Relation between JAK2 V617F Mutation and Chronic Myeloproliferative Disorders.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4638-4638
Author(s):  
Zhjian Xiao ◽  
Yue Zhang ◽  
Jianxiang Wang ◽  
Yushu Hao
Keyword(s):  
Bone Marrow ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Hemoglobin Level ◽  
Jak2 V617f Mutation ◽  
Control Group ◽  
Mutation Load ◽  
Chronic Myeloproliferative Disorders ◽  
V617f Mutation ◽  
Secondary Myelofibrosis

Abstract The chronic myeloproliferative disorders (cMPDs) are a group of clonal malignant tumors of the hematological system, and derived from the pluripotential hemopoietic stem cells, manifested as the proliferation of one or more series of cells in the bone marrow as well as the occurrence of excessive mature or naive cells in the peripheral blood. It was reported by several research groups that there was the acquired JAK2 V617F mutation in the majority of the PV patients and in a part of the ET or PMF patients, which provided the new ideas for the investigation of the pathogenesis of BCR/ABL- cMPDs. In the present study, the JAK2 V617F mutation was detected in a larger collection of Chinese cMPD patients, to give a picture of the incidence of JAK2 V617F mutation in the Asian pollutions. A total of 523 patients with the cMPDs, including 278 males and 245 females, were analyzed. Their median age was 50 years old (7 to 83 years old). According to the WHO diagnostic criteria, among the 523 patients were 88 cases of CML at the chronic phase (including 59 males and 29 females with a median age of 40 years old), 25 of CML complicated with myelofibrosis, 116 of PV (64 males and 52 females; a median age of 53; among them were six cases of PV with the secondary myelofibrosis), 153 of ET (63 males and 91 females; a median age of 50; 15 cases of ET with the secondary myelofibrosis), 142 of PMF (71 males and 71 females; a median age of 53.5), four of unclassified CMPD (CMPD-U) (2 males and 2 females; a median age of 60), seven of high eosinophil syndrome (HES) (6 males and 1 female; a median age of 32), and 13 of chronic eosinophilic leukemia (13 males; a median age of 34). In addition, 140 of healthy adults were included in the control group. Allele-specific PCR (ASP) was applied to identify JAK2 V617F mutation, the mutation status was analyzed by PCR-RFLP, and the results were confirmed by sequence analysis. The mutation load was calculated by the ratio of T/G. Then explore the correlation between the allele load and the clinical, hematologic features. To those without JAK2 V617F, MPL W515L mutation was analyzed. JAK2 V617F was detected in 66%(346/523) of all patients (94%(109/116) in PV, 79%(122/153) in ET, 78%(111/142) in PMF, 75%(3/4) in CMPD-U and 14%(1/7) in HES).Majority of patients carried JAK2 V617F mutation were heterozygous, homozygote was found in only 5 cases (4 in PV and 1 in ET). The mutation load in majority patients (71.5%) was low, PV>ET>MF when compared with mutation load (p=0.003). Hemoglobin level was significantly related to high mutation load in PV (p=0.033, r=0.203). Bone marrow megakaryocyte counts were found to be marked increased in ET with high JAK2 V617F loads (P=0.024, r=0.205), and hepatomegaly in PMF was also significiently associated with high JAK2 V617F mution load (p=0.003, 0.001)(p=0.001, r=0.315). Oue data showed that Majority of cMPD patients, especialy with PV, carried JAK2 V617F mutation, but JAK2 V617F was absent in CML; 98% of JAK2 V617F mutation occurs in a heterozygous status, only 4 patients with PV and 1 with ET were homozygouse.; PV> ET> MF when compared with mutation load. High JAK2 V617F loads were found to be significantly associated with higher hemoglobin level in PV and higher bone marrow megakaryocyte counts in ET; The correlation between hepatomegaly and JAK2 V617F mutation load were also found in PMF.

Prevalence of the JAK2-V617F mutation in Taiwanese patients with chronic myeloproliferative disorders

2008 ◽  
Vol 38 (6a) ◽  
pp. 422-426 ◽  
Author(s):  
C.-H. Lieu ◽  
H.-S. Wu ◽  
Y.-C. Hon ◽  
W.-H. Tsai ◽  
C.-F. Yang ◽  
...  
Keyword(s):  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Jak2 V617f Mutation ◽  
Chronic Myeloproliferative Disorders ◽  
V617f Mutation

The JAK2-V617F Mutation Load Remains Stable over Several Years in Most Patients with Myeloproliferative Disorders Analyzed in a Retrospective Single Center Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2526-2526 ◽  
Author(s):  
Alexandre Theocharides ◽  
Renate Looser ◽  
Hao-Shen Hui ◽  
Andreas S. Buser ◽  
Alois Gratwohl ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Jak2 V617f Mutation ◽  
Leukemic Transformation ◽  
Allelic Ratio ◽  
Single Center Study ◽  
V617f Mutation ◽  
Secondary Myelofibrosis

Abstract An acquired somatic mutation in the JAK2 gene (JAK2-V617F) is frequently found in patients with myeloproliferative disorders (MPD). In most studies the JAK2-V617F mutation has been analyzed at single time point. Here we performed a retrospective single center study on 73 MPD patients (36 polycythemia vera (PV), 29 essential thrombocythemia (ET), and 8 primary myelofibrosis (PMF)) from whom at least two blood samples (mean=5, range 2–17) were available with an interval of at least 8 months. The mean follow-up period was 35±17 months (range 8–78 months). The allelic ratio of JAK2-V617F (%T) was determined in DNA from purified peripheral blood granulocytes by allele-specific PCR. In 73 MPD patients studied, 53 (73%) carried the JAK2-V617F mutation (32 PV, 18 ET, 3 PMF). None of the 20 patients negative for JAK2-V617F acquired the JAK2-V617F mutation during the observation period (n=20, mean number of samples=4). In the majority of the JAK2-V617F positive patients (35/53; 66%) the JAK2-V617F allelic ratios remained remarkably stable during the follow-up period (variation ±5%T) (Figure 1 A and B). In 10/53 patients (19%) we observed an increase and in 8/53 (15%) a decrease in JAK2-V617F allelic ratio greater than 5%T. Interestingly, 3/10 patients (1 ET and 2 PV) who showed increase of JAK2-V617F developed secondary myelofibrosis. Twenty six patients (49%) received cytoreductive treatment (hydroxyurea: 24, interferon alpha: 1, anagrelide: 1). Cytoreduction with hydroxyurea did not significantly reduce the JAK2-V617F allelic ratios (Figure 1A) compared to untreated patients (Figure 1B). The only molecular remission was seen in one patient treated with interferon alpha (Figure 1 A). In one patient without cytoreduction JAK2-V617F became undetectable because of transformation to acute myeloid leukemia with blast cells negative for JAK2-V617F. A second patient treated with hydroxyurea showed a pronounced decrease of JAK2-V617F (–47%T in 6 months), but no clinical or laboratory signs of leukemic transformation were present. We conclude that the amount of JAK2-V617F remains very stable in a majority of JAK2-V617F positive patients. Prospective studies will help to elucidate whether increasing JAK2-V617F allelic ratios can predict secondary myelofibrosis or decreasing allelic ratios in absence of cytoreductive therapy (e.g. interferon alpha) are early signs of leukemic transformation. Figure 1A. Figure 1A. Figure 1B. Figure 1B.

JAK2 Mutation in Granulocytes and Platelets and X-Chromosome Gene-Based Clonal Analysis in Chronic Myeloproliferative Disorders.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4896-4896
Author(s):  
Kohtaro Toyama ◽  
Norifumi Tsukamoto ◽  
Irisawa Hiroyuki ◽  
Akihiko Yokohama ◽  
Takayuki Saitoh ◽  
...  
Keyword(s):  
Mutation Rate ◽  
X Chromosome ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Clonal Analysis ◽  
Jak2 V617f Mutation ◽  
P Value ◽  
Jak2 Mutation ◽  
Chronic Myeloproliferative Disorders ◽  
V617f Mutation

Abstract BCR/ABL-negative chronic myeloproliferative disorders (CMPDs) are considered to arise in a pluripotent progenitor cell. High prevalence of a point mutation in Janus Kinase 2 (JAK2) exon12 gene (JAK2-V617F) in CMPDs has been observed in many reports. Since most studies, however, are restricted mainly in granulocyte lineage, information about the JAK2 gene status in other cell lineage is limited. Heparinized peripheral blood was obtained from 49 patients with polycythemia vera (PV), 109 with essential thrombocytosis (ET), and 5 with chronic idiopathic myelofibrosis (CIMF). After centrifugation, platelets were collected from the upper plasma layer. The remaining blood layer was subjected to Ficoll-Hypaque density gradient centrifugation. Granulocytes were obtained from the pellet and T-cells recovered from the interface were further positively selected using either anti-CD3 or anti-CD4 immunoconjugated magnetic beads (Miltenyi Biotec, Germany). After DNA and RNA extraction, PCR amplified JAK2 exon 12 gene was sequenced to check the presence of JAK2-V617F mutation. Furthermore, X-chromosome linked clonal analysis using human androgen receptor (HUMARA) gene was carried out in 58 females. Correlation between the mutation status and clinical data was analyzed using statiscal software R (The R Development Core team). In PV, the frequency of JAK2-V617F mutation in granulocytes and platelets was 72.3 % and 74.3%, respectively (p-value 0.844). In ET, this mutation rate was 51.9% in granulocytes and 73% in platelets and the difference was significant (p-value 0.005). In all CMPDs, the cases showing JAK2-V617F mutation in granulocytes always had the mutation in platelets as well, but in one case of PV and 11 cases of ET, the JAK2-V617F mutation was observed only in platelets. T cell fraction was negative for JAK2-V617F mutation in all cases examined. White blood cell count was significantly higher in cases of JAK2-V617F mutation in their platelets compared to that in cases without this mutation (12.6 × 109/l vs. 9.2 × 109/l), but hemoglobin level and platelet count did not differ between the two groups (14.9g/l vs. 14.6 g/l, 81.4 × 109/l vs. 95.2 × 109/l). In addition, cases showing this mutation in platelets were more likely to be associated with thrombosis than cases showing the wild type gene (p-value 0.018). On clonal analyses using the HUMARA gene, 6/8 patients with PV, 15/27 patients with ET, and 1/1 patient with CIMF demonstrated a monoclonal pattern in their granulocytes. Interestingly, in 23 cases showing the JAK2-V617F mutation, 7 patients showed the polyclonal HUMARA pattern; in 13 cases without mutation, 7 showed the monoclonal HUMARA pattern. The discrepancy of JAK2-V617F mutation rate between platelets and granulocytes in ET suggests that analysis of platelet fraction is advantageous for detecting the mutation. This finding also suggests that the JAK2 mutation could be involved only in megakaryocyte lineage in some ET patients. HUMARA analysis confirmed that some ET patients with monoclonal disease lack the JAK2-V617F mutation, which is consistent with previous reports.

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