JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis

Barosi, Giovanni; Bergamaschi, Gaetano; Marchetti, Monia; Vannucchi, Alessandro M.; Guglielmelli, Paola; Antonioli, Elisabetta; Massa, Margherita; Rosti, Vittorio; Campanelli, Rita; Villani, Laura; Viarengo, Gianluca; Gattoni, Elisabetta; Gerli, Giancarla; Specchia, Giorgina; Tinelli, Carmine; Rambaldi, Alessandro; Barbui, Tiziano

doi:10.1182/blood-2007-07-099184

Cited by 232 publications

(219 citation statements)

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“…In addition, JAK2 V617F mutated patients were found to have higher Hb, leukocyte and platelet counts and more frequent pruritus than unmutated patients. 35 A recent study showed that a low JAK2V617F allele burden at diagnosis is associated with a myelodepletive rather than myeloproliferative phenotype and associated with shortened survival in PMF patients. 36 In our study, we found JAK2 V617F mutated IMF patients to have higher HCT and leukocyte levels than unmutated IMF patients.…”

Section: Discussionmentioning

confidence: 99%

JAK 2V617F Mutation: Frequency and Relation to Clinical and Laboratory Features of BCR-ABL Negative Myeloproliferative Diseases

İlhan¹,

Karakuş²,

Şahin³

2012

UHOD

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In this study, we planned to investigate frequency of the JAK2 V617F mutation and it's relation with clinical and laboratory findings of BCR-ABL negative myeloproliferative diseases (MPD) which consist of polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). Totally 65 patients were included in the study which composed of 28 (43.1 %) PV, 29 (44 %) ET and 8 (12.3 %) IMF patients. Forty one (63%) patients were female and 24 (37%) were male. Mean age of patients was 64.02±12.42. Frequency of the JAK2V617F mutation was found in 25 (89.3%) of PV, 18 (62.1%) of ET and 2 (25%) of IMF patients. We found no difference in gender and frequency of thrombosis, constitutional symptoms, pruritus, hemorrhage, splenomegaly, bone marrow fibrosis, cytoreductive treatment requirement, arterial/venous thrombosis between JAK2 V617F mutated and unmutated PV and ET and IMF patients. When compared homozygous and heterozygous JAK2 V617F mutated PV and ET patients according to these variables, there was no significant difference. There were no statistically significant difference in Hemoglobin (Hb), hematocrit (HCT), leukocyte, lactate dehidrogenase (LDH), EPO and ferritin levels between JAK2 V617F mutated and unmutated PV and ET patients. HCT levels and leukocyte counts were significantly higher in JAK2 V617F mutated than unmutated IMF patients (p=0.046, p=0.046). Other variables were not found different. Comprehensive prospective studies are necessary for determining the relationship of the JAK2 V617F mutation with clinical and laboratory findings . 3), ET hastalar›n›n 18'inde (% 62.1) ve IMF hastalar›n›n 2'sinde (%25) olarak bulundu. JAK2 V617F mutasyonu olan ve olmayan PV ve ET ve IMF hastalar› aras›nda cinsiyet, tromboz s›kl›¤›, konstitüsyonel semptomlar, pruritus, hemoraji, splenomegali, kemik ili¤i fibrozisi, sitoredüktif tedavi ihtiyac›, arteriyel/venöz tromboz geliflimleri aç›s›ndan bir fark bulamad›k. Heterozigot ve homozigot JAK2 V617F mutasyonu olan PV ve ET hastalar›, bu parametreler aç›s›ndan karfl›laflt›r›ld›¤›nda, anlaml› bir fark yoktu (p>0.05).

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Section: Discussionmentioning

confidence: 99%

JAK 2V617F Mutation: Frequency and Relation to Clinical and Laboratory Features of BCR-ABL Negative Myeloproliferative Diseases

İlhan¹,

Karakuş²,

Şahin³

2012

UHOD

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“…6 In PMF, the rate of homozygosity for JAK2 (V617F) has been recently reported to be 28%. 25 Constitutive mobilization of CD34 ϩ cells into peripheral blood represents a frequent phenomenon in post-PV MF, 7,18 and all patients tested in this study had high circulating CD34 ϩ cell count. Serum LDH measurement has been recently introduced in the proposed revision of WHO criteria for CMD as additional criterion to diagnose PMF.…”

Section: Org Frommentioning

confidence: 99%

A dynamic prognostic model to predict survival in post–polycythemia vera myelofibrosis

Passamonti

Rumi

Caramella

et al. 2008

Blood

105

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Post-polycythemia vera myelofibrosis (post-PV MF) is a late evolution of PV. In 647 patients with PV, we found that leukocytosis leukocyte count > (15 ؋ 10 9 /L) at diagnosis is a risk factor for the evolution of post-PV MF. In a series of 68 patients who developed post-PV MF, median survival was 5.7 years. Hemoglobin level less than 100 g/L (10 g/dL) at diagnosis of post-PV MF was an independent risk factor for survival. The course of post-PV MF, however, is a dynamic process that implies a progressive worsening of clinical parameters. Using a multivariate Cox proportional hazard regression with time-dependent covariates, we found that a dynamic score based on hemoglobin level less than 100 g/L (10 g/dL), platelet count less than 100 ؋ 10 9 /L, and leukocyte count more than 30 ؋ 10 9 /L is useful to predict survival at any time from diagnosis of post-PV MF. The resulting hazard ratio of the score was 4.2 (95% CI: 2.4-7.7; P < .001), meaning a 4.2-fold worsening of survival for each risk factor acquired during follow up. In conclusion, leukocytosis at diagnosis of PV is a risk factor for evolution in post-PV MF. A dynamic score based on hemoglobin level, and platelet and leukocyte count predicts survival at any time from diagnosis of post-PV MF. (Blood. 2008;111:3383-3387)

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“…7,8 In addition, a high %JAK2V617F has been associated with increased risk of thrombotic events in essential thrombocythemia; increased risk of cardiovascular events, larger spleen and greater treatment requirement in polycythemia vera; and higher leukocytosis and risk of acute transformation in primary myelofibrosis. [9][10][11] Some of these findings, however, are controversial: Pemmaraju et al 12 found no correlation between the %JAK2V617F in neutrophils and occurrence of thrombotic events. Thus reproducible quantification of the JAK2V617F burden is of major interest in the evaluation of myeloproliferative neoplasms.…”

Section: Introductionmentioning

confidence: 99%

Concordance of assays designed for the quantification of JAK2V617F: a multicenter study

Lippert¹,

Girodon²,

Hammond³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix. BackgroundMany different techniques have been designed for the quantification of JAK2V617F allelic burden, sometimes producing discrepant results. Design and MethodsJAK2V617F quantification techniques were compared among 16 centers using 11 assays based on quantitative polymerase chain reaction (with mutation-specific primers or probes, or fluorescent resonance energy transfer/melting curve analysis), allele-specific polymerase chain reaction, conventional sequencing or pyrosequencing. ResultsA first series of blinded samples (granulocyte DNA, n=29) was analyzed. Seven assays (12 centers) reported values inside the mean±2SD; the mean coefficient of variation was 31%. Sequencing techniques lacked sensitivity, and strong discrepancies were observed with four techniques, which could be attributed to inadequate standards or to different modes of expression of results. Indeed, quantification of JAK2V617F in relation to another control gene produced higher than expected values, suggesting the possibility of more than two JAK2 copies/cell. After calibration of assays with common 1% to 100% JAK2V617F standards (dilutions of UKE-1 cells in normal leukocytes), 14 centers tested ten new samples. JAK2V617F allelic burdens greater or equal than 1% were then reliably quantified by five techniques -one allele specific-polymerase chain reaction and four TaqMan allele-specific quantitative polymerase chain reaction assays, including one previously giving results outside the mean±2SD -with a lower mean coefficient of variation (21%). Of these, only the two TaqMan allele-specific quantitative polymerase chain reaction assays with primerbased specificity could detect 0.2% JAK2V617F. ConclusionsTechniques expressing the allelic burden as JAK2V617F/total JAK2 and using a common set of standards produced similar quantification results but with variable sensitivity. Calibration to a reference standard improved reproducibility.Key words: JAK2V617F, quantification, standardization, allele-specific PCR, myeloproliferative diseases, multicenter study. Citation

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JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis

Cited by 232 publications

References 38 publications

JAK 2V617F Mutation: Frequency and Relation to Clinical and Laboratory Features of BCR-ABL Negative Myeloproliferative Diseases

JAK 2V617F Mutation: Frequency and Relation to Clinical and Laboratory Features of BCR-ABL Negative Myeloproliferative Diseases

A dynamic prognostic model to predict survival in post–polycythemia vera myelofibrosis

Concordance of assays designed for the quantification of JAK2V617F: a multicenter study

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