Markers of Myeloproliferative Diseases in Childhood Polycythemia Vera and Essential Thrombocythemia

Teofili, Luciana; Giona, Fiorina; Martini, Maurizio; Cenci, Tonia; Guidi, Francesco; Torti, Lorenza; Palumbo, Giuseppe A.; Amendola, Angela; Foà, Robin; Larocca, Luigi Maria

doi:10.1200/jco.2006.08.6884

Cited by 104 publications

(119 citation statements)

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“…Frequency of the JAK2V617F mutation seems to be even lower in childhood ET. Randi et al found that only 4 of 20 children with ET harbored the mutation (20%), 23 while 7 of 18 children (38%) were mutated in the study by Teofili et al 24 Finally, there are reports of a few patients with ET in which the mutation was apparently restricted to the megakaryocytic lineage. 25 Therefore, while pathognomonic of a CMPD, presence of the JAK2V617F mutation in the setting of an isolated thrombocytosis lacks specificity in regards to diagnostic subtype; consequently, assessment of bone marrow morphology remains mandatory in the diagnostic work-up of ET 10,26,27 (Table 1 and Figure 2).…”

Section: Differential Diagnosis Of Thrombocytosismentioning

confidence: 99%

Thrombocytosis and Thrombosis

Vannucchi¹,

Barbui²

2007

Hematology

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The aim of this review is to discuss current diagnostic approaches to, and classification of, patients presenting with thrombocytosis, in light of novel information derived from the discovery of specific molecular abnormalities in chronic myeloproliferative disorders (CMPD), which represent the most common cause of primary thrombocytosis. The JAK2V617F and the MPLW515L/K mutations have been found in patients with essential thrombocythemia, polycythemia vera, and primary myelofibrosis, and less frequently in other myeloproliferative disorders complicated by thrombocytosis. However, neither mutation is disease specific nor is it universally present in patients with elevated platelet counts due to a CMPD; therefore, distinguishing between reactive and primary forms of thrombocytosis, as well as among the different clinical entities that constitute the CMPD, still requires a multifaceted diagnostic approach that includes as a key step the accurate evaluation of bone marrow histology. The role of elevated platelet counts in thrombosis, which represent the predominant complication of CMPD,significantly affecting prognosis and quality of life as well as, paradoxically, in the pathogenesis of the hemorrhagic manifestations, will be discussed. Established and novel potential risk factors for thrombosis, including the clinical relevance of the JAK2V617F mutation, and current management strategies for thrombocytosis are also briefly discussed.

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Section: Differential Diagnosis Of Thrombocytosismentioning

confidence: 99%

Thrombocytosis and Thrombosis

Vannucchi¹,

Barbui²

2007

Hematology

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“…Thus, in the light of the evidence that the MPL Ser505Asn mutation affects both overall and thrombosis-free survival, patients with this mutation would probably benefit from treatment with low dose aspirin. The increased thrombotic risk in patients with the MPL Ser505Asn mutation is in accordance with the detection of functionally similar mutations in both essential thrombocythemia and primary myelofibrosis [9][10][11][12][13][14][15][16][17][18][19][20][21][22] and suggests that this defect, like the JAK2 V617F mutation, is able to induce platelet or leukocyte activation. 14,17 In accordance with this hypothesis, the expression of CD11b in granulocytes of three patients with the MPL Ser505Asn was similar to that observed in patients with essential thrombocythemia and significantly higher than in normal controls.…”

Section: Discussionmentioning

confidence: 54%

“…Twelve of them are part of a previously reported series of children with myeloproliferative diseases (Table 1 and Figure 1, patients C2, C3, I2, I3, I4, I5, T11, T8, T9, S3, M9, M11). [11][12][13] Furthermore, the same patients and patients S2, B13 and B8, ( Table 1 and Figure 1) were included in the study by Liu et al, who showed a common founder effect in these families. 15 In this study we included seven out of the eight identified families, whose pedigrees are shown in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

“…Mutation analysis of the MPL (exon 10) gene was carried out by sequencing, as described elsewhere. 11 The presence of THPO 5'untranslated region mutations and of JAK2 V617F mutations was excluded. Moreover, clonality of hematopoiesis was examined in all female patients by the human androgen receptor assay (HUMARA) and by HUMARA methylation-specific polymerase chain reaction analysis.…”

Section: Molecular Analysismentioning

confidence: 99%

“…10 The authors clearly demonstrated that cells expressing MPL Ser505Asn showed autonomous phosphorylation of both Mek1/2 and STAT5 down signaling transduction pathways, but the clinical course of the disease in the affected individuals was not reported. 10 Recently, we evaluated a large cohort of Italian children with familial thrombocythemia and detected the germ line MPL Ser505Asn mutation in many of them, [11][12][13] suggesting that this molecular defect might be rather frequent in our country. For this reason, we extended the search for the MPL Ser505Asn mutation also to adult patients with essential thrombocythemia who had a positive family history of essential thrombocythemia or thrombocytosis.…”

Section: Introductionmentioning

confidence: 99%

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Acknowledgments / The Authors

Glasner¹,

Ott²

2013

Wonder Wood

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The online version of this article has a supplementary appendix. BackgroundThe MPL Ser505Asn mutation has been reported to be a cause of hereditary thrombocythemia. Recently, we detected this mutation in a large proportion of children with familial thrombocythemia, suggesting that in Italy the incidence of MPL Ser505Asn mutation could be underestimated. Design and MethodsWe extended the search for this mutation to all patients with essential thrombocythemia who had a positive family history for thrombocytosis or essential thrombocythemia. We identified eight Italian families positive for the MPL Ser505Asn mutation. Clinical and hematologic data were available for members of seven families, including 21 patients with a proven mutation and 20 relatives with thrombocytosis. ResultsFifteen major thrombotic episodes, nine of which were fatal, were recorded among 41 patients. The thrombotic manifestation was stroke in four cases, myocardial infarction in seven cases, fetal loss in two cases, deep vein thrombosis of the leg in one case and Budd Chiari syndrome in one case. Almost all patients over 20 years old had splenomegaly and bone marrow fibrosis, while these were rarely observed in patients under 20 years old, suggesting that these manifestations are associated with aging. Finally, the life expectancy of family members with thrombocytosis was significantly shorter than that of members without thrombocytosis (P=0.003). ConclusionsPatients with familial thrombocytosis caused by a MPL Ser505Asn mutation have a high risk of thrombosis and, with aging, develop splenomegaly and bone marrow fibrosis, significantly affecting their life expectancy.Key words: MPL Ser505Asn , hereditary thrombocytosis, splenomegaly, bone marrow fibrosis. Giona F, Torti L, Cenci T, Ricerca BM, Rumi C, Nunes V, Foà R, Leone G, Martini M, and Larocca LM. Hereditary thrombocytosis caused by MPL Ser505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Haematologica. 2010; 95:65-70. doi:10.3324/haematol.2009 Hereditary thrombocytosis caused by MPL Ser505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis

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Chronic Myeloproliferative Neoplasms: Clinical and Molecular Genetics

Albitar¹

2011

Encyclopedia of Life Sciences

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Chronic myeloproliferative neoplasms (previously called myeloproliferative diseases) are group of haematopoietic neoplasms characterised by clonal proliferation of differentiated cells from the myeloid lineage. This includes granulocytes, erythrocytes and megakaryocytes. In general, the course of these neoplasms is chronic and some patients may live more than 20 years and die from other causes, however, in some patients, they may manifest aggressively and kill patients in short time. Significant progress have been made in understanding the molecular basis of these diseases and recently new pharmaceutical agents have been developed that specifically target these molecular abnormalities and converted these neoplasms to chronic diseases to live with as any other chronic disease. We find in this group of diseases chronic myeloid leukaemia and polycythaemia vera, which are perhaps the most molecularly defined two neoplasms. The BCR‐ABL1 fused gene is the cause of the first neoplasm and the mutated JAK2 gene cause the second disease, both of which are targeted in the current treatment of these two diseases. Key Concepts Mutations cause the uncontrolled growth of cells, but these cells are capable of differentiation. The ability of these leukaemic cells to differentiate leads to their death at some point making these diseases less aggressive than acute leukaemias. Chromosomal translocations and mutations in specific genes are implicated in these groups of diseases. Most of the genomic abnormalities in these diseases lead to activating specific kinases and this leads to uncontrolled cell proliferation. By targeting these kinases, cell growth can be controlled and these diseases can be managed successfully. Translocations may lead to fusing two genes and the expression of a fused protein or may lead to a change in the regulation of the gene and its deregulation. Activation of a gene via translocation is usually into other genomic locus and a specific partner gene, but occasionally can be promiscuous and accept other partners. Historically the Philadelphia chromosome is considered the first hint for the fact cancer is genomic disease was discovered in CML, which is one of the cMPNs discussed here.

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Markers of Myeloproliferative Diseases in Childhood Polycythemia Vera and Essential Thrombocythemia

Abstract: This study demonstrates that familial and sporadic ET recognize different pathogenetic mechanisms. Myeloproliferative markers are specific tests for the diagnosis of ET in children with sporadic forms, while a significant proportion of children with PV can prove negative.

Cited by 104 publications

References 35 publications

Thrombocytosis and Thrombosis

Thrombocytosis and Thrombosis

Acknowledgments / The Authors

Chronic Myeloproliferative Neoplasms: Clinical and Molecular Genetics

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