Correlations of JAK2–V617F mutation with clinical and laboratory findings in patients with myeloproliferative disorders

Speletas, Matthaios; Katodritou, Eirini; Daiou, C; Μανδαλά, Ευδοκία; Papadakis, Emmanouil; Kioumi, Anna; Ritis, Konstantinos; Korantzis, Ioannis

doi:10.1016/j.leukres.2006.09.005

Cited by 48 publications

(104 citation statements)

References 28 publications

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“…Similar to previous findings (24,29,45), patients carrying the JAK2 V617F mutation were older (P < 0.001) and had higher Hb levels (P < 0.001). Vascular complications (thrombotic and hemorrhagic) were more common in V617F carrier patients [P = 0.039; 26.6% (64 of 241) versus 15.2% (12 of 79)].…”

Section: Discussionsupporting

confidence: 89%

HFEC282Y Mutation as a Genetic Modifier Influencing Disease Susceptibility for Chronic Myeloproliferative Disease

Andrikovics

Meggyesi

Szilvási

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Iron metabolism has been implicated in carcinogenesis and several studies assessed the potential role of genetic variants of proteins involved in iron metabolism (HFE C282Y, TFR S142G) in different malignancies. Few reports addressed this issue with relation to chronic myeloproliferative disorders (CMPD). The aims of our study were (a) to examine the potential associations of CMPD development with genetic modifiers of iron metabolism in a large cohort of CMPD patients; (b) to examine associations of genetic variants of proteins involved in iron metabolism; and acquired JAK2 V617F mutation with clinical characteristics of CMPD. HFE C282Y was genotyped in 328 CMPD patients and 996 blood donors as controls, HFE H63D, and TFR S142G were tested in CMPD patients and 171 first time blood donors. JAK2 V617F mutation was tested in CMPD patients and in 122 repeated blood donors. Decreased C282Y allele frequency (allele frequency F 95% confidence interval) was found in the CMPD group (1.8% F 1.0%) compared with controls (3.4% F 0.8%; P = 0.048). TFR S142G allele frequency was reduced among V617F-negative CMPD patients (34.8% F7.6%) compared with controls (47.8% F 5.4%; P = 0.02). The frequency of JAK2 V617F was 75.9% (249 of 328) in the CMPD group. At presentation, elevated hemoglobin levels were found in V617F-positive patients compared with V617F-negative counterparts (P < 0.000). Vascular complications (26.6% versus 15.2%; P = 0.039) as well as female gender (57.4% versus 41.8%; P = 0.019) were more common in V617F-positive patients. We found that HFE C282Y might be associated with a protective role against CMPD. Because chronic iron deficiency or latent anemia may trigger disease susceptibility for CMPD, HFE C282Y positivity may be a genetic factor influencing this effect. (Cancer Epidemiol Biomarkers Prev 2009;18(3):929 -34)

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Section: Discussionsupporting

confidence: 89%

HFEC282Y Mutation as a Genetic Modifier Influencing Disease Susceptibility for Chronic Myeloproliferative Disease

Andrikovics

Meggyesi

Szilvási

et al. 2009

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Furthermore, the observed tendency for larger spleens to occur in JAK2 V617F -positive cases agrees with a previous report of 166 CMPD patients (43 PV, 111 ET, 12 CIMF) demonstrating the JAK2 V617F mutation to confer a higher probability of splenomegaly. 37 Thus, the various JAK2/ STAT5 signal transduction pathways, including activated expression of Bcl-xL, may be important to the extramedullary expansion of neoplastic myeloid cells.…”

Section: Discussionmentioning

confidence: 99%

The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders

et al. 2007

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Extramedullary hematopoiesis (EMH) in the spleen is a characteristic feature of the chronic myeloproliferative disorders (CMPDs) and various other neoplastic or reactive myeloid conditions. However, the origin of these hematopoietic precursor cells and the molecular mechanisms underlying their development in the spleen is uncertain. The V617F mutation in the Janus Kinase 2 gene (JAK2 V617F ) was recently shown to be frequently and preferentially present in the peripheral blood and bone marrow cells of CMPD patients, and the resulting dysregulation of its downstream targets is important to CMPD pathogenesis. To determine the occurrence and potential role of JAK2 V617F in splenic EMH cells, we studied splenectomy specimens from 47 patients with significant EMH. JAK2 V617F was detected by real-time PCR melting curve analysis in 22 specimens, including 11/17 chronic idiopathic myelofibrosis, 7/7 polycythemia vera, 1/1 essential thrombocythemia, 1/3 CMPD unclassifiable, 1/5 chronic myelomonocytic leukemia, 0/5 chronic myelogenous leukemia, 1/3 myelodysplastic syndrome and 0/6 acute myeloblastic leukemia cases, whereas only the JAK2 wild-type allele was detected in the other 25. Nineteen of 20 cases with adequate bone marrow samples available for molecular examination demonstrated concordant JAK2 genotypes. Laser-capture microdissection was then used to enrich the EMH and non-EMH splenic cell fractions, confirming that the mutant alleles specifically originated from the EMH cells. Furthermore, megakaryocytes in the JAK2 V617F -positive splenectomy specimens expressed higher levels of Bcl-xL, an antiapoptotic protein and downstream target of the JAK2/STAT5 pathway. Thus, JAK2 V617F is frequently present in splenic EMH cells associated with CMPD, but it is rarely identified in splenic EMH cells associated with other myeloid disorders. Our results indicate that the precursor cells leading to extramedullary hematopoietic expansion in CMPD most likely originate from the transformed bone marrow clone. Also, dysregulation of downstream pathways such as Bcl-xL may be important to CMPD disease pathogenesis in the spleen. Modern Pathology (2007) 20, 929-935;

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“…According to the revised 2008 WHO diagnostic criteria, this mutation is diagnostic of PV as it is found in virtually all patients with PV, whereas, in ET or in CIMF, the JAK2 mutation serves as a clonal marker [2]. Interestingly, the presence of the JAK2 V617F mutation in ET is correlated with a polycythemic phenotype and/or thrombotic events [3][4][5][6][7][8][9][10][11][12][13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Comparison of clinicopathologic findings according to JAK2 V617F mutation in patients with essential thrombocythemia

et al. 2008

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The JAK2 V617F mutation is present in most patients with polycythemia vera, but in fewer patients with essential thrombocythemia (ET). We have assessed the frequency of this mutation in ET patients using amplification refractory mutation system PCR and determined the relationship of the mutation with disease phenotypes. Clinical-laboratory findings and histomorphological features were compared according to mutational status in 108 ET patients. The mutation was detected in 61 patients (56.5%) including one homozygous patient. Those with the mutation had significantly higher leukocyte (P = 0.003) and neutrophil (P = 0.007) counts. However, the incidences of thrombotic events and progression to advanced stages did not differ significantly between patients with and without the mutation. Thrombotic events were significantly correlated with older age (P = 0.025). Morphological analysis revealed that erythroid hypoplasia was exclusively found in the mutation-negative patients (P = 0.027). We could confirm previous findings of higher leukocyte count in ET patients with JAK2 mutation, but could not find any correlation with thrombotic events. Therefore, the detection of the mutation could characterize a subset of ET patients with distinct phenotype, despite its clinical significance being still undetermined.

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Correlations of JAK2–V617F mutation with clinical and laboratory findings in patients with myeloproliferative disorders

Cited by 48 publications

References 28 publications

HFEC282Y Mutation as a Genetic Modifier Influencing Disease Susceptibility for Chronic Myeloproliferative Disease

HFEC282Y Mutation as a Genetic Modifier Influencing Disease Susceptibility for Chronic Myeloproliferative Disease

The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders

Comparison of clinicopathologic findings according to JAK2 V617F mutation in patients with essential thrombocythemia

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