Tissue Factor and Soluble Markers of Platelet and Endothelial Activation in Essential Thrombocythemia: Relationship with Thrombosis and JAK2 V617F Mutation Status.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2707-2707
Author(s):  
Francisco Cervantes ◽  
Eduardo Arellano-Rodrigo ◽  
Alberto Alvarez-Larran ◽  
Juan-Carlos Reverter ◽  
Neus Villamor ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Essential Thrombocythemia ◽  
Plasma Concentrations ◽  
Jak2 V617f ◽  
Endothelial Activation ◽  
Jak2 V617f Mutation ◽  
Jak2 Mutation ◽  
Mutation Status ◽  
Significant Difference ◽  
V617f Mutation

Abstract There is increasing evidence that platelet and leukocyte activation plays an important role in the thrombotic complications of patients with essential thrombocythemia (ET), but the relationship of both thrombosis occurrence and JAK2 V617F mutation status with the levels of circulating tissue factor (TF) and of soluble markers of platelet and endothelial activation is not known. In 53 ET patients (26 of whom had a previous history of thrombosis), platelet TF expression and plasma levels of TF, soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), von Willebrand factor antigen (VWF:Ag), soluble thrombomodulin (sTM), D-dimer, and prothrombin fragment 1+2 (F1+2), measured by ELISA, were compared with those in matched healthy individuals and correlated with thrombosis occurrence and JAK2 V617F mutation status. ET patients with thrombosis had significantly higher levels of sP-selectin than patients without thrombosis and the controls, whereas ET patients without thrombosis had significantly higher levels than the controls (99.8 ± 47.1 ng/mL versus 70.6 ± 37.8 ng/mL versus 32.4 ± 11.9 ng/mL; p= 0.0001 for all comparisons). The same applied to sCD40L levels (226.7 ± 104.7 pg/mL in patients with thrombosis, 186.4 ± 92.1 pg/mL in patients without thrombosis, and 81.3 ± 22.0 pg/mL in controls; p= 0.0001 for all comparisons). Circulating VWF:Ag and F1+2 levels were higher in ET patients than in controls, but no significant difference was observed between patients with and without thrombosis. No differences in TF platelet expression, TF and sTM plasma concentrations were found between patients and controls. A positive correlation was observed between sP-selectin and F1+2, a marker of thrombin generation (r= 0.378, p= 0.01). Patients with the JAK2 mutation (22 out of 52 assessable patients), as compared with those with the wild-type allele, had significantly higher levels of sP-selectin (p= 0.002), sCD40L (p= 0.03), TF (p= 0.016), VWF:Ag (p= 0.0001), and sTM (p= 0.032). These results support a role for soluble markers of platelet activation in the thrombosis of ET as well as their potential to identify ET patients at greater risk of thrombosis. The association between JAK2 mutation and increased levels of TF and soluble markers of platelet and endothelial activation would suggest that the mutation could promote an enhanced prethrombotic state in ET.

Activation of the tissue factor-dependent extrinsic pathway and its relation to JAK2 V617F mutation status in patients with essential thrombocythemia

2016 ◽  
Vol 27 (7) ◽  
pp. 817-821 ◽  
Author(s):  
Grażyna Gadomska ◽  
Katarzyna Stankowska ◽  
Joanna Boinska ◽  
Alicja Bartoszewska-Kubiak ◽  
Olga Haus ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Essential Thrombocythemia ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Extrinsic Pathway ◽  
Mutation Status ◽  
V617f Mutation

JAK2 (V617F) Mutation Status and Neutrophil Apoptotic Resistance in Myelofibrosis with Myeloid Metaplasia (MMM): Correlation and Potential Identification through Phosphorylation Status of STAT3.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3503-3503
Author(s):  
Ruben A. Mesa ◽  
Ayalew Tefferi ◽  
Heather Powell ◽  
Terra Lasho ◽  
David Loegering ◽  
...  
Keyword(s):  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Neutrophil Apoptosis ◽  
Wild Type ◽  
Jak2 Mutation ◽  
Myeloid Metaplasia ◽  
Mutation Status ◽  
Stat3 Phosphorylation ◽  
V617f Mutation ◽  
Myelofibrosis With Myeloid Metaplasia

Abstract Background: We have previously described a resistance to the normal process of apoptosis in neutrophils of patients with myelofibrosis with myeloid metaplasia (MMM) (Blood2003;102:11). Most recently, an activating mutation of JAK2 (V617F) has been described in approximately half of the patients with MMM as well as in variable proportion of patients with other myeloproliferative disorders (MPD). In the current study, we investigated the correlation between JAK2 V617F mutation status and neutrophil apoptosis in MMM. Methods: Neutrophils were isolated by density centrifugation from patients with MMM, other MPDs, and normal controls and assessed for apoptosis at baseline and after 24 hours in culture (IMDM with 20% sterilized fetal calf serum to simulate spontaneous apoptosis). Apoptosis was quantified using three-color flow cytometry using CD45 (to confirm leukocyte presence), annexin V (AN) (marker of apoptosis; detects aberrant externalization of phosphatidylserine during apoptosis), and propidium iodide (PI) (marker of dead cells). Mutation analysis for JAK2 V617F was performed in DNA derived from the isolated neutrophils using genomic DNA amplified by PCR, or extracted from cytogenetic pellets in archived specimens. Apoptotic rates after 24 hours in culture were correlated between patients and controls for both JAK2 mutation status and clinical parameters. Immunoblotting was performed on a subset of patients for correlation of JAK2 mutation status and downstream phosphorylation of the JAK2 target, STAT3, which transcriptionally activates several antiapoptotic genes. Results: Spontaneous neutrophil apoptosis was significantly decreased in MMM patients (n=50; median % apoptotic cells at 41%) compared to both healthy volunteers (n=9; 66%) and patients with other MPD (n=11; 53%) (p=0.002). Resistance to apoptosis in MMM correlated with both anemia (p=0.01) and the presence of the JAK2 V617F mutation (p=0.01). Furthermore, the specific abnormality was more pronounced in patients with homozygous JAK2 V617F; median % apoptotic cells of 47% for patients with wild-type allele (n=22) vs. 39% for heterozygotes (n=23) vs. 22% for homozygotes (n=5; p=0.008). The JAK2 mutation status did not appear dependent on other peripheral blood or clinical features. Neutrophils from 14 MMM patients were assessed simultaneously for both JAK2 mutation and STAT3 phosphorylation status by immunoblotting. Strong expression of phosphorylation of STAT3 was seen in all 3 homozygotes and 4 of 5 heterozygotes, but only 1 of 6 with wild-type allele (p=0.026). Conclusions: Impaired neutrophil apoptosis in patients with MMM correlates with the functional presence of JAK2 V617F in an allele-dose dependent manner and STAT3 phosphorylation. The current observation supports a pathogenetic role for the specific mutation in sustaining clonal myeloproliferation.

Correlation of JAK2 V617F Mutation Status and Cytogenetic Findings in Myeloproliferative Disorders.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3633-3633
Author(s):  
Guoxian Sun ◽  
Frank Buccini ◽  
Elizabeth Fuentes ◽  
James Weisberger
Keyword(s):  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Chromosome Abnormalities ◽  
Jak2 V617f Mutation ◽  
Homozygous Mutation ◽  
Jak2 Mutation ◽  
Mutation Status ◽  
Trisomy 9 ◽  
V617f Mutation ◽  
Trisomy 9P

Abstract Detection of JAK2 V617F mutation is quickly becoming a front-line screening test for suspected myeloproliferative disorders (MPDs), as the mutation shows high frequency and specificity in non-CML MPDs, PV, ET or CIMF. Routine cytogenetics can detect chromosome abnormalities in approximately 20% of MPDs and is very helpful in establishing or confirming the presence of aberrant clonality, although chromosome changes are often numerical gains and losses, deemed non-specific. To see if there is correlation between JAK2 mutation and karyotypes, we studied 57 consecutive patients with clinically and morphologically confirmed diagnosis of non-CML MPDs. JAK2 V617F mutation performed using allele-specific PCR (sensitive to 10% using pyrosequencing) was found in 72% of patients (41/57), whereas clonal chromosome abnormalities were observed in 15.8% (9/57). There was no correlation between JAK2 mutational status and karyotypes. In 41 patients positive for the JAK2 mutation, 6 were cytogenetically abnormal and 35 normal. In 16 patients negative for the mutation, 3 showed abnormal karyotypes and 13 had normal karyotypes (X2 test, p>0.5). Among 6 patients with both JAK2 mutation and an abnormal karyotype, JAK2 mutation was seen in >50% of each sample in 4 patients, consistent with a homozygous mutation. Interestingly, in two cases, one with PV and trisomy 9 and another with MPD unclassifiable and trisomy 9p resulting from an unbalanced translocation between chromosomes 9p and 13, JAK2 mutation was present in >65% of each sample. Trisomy 9 and trisomy 9p are common abnormalities in MPDs, particularly in PV, seen in over 20% of cytogenetically abnormal cases. JAK2 gene is located on 9p24. Mitotic recombination is considered the most likely cause of loss of heterozygosity (LOH) and thus mutant homozygosity which is undetectable at the cytogenetic level. However, in cases with trisomy 9 or 9p, the JAK2 allele genotypes may be G/T/T and/or T/T/T as well as the usual G/T and/or T/T. Our observations suggest that trisomy 9 or 9p should be taken into consideration when interpreting JAK2 mutation status and that further molecular studies are needed to delineate the implication of trisomy 9 or 9p in potential mutant allele selective advantage and clonal evolution in JAK2 mutation positive MPDs.

JAK2 Mutation Status in Granulocytes, Platelets and Erythrocytes Differs Between Polycythemia Vera and Essential Thrombocythemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5228-5228
Author(s):  
Kohtaro Toyama ◽  
Norifumi Tsukamoto ◽  
Akio Saito ◽  
Hirotaka Nakahashi ◽  
Yoko Hashimoto ◽  
...  
Keyword(s):  
T Cells ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Mononuclear Cells ◽  
Rna Extraction ◽  
Jak2 V617f ◽  
Janus Kinase ◽  
Jak2 V617f Mutation ◽  
Mutation Status ◽  
V617f Mutation

Abstract Background The gain-of-function point mutation in Janus kinase 2 exon 14 gene (JAK2-V617F) influences the diagnosis of bcr/abl-negative chronic myeloproliferative disorders (CMPDs). We previously reported that analyzing platelets is advantageous in detecting the JAK2-V617F mutation, particularly in essential thrombocythemia (ET), when compared to granulocytes. However, there have been few reports analyzing the JAK2-V617F mutation in erythroid lineage cells, and comparing the mutation status in all three lineages. Method Study protocols were approved by the Institutional Review Board of Gunma University Hospital, and written informed consent was obtained from all the patients. Heparinized peripheral blood was obtained from 113 patients with CMPDs (82 with ET, 25 with polycythemia vera (PV), and 6 with primary myelofibrosis (PMF). After centrifugation, platelets were collected from the upper plasma layer. Remaining blood was mixed with Hank’s Balanced Salt Solution and was subjected to Ficoll-Hypaque density gradient centrifugation. Granulocytes were obtained from the pellet. Mononuclear cells were resuspended in RPMI 1640 medium; 5 × 105 cells were plated in duplicate in 1 ml of methylcellulose medium and cultured in a humidified atmosphere of 5 % of carbon dioxide at 37°C for 14 days in the presence of erythropoietin to obtain erythroid colonies (BFU-E). T-cells were obtained from the remaining mononuclear cells using anti-CD3 immunoconjugated magnetic beads. After extraction of DNA from granulocytes, T-cells and BFU-E, and RNA extraction from granulocytes and platelets, PCR amplification and sequencing of exon 14 of the Jak2 gene was performed to confirm the presence of JAK2-V617F mutations. To confirm the mutation status of granulocytes, T-cells and BFU-E, allele-specific PCR (AS-PCR) was performed. Results For ET, 57 out of 82 patients (69.5%) had the JAK2-V617F mutation. In the 57 patients with the JAK2-V617F mutation, 38 (67%) had the mutation in all three lineages, 5 had the mutation in granulocytes and platelets, 2 had the mutation in platelets and BFU-E, 10 patients had the mutation only in platelets and 2 patients had the mutation only in BFU-E. In contrast, for PV, 22/25 patients (88%) had the JAK2-V617F mutation. Of note, in 22 patients having JAK2-V617F mutation, 20 (91%) were JAK2-V617F mutation-positive in all three lineages; the remaining two patients had the mutation in either platelets or BFU-E. The frequency of JAK2-V617F in all three lineages was significantly higher in PV than in ET (p < 0.05). For PMF, 5 of 6 patients had the mutation in granulocytes, and 3 of these had it in all three lineages. Conclusion Among JAK2-V617F mutation-positive CMPDs, most PV patients had the JAK2-V617F mutation in all three lineages, thus suggesting that the JAK2-V617F mutation occurs in progenitor cell(s) common to granulocytes, platelets and erythrocytes. In contrast, only 67% of ET patients had the JAK2-V617F mutation in three lineages; in the remaining cases, not all of the three lineages have the mutation. This difference in lineages showing the JAK2-V617F mutation between the ET and PV may be related to the pathophysiological differences in ET and PV. Furthermore, the heterogeneous mutation status in ET may be related to its heterogeneous clinical manifestation.

Analysis of JAK2 V617F Mutation and Its Clinical Significance in Patients with Thrombocythemia and Other Myeloproliferative Neoplasms in Chinese

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4687-4687
Author(s):  
Yue Xu ◽  
Changxin Yin ◽  
Han He ◽  
Lingling Shu ◽  
Fuqun Wu ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Jak2 Mutation ◽  
Western Countries ◽  
Arms Pcr ◽  
V617f Mutation

Abstract Abstract 4687 JAK2 mutation is commonly found in Philadelphia-negative myeloproliferative neoplasms (MPNs). In Western countries, this mutation is found in approximately 96 percent of people with polycythemia vera, half of individuals with essential thrombocythemia or primary myelofibrosis. We used the method of amplification refractory mutation PCR (ARMS-PCR) to investigate MPN patients in China. We focused our study on patients with essential thrombocythemia (ET). ARMS-PCR was used to detect JAK2 V617F mutation in the bone barrow (BM) or peripheral blood of 37 MPN patients, which consisting of 7 ET, 5 polycythemia vera (PV), 5 chronic myeloid leukemia (CML), 5 chronic idiopathic myelofibrosis (CIMF), as well as 15 suspected MPNs. 17 cases of JAK2 V617F mutation (45.9%) were found in 37 patients, including 4 ET (57.1%), 4 PV (80.0%), 3 CIMF (60.0%), 6 suspected MPNs (40.0%). We did not find JAK2 V617F in the patients with CML. Our results indicated that the frequency of JAK2 V617F mutation in bcr/abl-negative MPNs in Chinese is similar to that in MPN patients in Western countries. At the same time, ARMS-PCR can distinguish the mutation is heterozygous or homozygous. Most patients were heterozygous for JAK2 but only a few were homozygous. In conclusion, our study showed that JAK2 V617F mutation frequency in Chinese MPN patients is similar to that in patients with this disorder in the West. It is the major molecular genetic abnormality in bcr-abl negative MPN and it can be used for diagnosis of MPN in China. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Impact of JAK2(V617F) mutation status on treatment response to anagrelide in essential thrombocythemia: an observational, hypothesis-generating study

2015 ◽  
pp. 2687
Author(s):  
Alessandro M Vannucchi ◽  
Nicola Cascavilla ◽  
Valerio De Stefano ◽  
Alessandro Pancrazzi ◽  
Alessandra Iurlo ◽  
...  
Keyword(s):  
Treatment Response ◽  
Essential Thrombocythemia ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Mutation Status ◽  
V617f Mutation

The Relationship Between Wild Type and Mutant-Positive Platelets in Essential Thrombocythemia Patients with a JAK2 V617F Mutation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3728-3728
Author(s):  
Jonathan R Lambert ◽  
Rosemary Gale ◽  
David C. Linch
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Jak2 V617f ◽  
Absolute Number ◽  
Jak2 V617f Mutation ◽  
Secondary Process ◽  
Wild Type ◽  
Significant Difference ◽  
V617f Mutation ◽  
The Absolute

Abstract The myeloproliferative condition essential thrombocythemia (ET) is characterized by a persistent thrombocytosis in the absence of a recognizable cause. Approximately 50% of patients carry the acquired mutation JAK2 V617F, but it is unclear whether this is the initiating event in the overproduction of platelets or a secondary process arising in a situation where the thrombopoietic drive is already increased. In vitro studies have shown that mutant-positive erythroid cells have a proliferative advantage compared to wild-type (WT) cells. However, in JAK2 V617F-positive ET patients, the mutation is only found in a proportion of neutrophils, with the mutant level remaining stable over many years, and the JAK2 WT neutrophils are polyclonal by X-chromosome inactivation analysis. This may not be true of platelets as expansion of the mutant-positive cells may be restricted to the megakaryocytic lineage. We therefore quantified the mutant level in neutrophils and platelets purified from 10 JAK2 V617F-positive ET patients prior to the initiation of cytoreductive therapy using PCR with a fluorescently-labeled reverse primer and a mismatch forward primer that allowed discrimination between WT and JAK2 V617F alleles following AflIII digestion. There was no significant difference in the mutant levels determined using neutrophil DNA and RNA (median 15% [range, 11%–27%] and 21% [12%–31%] respectively). Mutant levels in platelet RNA were significantly higher than those in neutrophil RNA (median 27% [range, 20%–39%] versus 21% [12%–31%] respectively; P = 0.002), but still indicated that the JAK2 mutant was present in only a subpopulation of platelets. Assuming that all cells were heterozygous for the mutation, the data indicate that a median of only 54% (range 40%–78%) of the platelets were mutant-positive. We then calculated the absolute number of JAK2 WT and mutant-positive platelets for each patient from the quantified proportion of mutant alleles in platelet RNA and the total platelet count at the time of testing. The absolute number of JAK2 mutant-positive platelets in the patients varied between 263 and 798 × 109/L, and strongly correlated with the percentage of JAK2 mutant alleles (r2 = 0.81, P = 0.0004). The WT platelet count varied between 225 and 426 × 109/L, and there was a significant negative correlation between the absolute number of WT and mutant-positive platelets (r2 = 0.70, P = 0.002). However, when the absolute number of WT platelets was plotted against the total platelet count, there was no relationship between them (r2 = 0.003, P = 0.87). These data suggest that the negative feedback from the total platelet mass on normal (JAK2 WT) thrombopoiesis was incomplete; in no case was the WT platelet count below the lower limit of normal. This may relate to the observation that in ET, levels of thrombopoietin, the lineage-specific cytokine which drives platelet production, are often normal or even increased, unlike the situation in polycythemia vera where erythropoietin levels are reduced and normal red cell production is suppressed. Furthermore, extrapolation of the data from the WT platelet counts and JAK2 V617F mutant levels raises the possibility that when the mutation was first acquired and mutant levels were very low, the WT platelet count was at the upper limit of normality or elevated. This suggests that the JAK2 V617F mutation could have arisen on a background of increased thrombopoiesis, and was not the initiating event in the development of the disorder.

scholarly journals Evaluation of JAK2 (V617F) Mutation in Iranian Veterans with Delayed Complications of Sulphur Mustard Poisoning

2016 ◽  
Vol 10 (3) ◽  
pp. 21-24
Author(s):  
Mohammad Reza Keramati ◽  
◽  
Mohammad Hadi Sadeghian ◽  
Hossein Ayatollahi ◽  
Mohammad Hosein Basharati ◽  
...  
Keyword(s):  
Sulfur Mustard ◽  
Preventive Measure ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Control Group ◽  
Case Group ◽  
Jak2 Mutation ◽  
Significant Difference ◽  
V617f Mutation

Background: Sulfur mustard was the most widely applied chemical warfare agent by the Iraqi army in Iran–Iraq war (1983-1988). Considering the role of sulfur mustard toxicity in hematopoietic neoplasms and also new role of JAK2 mutation in these neoplasms, we assessed this mutation and delayed hematologic complications in veterans exposed to sulfur mustard. Methods: This case control study was performed in Mashhad University of Medical Sciences, Mashhad, Iran in collaboration with Janbasan Foundation of Khorasan Razavi, Iran in 2012. The case group consists of 42 patients who exposed to sulfur mustard about 30 yr ago and the control group includes 30 healthy persons. For all subjects complete blood counts and ARMSpolymerase chain reaction for JAK2 (V617F) mutation was carried out. Data were analyzed by statistical software using independent sample t-testand Mann- Whitney U test. Results: JAK2 (V617F) mutation was detected, neither in the sulfur mustardveterans nor in the control group. Moreover no significant difference was detected in hematologic parameters between the two groups. Conclusion: Despite sulfur mustard can increase risk of tumor genesis especially hematologic neoplasms but this is probablyas result of other genetic mechanism apart from JAK2 mutation. Considering the health and importance of preventive measure for the sulfur mustard victims, we suggest other genetic aspects of tumor genesis to be assessed in these patients.

Relationship between JAK2 V617F Mutation Status and Constitutive Mobilization of CD34-Positive Cells into Peripheral Blood in Patients with Chronic Myeloproliferative Disorder.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2586-2586
Author(s):  
Francesco Passamonti ◽  
Elisa Rumi ◽  
Emanuela Boveri ◽  
Daniela Pietra ◽  
Laura Vanelli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Count ◽  
Peripheral Blood ◽  
Jak2 V617f ◽  
Myeloproliferative Disorder ◽  
Jak2 V617f Mutation ◽  
Jak2 Mutation ◽  
Mutation Status ◽  
Cell Counts ◽  
V617f Mutation

Abstract A gain-of-function mutation of the Janus kinase 2 (JAK2) gene has been recently reported in patients with polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (CIMF) [N Engl J Med. 2005 Apr 28;352(17):1779–90]. Abnormal trafficking of CD34-positive cells with increased numbers in the peripheral blood is found in CIMF and in advanced stages of other myeloproliferative disorders. To determine whether the unique JAK2 V617F mutation affects the mobilization of CD34-positive cells into peripheral blood, we studied the relationship between JAK2 mutation status, bone marrow and circulating CD34-positive cells in 72 patients diagnosed according to the WHO criteria. A quantitative real-time polymerase chain reaction (PCR)-based allelic discrimination assay was used for the quantitative detection of the JAK2 V617F alleles in circulating granulocytes. Bone marrow CD34-positive cells were quantitatively assed on paraffin immunostained sections, while circulating CD34-positive cells were enumerated by flow cytometry using a single-platform assay. Overall, 57% of the patients studied carried the JAK2 V617F mutation. Within these patients, median values for JAK2 V617F alleles in circulating granulocytes were as follows: 29% in PV, 4% in ET, 12% in prefibrotic CIMF, 27% in fibrotic CIMF, and 99% in post-PV myelofibrosis. The vast majority of circulating granulocytes were homozygous for the mutation in all but one of patients with post-PV myelofibrosis. Decreased numbers of bone marrow CD34-positive cells and increased counts of circulating CD34-positive cells were detected in patients with fibrotic bone marrow. The higher the degree of fibrosis, the higher the circulating CD34-positive cell count (P<0.001) and the lower the bone marrow CD34-positive cell count (P<0.01). All patients with PV, ET and prefibrotic CIMF, and 7 out of 21 patients with fibrotic CIMF had circulating CD34-positive cell counts lower than 10 x 106/L. Conversely, all patients with post-PV myelofibrosis had counts higher than 10 x 106/L. In univariate analysis, there was an inverse relationship between percentage of JAK2 V617F alleles and bone marrow CD34-positive cells (r=−0.35, P<0.01), and a direct relationship between percentage of JAK2 mutant alleles and circulating CD34-positive cells (r=0.46, P=0.001). Multivariate analysis showed that disease category (P=0.0008) and percentage of JAK2 V617F alleles (P=0.03) were independently related to circulating CD34-positive cell counts. These observations suggest that the JAK2 V617F mutation might be involved in the constitutive mobilization of CD34-positive cells into peripheral blood that is found in patients with myeloproliferative disorder. Nonetheless, constitutive mobilization is present in a considerable portion of patients who do not carry the JAK2 mutation, pointing to additional pathogenetic mechanisms. Findings on patients with PV suggest that transition form heterozygosity to homozygosity for JAK2 V617F may represent an important step in the progression of PV to myelofibrosis. Thus, sequential evaluation of the percentage of JAK2 mutant alleles and enumeration of circulating CD34-positive cells may be useful for disease monitoring in PV.

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