Impact of JAK2V617F Mutation Burden on Disease Phenotype in Chinese Patients with JAK2V617F-positive Polycythemia Vera (PV) and Essential thrombocythemia (ET)

Zhao, Sihai; Zhang, Xiang; Xu, Yongfen; Feng, Yufeng; Sheng, Wenhong; Wu, Depei; Han, Yue

doi:10.7150/ijms.10539

“…This is in line with a study from the West by Tefferi et al; however, Zhao et al did not find any effect of age in Chinese population. [8,21] We observed that the patients with splenomegaly had significantly higher JAK2V617F allele burden as compared to patients without splenomegaly (P < 0.017). Our results are in concordance with the study conducted by Vannucchi et al in Italian population and Zhao et al in Chinese population.…”

Section: Discussionmentioning

confidence: 74%

“…Our results are in concordance with the study conducted by Vannucchi et al in Italian population and Zhao et al in Chinese population. [11,21] However, Tefferi et al did not find any correlation of allele burden with splenomegaly. [12] The impact of JAK2V617F mutation on thrombosis is reported to be controversial in MPN patients.…”

Section: Discussionmentioning

confidence: 96%

Influence of JAK2V617F allele burden on clinical phenotype of polycythemia vera patients: A study from India

Sazawal

¹

,

Singh

²

,

Chhikara

³

et al. 2019

South Asian J Cancer

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Background: Elevated JAK2V617F allele burden is associated with enhanced expression of downstream target genes in Philadelphia negative chronic myeloproliferative neoplasms (CMPNs) which include PV, ET & PMF. Previous studies have shown the impact of JAK2V617F allele burden on clinical phenotype of CMPNs. However, there is no data from India regarding the association between JAK2V617F allele burden and clinical phenotype in PV. Aims/Settings and Design: We aimed to investigate the effect of allele burden on clinical phenotype in 90 JAK2V617F positive PV patients and to see its influence on disease related complications. Material and Methods: Allele burden of 90 JAK2V617F positive PV patients was quantified by Real-time polymerase chain reaction (RQ-PCR). Results: 74/90 (82.22%) were males and 16/90 (17.78%) were females (median 45 years, range 35-78). Patients with age >50 years had significantly higher JAK2V617F allele burden (median 40.15%, range 0.49–91.62 %) than patients with ≤ 50 years age (median 48.59 %, range 0.56–86.74 %; P < 0.032). Patients with splenomegaly had significantly higher JAK2V617F allele burden (mean 50.24%, range 6.91–84.17%) than patients without splenomegaly (mean 33.82 %, range 0.49–71.83 %; P < 0.017). Patients with higher allele burden (median 57.20, range 43.4–72.03%) had significantly raised thrombotic events than the patients with lower allele burden (median 37.38, range 0.49–84.17% P < 0.043). 49/90 (54%) were homozygous and 41/90 (46%) were heterozygous. Conclusions: Higher JAK2V617F allele burden showed association with increased age, splenomegaly and thrombotic events. Thus, it may be considered for prognostication and setting up the treatment protocol in PV patients.

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“…Furthermore, ASXL1 mutations include not only point mutations, but frameshifts and nonsense mutations, of which the most common ones are frameshift mutations (c.1934dupG), accounting for nearly 50% of the reported ASXL1 mutations ( 14 – 16 ). Furthermore, in patients with ET, the frequency of Janus kinase (JAK)2 V617F, calreticulin (CALR) and myeloproliferative leukemia (MPL) W515 mutations was reported to be ~50, <5 and ~11% in Western countries ( 17 – 20 ) and ~60, ~30 and <5% in China, respectively ( 21 – 23 ). However, the occurrence and precise roles of ASXL1 mutations in Chinese ET patients have remained elusive.…”

Section: Introductionmentioning

confidence: 99%

ASXL1 mutations in Chinese patients with essential thrombocythemia

Nie

¹

,

Sun

²

,

He

³

et al. 2018

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Essential thrombocythemia (ET) is characterized by thrombotic and hemorrhagic events. The association of clinical characteristics of Chinese ET patients and additional sex combs like 1 (ASXL1) mutations in these patients has remained to be elucidated. In the present study, 72 newly diagnosed Chinese ET patients were enrolled to determine ASXL1 mutations. Mutations in ASXL1, Janus kinase (JAK)2, calreticulin (CALR) and myeloproliferative leukemia (MPL) genes were detected using Sanger sequencing, and data were statistically analyzed. The frequencies of ASXL1, JAK2 V617F, CALR and MPL W515 mutations in ET patients were 19.4% (14/72), 29.2% (21/72), 31.9% (23/72) and 0% (0/72), respectively. Of note, 28 ET patients (38.9%) were negative for JAK2, CALR and MPL mutations; these patients were classified as triple-negative (TN). The frequency of ASXL1 mutations in patients with JAK2 V617F, CALR and TN mutations was 23.8% (5/21), 21.7% (5/23) and 14.3% (4/28), respectively. ASXL1-mutant patients exhibited significant propensities for thrombotic events compared with the ASXL1 wild-type (wt) cohort (42.9 vs. 12.1%; P=0.021). In addition, JAK2 V617F-mutant patients had a higher mean age compared with CALR-mutant (64.76 vs. 52.96 years; P=0.008) or TN patients (64.76 vs. 51.14 years; P=0.002). Furthermore, more white blood cells in the peripheral blood (PB) were observed in JAK2 V617F-mutant patients compared with those in TN patients (12.40 vs. 8.20×109/l; P=0.02). In addition, CALR-mutant patients exhibited more platelets (PLT) in PB than JAK2 V617F-mutant patients (787.91 vs. 562.17×109/l; P=0.047). TN patients had a significantly lower incidence of clinical symptoms, including dizziness, palpitation and chest congestion compared with CALR- or JAK2 V617F-mutant patients (14.1 vs. 39.1%; P=0.043 and 14.1 vs. 38.1%; P=0.050). No significant difference in progression-free survival was observed between ASXL1-mutant and ASXL1-wt patients (P=0.590). In conclusion, ASXL1-mutant ET patients are prone to experiencing thrombotic events. There was no significant difference in the occurrence of thrombotic events among CARL-mutant, JAK2 V617F-mutant and TN patients. Furthermore, ASXL1-mutant/TN patients exhibited a higher number of PLT than ASXL1/JAK2 V617F-double mutant patients. Therefore, ASXL1 mutations may be a risk factor for the occurrence of thrombotic events in ET patients.

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“…Molecular diagnosis of PV was made possible after discovery of V617F a gain of function mutation in janus kinase 2 gene 2 which is now an important criterion to identify Philadelphia negative myeloproliferative neoplasms (Ph -ve MPNs) 3 . This mutation is found in majority (95%) of polycythemia vera patients, leading to constitutive tyrosine kinase phosphorylation inducing cytokine hypersensitivity and erythrocytosis 4 - 7 . JAK2 is part of the janus kinase family having 7 JAK homology domains (JH1-JH7).…”

Section: Introductionmentioning

confidence: 99%

Detection of Exon 12 and 14 Mutations in Janus Kinase 2 Gene Including a Novel Mutant in V617F Negative Polycythemia Vera Patients from Pakistan

Akram

¹

,

Kausar

²

,

Chaudhary

³

et al. 2018

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The most frequently reported genetic aberration among polycythemia vera (PV) patients is a gain of function mutation V617F in exon 14 of Janus kinase 2 (JAK2) gene. However in many investigations, V617F negative PV patients have been reported to harbor mutations in JAK 2 exon 12. We investigated 24 patients with PV (diagnosed following 2016 WHO guidelines) to detect V617F mutation through allele specific PCR. The frequency of which was found to be 19/24 (79.2 %). Later on JAK2 exon 12 and 14 was amplified by conventional PCR in V617F negative patients and subjected to sequence analysis. A total of 03 mutated sites in exon 12 were detected in only two V617F-negative patients 2/5 (40%). All three substitutions were heterozygous i.e. F537F/I found in both patients and R528R/T, which is a novel mutation. In addition, one patient 1/5 (10%) manifested amino acid substitution V617A in JAK2 exon 14. Hematological parameters of individuals harboring mutations do not vary significantly than rest of the PV patients. Previous history and 2.3 years of follow-up studies reveal 15-year survival of V617F positive patients (n=19) to be 76%, while it is 94% for wild type V617 patients (n=05). Mean TLC of the patient cohort was 17.6± 9.1 x 109/L, mean platelet count was 552± 253 x 109/L, mean hemoglobin was 16.9± 3.2 g/dl, mean corpuscular volume (MCV) was 77.2± 13.0 fl and mean corpuscular hemoglobin (MCH) was 25.6± 3.9 pg. This is the very first attempt from Pakistan to screen JAK2-exon 12 mutations in PV patients. We further aim to investigate Jak2 exon 12 mutations in larger number of PV patients to assess their clinical relevance and role in disease onset, progression and transformation.

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Impact of JAK2V617F Mutation Burden on Disease Phenotype in Chinese Patients with JAK2V617F-positive Polycythemia Vera (PV) and Essential thrombocythemia (ET)

Cited by 22 publications

References 29 publications

Influence of JAK2V617F allele burden on clinical phenotype of polycythemia vera patients: A study from India

Influence of JAK2V617F allele burden on clinical phenotype of polycythemia vera patients: A study from India

ASXL1 mutations in Chinese patients with essential thrombocythemia

Detection of Exon 12 and 14 Mutations in Janus Kinase 2 Gene Including a Novel Mutant in V617F Negative Polycythemia Vera Patients from Pakistan

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