PV who developed Budd-Chiari syndrome indicates that endothelial cells are involved by the PV malignant process, and suggested that the disease might originate from a common cell of origin in some patients. (less)

Polycythemia Vera, Thrombocythemia, Myelofibrosis, or Erythrocytosis In 71 (97%) of 73 patients with polycythemia vera (PV; 263300), 29 (57%) of 51 with essential thrombocythemia (THCYT3; 614521), and 8 (50%) of 16 with idiopathic myelofibrosis (254450), Baxter et al. (2005) identified a somatic G-to-T transversion in the JAK2 gene, resulting in a val617-to-phe (V617F) substitution in the negative regulatory JH2 domain. The mutation was predicted to dysregulate kinase activity. It was heterozygous in most patients, homozygous in a subset as the result of mitotic recombination, and arose in a multipotent progenitor capable of giving rise to erythroid and myeloid cells. In all 51 patients with loss-of-heterozygosity (LOH) of chromosome 9p, Kralovics et al. (2005) identified a somatic V617F mutation. Of 193 patients without 9p LOH, 66 were heterozygous for V617F and 127 did not have the mutation. The frequency of V617F was 65% (83 of 128) among patients with polycythemia vera, 57% (13 of 23) among patients with idiopathic myelofibrosis, and 23% (21 of 93) among patients with essential thrombocythemia. James et al. (2005) identified a somatic V617F mutation in 40 of 45 patients with polycythemia vera. They found that the mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. Jamieson et al. (2006) identified the V617F mutation in peripheral blood and bone marrow cells in 14 of 16 PV patients. In all PV peripheral blood samples analyzed, there were increased numbers of hematopoietic stem cells compared to controls. The V617F mutation was detected in hematopoietic stem cells of all 6 PV samples examined further, and those stem cells showed skewed differentiation towards the erythroid lineage. However, the mutation was also identified in most myeloid precursor cells examined, indicating that the mutation was clonally transmitted to all stem cell progeny. Aberrant erythroid potential of PV stem cells was potently inhibited by the JAK2 inhibitor AG490. An acquired V617F mutation in JAK2 occurs in most patients with polycythemia vera, but is seen in only half those with essential thrombocythemia and idiopathic myelofibrosis. Campbell et al. (2005) attempted to determine whether essential thrombocythemia patients with the mutation are biologically distinct from those without, and why the same mutation is associated with different disease phenotypes. The mutation-positive patients had lower serum erythropoietin and ferritin concentrations than did mutation-negative patients. Mutation-negative patients did, nonetheless, show many clinical and laboratory features characteristic of a myeloproliferative disorder. These V617F-positive individuals were more sensitive to therapy with hydroxyurea, but not anagrelide, than those without the JAK2 mutation. Thus, Campbell et al. (2005) concluded that V617F-positive essential thrombocythemia and polycythemia vera form a biologic continuum, with the degree of erythrocytosis determined by physiologic or genetic modifiers. Most patients with myeloproliferative neoplasms (MPNs) like myelofibrosis have the acquired V617F mutation of JAK2 in hematopoietic stem cells (HSCs), which 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. Ortmann et al. (2015) determined mutation order in patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or by means of next-generation sequencing. Stem cells and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. The age at which a patient presented with a myeloproliferative neoplasm, acquisition of JAK2 V617F homozygosity, and the balance of immature progenitors were all influenced by mutation order. As compared with patients in whom the TET2 (612839) mutation was acquired first (hereafter referred to as 'TET2-first patients'), patients in whom the JAK2 mutation was acquired first (JAK2-first patients) had a greater likelihood of presenting with polycythemia vera (263300) than with essential thrombocythemia, an increased risk of thrombosis, and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. Mutation order influenced the proliferative response to JAK2 V617F and the capacity of double-mutant hematopoietic cells and progenitor cells to generate colony-forming cells. Moreover, the hematopoietic stem-and-progenitor-cell compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2-TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2 V617F in a cell-intrinsic manner and prevented JAK2 V617F from upregulating genes associated with proliferation. Ortmann et al. (2015) concluded that the order in which JAK2 and TET2 mutations were acquired influenced clinical features, the response to targeted therapy, the biology of stem and progenitor cells, and clonal evolution in patients with myeloproliferative neoplasms. Acute Myelogeneous Leukemia Lee et al. (2006) identified heterozygosity for the V617F mutation in bone marrow aspirates from 2 of 113 patients with acute myelogenous leukemia (AML; 601626). Neither patient had a history of previous hematologic disorders and or evidence of erythroid lineage proliferation on bone marrow biopsy. Susceptibility to Pregnancy Loss Mercier et al. (2007) screened for the JAK2 V617F mutation in 3,496 pairs of women enrolled in a matched case-control study of unexplained pregnancy loss (see RPRGL1, 614389) and found that the mutation was significantly associated with the risk of fetal loss (OR, 4.63; p = 0.002) and embryonic loss (OR, 7.20; p = 0.009). The mutation was more frequent in women with embryonic loss than in those with fetal loss (p less than 0.001); clinical examination and complete blood count were normal in all women with the mutation. The increased risks were independent of those associated with the 1691A mutation in the factor V Leiden gene (612309.0001) and the 20210A mutation in the prothrombin gene (176930.0009). Dahabreh et al. (2008) screened 389 women with a history of at least 3 consecutive early or 1 late pregnancy loss but did not find the JAK2 V617F mutation in any case; the authors concluded that latent maternal JAK2 V617F-positive myeloproliferative neoplasm is an unlikely cause of miscarriage. Budd-Chiari Syndrome Chung et al. (2006) described Budd-Chiari syndrome (600880) in a 46-year-old woman who was well until the onset of increasing abdominal distention over a period of several days. She was found to have a combination of the V617F mutation and the factor V Leiden mutation (612309.0001). This somatic JAK2 mutation was found by Patel et al. (2006) in a high proportion of patients with the Budd-Chiari syndrome, providing evidence that these patients have a latent myeloproliferative disorder. Sozer et al. (2009) identified somatic homozygous V617F mutations in liver venule endothelial and hematopoietic cells from 2 unrelated PV patients who developed Budd-Chiari syndrome. However, analysis of endothelial cells from a third PV patient with Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis without PV showed only wildtype JAK2. Endothelial and hematopoietic cells are believed to come from a common progenitor called the hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive endothelial cells and hematopoietic cells from patients with PV who developed Budd-Chiari syndrome indicates that endothelial cells are involved by the PV malignant process, and suggested that the disease might originate from a common cell of origin in some patients. 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