Latent Myeloproliferative Neoplasm May Underlie Retinal Vein Occlusion In Older Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5242-5242
Author(s):  
Katerina Zoi ◽  
Christine Zoi ◽  
Andreas Giannopoulos ◽  
Argyri Gialeraki ◽  
Kassiani Giannaki ◽  
...  
Keyword(s):  
Retinal Vein Occlusion ◽  
Older Patients ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Significant Risk ◽  
Jak2v617f Mutation ◽  
Thrombotic Complication ◽  
Allele Burden ◽  
Vein Occlusion ◽  
Increased Risk

Abstract Background Myeloproliferative neoplasms (MPNs) have been associated with a high incidence of thrombosis and bleeding episodes, which significantly contribute to disease-related morbidity and mortality. Clinical data indicate an association of the JAK2V617F mutation, seen in nearly all polycythemia vera (PV) cases and almost 60% of those with essential thrombocythemia (ET) and myelofibrosis (MF). The mutation is also seen in 37% of patients with in splachnic vein thrombosis (SVT) and its presence was associated with an increased risk for SVT. However, the prevalence of JAK2V617 seems to be low in patients with other thromboembolic events in unusual sites such as cerebral sinus, upper limb deep venous thrombosis (DVT). Additionally, activating mutations of MPL gene, seen in 3% of ET and 5% of MF patients, are considered as a significant risk factor for microvessel disturbances and have been associated with an increased risk of arterial thrombosis. Retinal vein occlusion (RVO) is a thrombotic complication in an uncommon site that may result in sight threatening disease. In this study we investigated the prevalence of JAK2V617F and MPLW515L/K mutations in a prospectively assembled cohort of patients with RVO, hypothesizing that some cases may be associated with an underlying undiagnosed MPN. Patients and Methods We studied 52 (23 males and 29 females) consecutive patients with no evidence of an underlying MPN who had been diagnosed with RVO confirmed with fluorangiography from January 2007 to September 2011. The mean age was 70 years (range: 49-85) Twenty eight patients (53.8%) presented with central RVO and 24 patients with branched RVO (46.5%). DNA was extracted from peripheral blood samples by standard procedures. The JAK2V617F mutation was detected using a tetra-primer amplification refractory mutation system (ARMS) polymerase chain reaction (PCR) assay with a sensitivity of 1% and the allele burden was estimated with a semi-quantitative method. MPLW515L/K were detected using allele-specific PCR (AS-PCR) assays with a sensitivity of 1%. Results Overall, MPN associated mutations were detected in 5/52 cases. JAK2V617F was detected in 2/52 cases (3.8%; 95%CI-1.4%-9%), while MPL exon 10 mutations were detected in 3/52 (5.7%; 95%CI-0.6%-12%). The JAK2V617F allele burden in the two positive patients was 45% and 52% respectively. Both patients who carried the JAK2V617F mutation were female. The first patient had been already diagnosed with ET according to the WHO criteria at the time of RVO screening. She was receiving hydroxyurea and aspirin and her platelet count was normal. The second patient who also carried the JAK2V617F mutation had a PLT count of 850.000/μl at the time of screening and was diagnosed with ET within the 3 following months. The patients with MPL mutations presented with normal blood counts. Conclusions Our findings indicate that a latent MPN could underlie RVO even in the absence of conventional diagnostic criteria. Our results represent the first report that MPL mutations could underlie RVO cases and suggest that routine screening of RVO cases for MPN mutations may be useful, especially in older patients. Disclosures: No relevant conflicts of interest to declare.

Clinical and Biological Characteristics According to the Burden of JAK2V617F Mutated Allele in BCR-ABL Negative MPNs

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1437-1437
Author(s):  
Lurdes Zamora ◽  
Marta Cabezon ◽  
Olga Garcia ◽  
Esther Alonso ◽  
Silvia Marce ◽  
...  
Keyword(s):  
Clinical Data ◽  
Conflicts Of Interest ◽  
Leukocyte Count ◽  
Myeloproliferative Neoplasms ◽  
Hemoglobin Level ◽  
Jak2v617f Mutation ◽  
P Value ◽  
Continuous Variables ◽  
Jak2 Mutation ◽  
Allele Burden

Abstract Abstract 1437 JAK2 mutation testing and karyotye are routinely used for diagnosis of myeloproliferative neoplasms (MPNs) but they have not been incorporated into risk stratification. Although JAK2V617F mutation in MPNs has been one of the most seminal medical discoveries in recent years, it is not clear the importance of the amount of JAK2V617F allele. Some studies correlate the JAK2 allele burden with a higher hemoglobin level, leukocyte count, splenomegaly and thrombosis and more probability of transformation to MF or AML. The aim of this study was to determine whether cytogenetic data, JAK2 mutation status and allele burden correlates with cytological subtypes, clinical complications or provide prognostic information. Methods A retrospective study was conducted with samples centralized in a unique laboratory since 2005. A total of 526 patients were included (median age 63; 243 males) with classic MPNs (348 ET, 135 PV, 43 PMF) fulfilling 2008 WHO criteria and in accordance with the Declaration of Helsinki. Conventional cytogenetic was performed in bone marrow samples obtained at diagnosis (n=205) and at progression to MF or AML (n=46). DNA was extracted from peripheral blood using QIAamp DNA mini kit (Qiagen). All samples were coded and assayed blindly in duplicate to detect JAK2V617F mutation with an allele-specific PCR using TaqMan allelic discrimination, with 2 specific probes to measure the respective fluorescence of each allele. Then, JAK2 MutaQuant assay (Ipsogen, Luminy Biotech) was used to detect the JAK2V617F quantity by real-time PCR, detecting fluorescent signals using double-dye hyrolysis oligonucleotide probes with calibration standards at 4 different concentrations. Homozygous (HOZ) ratio was considered when percentage was higher than 50. Laboratory (hemoglobin, WBC and platelet counts) and clinical data (constitutional symptoms, splenomegaly, complications, OS and DFS) were collected. For continuous variables parametric and non parametric statistics were used. Survival analysis was performed using Kaplan-Meier estimate and log-rank tests were used for comparisons. The χ2 and Fisher's exact tests were used to analyze differences in the distribution of variables among patient subsets. p-value less than 0.05 were considered statistically significant. Results Aberrant karyotypes were seen in 15/205 (7%) cases at diagnosis (4% in ET and PV and 40% in PMF). At progression to MF or AML we have cytogenetic studies in 22 patients, and 10 (45%) harbor alterations. A total of 283 patients (64%) were JAK2V617F, 61% ET (4% HOZ), 75% PV (28% HOZ) and 55% PMF (16% HOZ). The median value of JAK2V617F was 26% (range, 1–99.9%). No correlation was seen between JAK2 and karyotype at diagnosis, but 7/9 patients with aberrant karyotype at progression had JAK2V617F mutation. JAK2 correlations with laboratory and clinical data are summarized in Table 1 and 2. Conclusions JAK2V617F is associated with a more pronounced myeloproliferative phenotype (higher hemoglobin level, platelet or leukocyte count). Patients with JAK2V617F HOZ have a higher probability of splenomegaly. Hematological complications do not depend on JAK2 ratio but mutated patients have more probability of thrombosis or hemorrhage. OS and PFS do not depend on JAK2 status, but patients with JAK2V617F heterozygous seem to have a slightly better outcome. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Effect of Antivascular Endothelial Growth Factor Therapy on the Development of Neovascular Glaucoma after Central Retinal Vein Occlusion: A Retrospective Analysis

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Christina L. Ryu ◽  
Adrian Elfersy ◽  
Uday Desai ◽  
Thomas Hessburg ◽  
Paul Edwards ◽  
...  
Keyword(s):  
Macular Edema ◽  
Retinal Vein Occlusion ◽  
Central Retinal Vein Occlusion ◽  
Significant Risk ◽  
Case Series ◽  
Neovascular Glaucoma ◽  
Vein Occlusion ◽  
Anti Vegf ◽  
Central Retinal Vein

Purpose. Ischemic central retinal vein occlusion (CRVO) eyes are at high risk of developing neovascular glaucoma (NVG). Our purpose is to investigate the effect of anti-VEGF therapy for macular edema after CRVO on the development of neovascular glaucoma (NVG) in ischemic CRVO eyes.Methods. This is a retrospective case series of 44 eyes from 44 patients with CRVO treated with anti-VEGF therapy for macular edema. The primary outcome was the development of NVG.Results. Of the 44 eyes, 14 eyes had ischemic CRVO, and 30 eyes had nonischemic CRVO. Nonischemic eyes received a mean of 8.4 anti-VEGF doses, over mean follow-up of 24 months. One nonischemic eye (3.3%) developed NVD but not NVG. The 14 ischemic eyes received a mean of 5.6 anti-VEGF doses, with mean follow-up of 23 months. Of these 14 ischemic eyes, two eyes (14%) developed iris neovascularization and 3 eyes (21%) developed posterior neovascularization. Three of these 5 eyes with neovascularization progressed to NVG, at 19.7 months after symptom onset, on average.Conclusion. Anti-VEGF therapy for macular edema may delay, but does not prevent, the development of ocular NV in ischemic CRVO. Significant risk of NVG still exists for ischemic CRVO eyes.

Increased risk of cancer in patients with retinal vein occlusion: a 12-year nationwide cohort study

2020 ◽  
pp. bjophthalmol-2020-316947
Author(s):  
Min Seok Kim ◽  
Joon Hee Cho ◽  
Seong Jun Byun ◽  
Chang-Mo Oh ◽  
Kyu Hyung Park ◽  
...  
Keyword(s):  
Retinal Vein Occlusion ◽  
Cox Regression ◽  
Subsequent Development ◽  
Population Based ◽  
Control Group ◽  
Time Varying ◽  
Vein Occlusion ◽  
Increased Risk ◽  
Risk Of Cancer ◽  
Subsequent Cancer

AimsTo investigate the association between incident retinal vein occlusion (RVO) and the subsequent development of cancer.MethodsIn this nationwide population-based retrospective study using 2002–2013 National Health Insurance Service database which covers the entire South Korean population, 186 701 incident RVO patients and their 1:1 propensity-score matched controls were included. We defined the fixed cohort from January 1st, 2004 to December 31st, 2013; the cohort included patients who suffered incident RVO after entering the cohort and their matched controls, and excluded patients having any cancer history before entering the cohort. The association of RVO and cancer was assessed by time-varying covariate Cox regression models; Model 1 included RVO as a time-varying covariate, Model 2 included Model 1 plus demographic information and Model 3 included Model 2 and comorbidities.ResultsRVO was associated with an increased risk of subsequent cancer (HR=1.29; 95% CI, 1.26–1.31 in Model 1), which was consistent in Models 2 and 3. The incidence rate of overall cancer during the study period was 25.55 (95% CI, 25.19–25.91) per 1000 person-years in the RVO group and 18.62 (95% CI, 18.46–18.79) per 1000 person-years in the control group. In the subgroup analysis, haematological malignancies showed the highest association with RVO (HR=1.65; 95% CI, 1.49–1.83).ConclusionPatients with RVO have an increased risk of subsequent cancer development even after adjusting for demographic factors and comorbidities. Further study is warranted to elucidate these associations to provide proper recommendations for RVO patients regarding the cancer screening.

Risk factors for central retinal vein occlusion in young adults

2020 ◽  
pp. 112067212096033
Author(s):  
Tony Y. Chen ◽  
Aditya Uppuluri ◽  
Marco A. Zarbin ◽  
Neelakshi Bhagat
Keyword(s):  
Risk Factors ◽  
Young Adults ◽  
Retinal Vein Occlusion ◽  
Central Retinal Vein Occlusion ◽  
Retinal Vasculitis ◽  
Significant Risk ◽  
Pseudotumor Cerebri ◽  
Vein Occlusion ◽  
Chi Square Analysis ◽  
Central Retinal Vein

Purpose: Several risk factors have been identified for central retinal vein occlusion (CRVO) in older population. CRVO in young is uncommon, and the risk factors for this group are unclear. This large retrospective, cross-sectional study used the National Inpatient Sample (NIS) database to evaluate the risk factors for CRVO in patients 18 to 40 years of age. Methods: The 2002 to 2014 NIS database was used. All patients 18 to 40 years of age with a primary diagnosis of CRVO were identified. Age- and gender-matched non-CRVO controls were randomly selected. The primary outcome was identification of risk factors for CRVO. Chi-square analysis and Firth logistic regression were performed with IBM SPSS 23 and R packages versions 3.4.3, respectively. p < 0.05 was considered significant. Results: A total of 95 weighted young CRVO patients were identified. The average age was 31.44 ± 6.41 years with no gender predilection. Systemic and ocular conditions found to have statistically significant associations with CRVO included primary open-angle glaucoma (POAG) (OR 836.72, p < 0.001), retinal vasculitis (OR 705.82, p < 0.001), pseudotumor cerebri (OR 35.94, p < 0.001), hypercoagulable state (OR 25.25, p < 0.001), history of deep vein thrombosis/pulmonary embolism (DVT/PE) (OR 21.88, p < 0.001), and hyperlipidemia (OR 3.60, p = 0.003). Conclusion: The most significant risk factors for CRVO in young adults were POAG, retinal vasculitis, and pseudotumor cerebri. Hypercoagulable states and DVT/PE were also associated with CRVO in this population. Systemic inflammatory conditions were not associated with CRVO. Traditional risk factors such as hypertension and diabetes did not pose significant risks, whereas hyperlipidemia was deemed a significant risk factor.

scholarly journals A 12-month, multicenter, parallel group comparison of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion

2018 ◽  
Vol 28 (6) ◽  
pp. 697-705 ◽  
Author(s):  
Francesco Bandello ◽  
Albert Augustin ◽  
Adnan Tufail ◽  
Richard Leaback
Keyword(s):  
Visual Acuity ◽  
Retinal Vein Occlusion ◽  
Branch Retinal Vein Occlusion ◽  
Dexamethasone Intravitreal Implant ◽  
Vein Occlusion ◽  
Corrected Visual Acuity ◽  
Increased Risk ◽  
Intravitreal Implant ◽  
The Mean ◽  
Best Corrected Visual Acuity

Purpose: Dexamethasone intravitreal implant and intravitreal ranibizumab are indicated for the treatment of macular edema secondary to retinal vein occlusion. This non-inferiority study compared dexamethasone with ranibizumab in patients with branch retinal vein occlusion. Methods: In this randomized, 12-month head-to-head comparison, subjects with branch retinal vein occlusion were assigned to dexamethasone 0.7 mg at day 1 and month 5 with the option of retreatment at month 10 or 11, or ranibizumab 0.5 mg at day 1 and monthly through month 5 with subsequent as-needed injections at month 6–month 11. The primary efficacy outcome was the mean change from baseline in best-corrected visual acuity at month 12; secondary outcomes included average change in best-corrected visual acuity, proportion of eyes with ≥10- and ≥15-letter gain/loss, change in central retinal thickness, and change in Vision Functioning Questionnaire-25 score. Results: In all, 307 of a planned 400 patients were enrolled in the study and received (mean) 2.5 dexamethasone injections (n = 154) and 8.0 ranibizumab injections (n = 153) over 12 months. The mean change from baseline in best-corrected visual acuity at month 12 was 7.4 letters for dexamethasone versus 17.4 letters for ranibizumab (least-squares mean difference (dexamethasone minus ranibizumab), −10.1 letters; 95% confidence interval, −12.9, −7.2; p = 0.0006). Conclusion: Dexamethasone and ranibizumab improved best-corrected visual acuity and anatomical outcomes; however, dexamethasone did not show non-inferiority to ranibizumab in this under-powered study. Dexamethasone was associated with an increased risk of intraocular pressure elevation and cataract progression, but a lower injection burden, compared to ranibizumab.

Is JAK2 Inducible by Cytotoxic Chemotherapy?

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4979-4979
Author(s):  
Edmond A. Bendaly ◽  
Saud S. Rahman ◽  
Samiah Zafar ◽  
Karen Haglof ◽  
Sherif Ibrahim ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Case Reports ◽  
Lymphoblastic Leukemia ◽  
Myeloproliferative Neoplasm ◽  
Cytotoxic Chemotherapy ◽  
Jak2v617f Mutation ◽  
Platinum Based Chemotherapy ◽  
History Of ◽  
Increased Susceptibility

Abstract Abstract 4979 Introduction The JAK2V617F mutation accounts for most cases of myeloproliferative neoplasms (MPN). Only a few case reports of MPN following cytotoxic chemotherapy have been reported, and all of them were published prior to the discovery of the JAK2V617F mutation. We report a series of 6 patients who developed a JAK2V617F positive MPN following cytotoxic chemotherapy. Patients From 2006 to 2009, 6 patients with a history of a hematologic or an oncologic malignancy who developed an MPN were identified and their medical records retrospectively reviewed. One patient had acute lymphoblastic leukemia, 1 had Hodgkin lymphoma, 1 had squamous cell carcinoma of the head and neck, 1 had cervical cancer, and 2 had breast cancer. All patients were in remission from their primary malignancies at the time the MPN was diagnosed. Five were females. The median age at diagnosis was 72 years. Median time to development of the myeloproliferative neoplasm was 14 years. Type of chemotherapy exposure, MPN diagnosis and time to MPN in each case is shown in the table below. The JAK2V617F mutation was detected either in the peripheral blood or the bone marrow of all patients. There was no predominance of any specific MPN diagnosis. Patients who received platinum-based chemotherapy developed the MPN sooner than those who received alkylators (6 vs 17.5 years respectively). Treatment consisted of phlebotomy, hydroxyurea, anagrelide, aspirin or a combination as deemed appropriate by the treating hematologist. Conclusion These findings lead us to hypothesize whether the development of JAK2V617F positive MPN may be related to prior exposure to cytotoxic chemotherapy. Exposure to platinum-based chemotherapy may cause the disorder to appear sooner compared with exposure to alkylators. Recently, JAK2V617F positive MPN was found to be strongly associated with a specific constitutional haplotype, 46/11 suggesting increased susceptibility to this mutation. Chromosomal analyses are planned to show whether any of the reported patients exhibit this haplotype. Ref: 1.Jones et al, Nat Genet. 2009 Apr;41(4):446-9. 2009 Mar 15. The authors have no relevant disclosure. Disclosures No relevant conflicts of interest to declare.

Incidence of the JAK2V617F Mutation In Mexican Patients with Myeloproliferative Neoplasms (MPNs)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5180-5180
Author(s):  
Gregorio Ignacio ◽  
Rosa María Arana-Trejo ◽  
Verónica Gónzalez ◽  
Maria Paula Hérnandez ◽  
Yolanda Lugo ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Direct Sequencing ◽  
Jak2v617f Mutation ◽  
Normal Blood ◽  
Base Substitution ◽  
Blood Samples ◽  
Specific Pcr ◽  
Dna And Rna ◽  
Mexican Patients

Abstract Abstract 5180 Introduction: The V617F mutation in JAK2 gene has been described in approximately 50–90% of patients with ET, MF AND PV [essential trombocythaemia, idiopathic myelofibrosis and policithemia vera]; but has also been reported, albeit at a lower frequency, in patients with other myeloid malignancies such as atypical CML, CMML, AML, MDS, JMML and CNL. A single G>T base substitution in exon 12 results in the conversion of valine to a phenylalanine aminoacid at position 617 of the JAK2 gene. The identification in this study were using techniques such as allele-specific PCR, RFLP-PCR and direct sequencing; for to determine the incidence in Mexican patients with MPNs. Patients and Methods: The JAK2V617F mutation was determined in 88 patients and 5 normal blood samples for healthy individuals as controls. About the patients, 60 were cataloged like MPNs and 28 patients with features suggestive of MPNs vs CML. Samples for bone marrow or peripherical blood were taken either at time of diagnosis of MPNs or during treatment with cytoreductive or anti-thrombotic agents. DNA and RNA were extracted using the QIAamp DNA and RNeasy mini kit (Qiagen) and amplified by the three techniques mentioned for JAK2V617F and by nested RT-PCR for BCR/ABL. Results: The five normal blood samples for controls were negative for JAK2V617F mutation and to BCR/ABL. Patients had median age 65 years (47–85 years old), 46% male and 54% female. In de overall patients: 60 patients with MPNs all were BCR/ABL negative and 20 (33%) had JAK2V617F. In the 28 patients with likely MPNs vs CML, 23 were BCR/ABL positive/JAK2 negative, two had the coexistence of both genetics defects [BCR/ABL+ and JAK2V617F+] and 3 BCR/ABL and JAK2 negative. Finally the patiens with JAK2V617F+, were 12 ET, PV 1, MF 2, CML 2, and 5 continued like MPNs. Discussion: The incidence of the JAK2V617F in this study for MPNs patiens were 33% and the incidence varied between MPNs subtype. Less than ten cases of BCR/ABL+ CML with JAK2V617F have been published; we report two patients with the coexistence and we agree with previous reports that screening for JAK2V617F mutation should be considered in any BCR/ABL+ CML patients and the clinical outcome will be define in long period. Disclosures: No relevant conflicts of interest to declare.

Correlations Between TET2 Mutation and Clinicohematologic Parameters in Myeloproliferative Neoplasms

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1455-1455
Author(s):  
Jung Sook Ha ◽  
Jae Hee Lee ◽  
Sung Gyun Park ◽  
Nam Hee Ryoo ◽  
Dong Suk Jeon ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Direct Sequencing ◽  
Jak2 V617f ◽  
Putative Tumor Suppressor Gene ◽  
Allele Burden ◽  
Frame Shift ◽  
Mutational Status ◽  
Tet2 Mutation ◽  
Disease Specific

Abstract Abstract 1455 Background: Since the acquired somatic mutation, JAK2 V617F, was discovered as a first molecular marker of myeloproliferative neoplasms (MPN), and it has been detected variably in each MPN subtypes. However, JAK2 V617F does not found in all of MPN cases and not necessarily specific to a particular clinicpathologic entity. Recently, mutation of the putative tumor suppressor gene, Ten-Eleven-Translocation-2(TET2), has been identified in MPN patients. However, the frequency of TET2 mutation or its relationship with JAK2 V617F mutation or pathologic function in MPN has not been concluded, yet. The aim of our study was to evaluate the frequency of TET2 in MPN patients, and whether there is any correlation of TET2 mutation with JAK2V617F mutation or the clinicohematologic parameters. Materials and Methods: Total 99 adult MPN patients (18 PV, 62 ET, 11 PMF and 8 MPN unclassified) whose bone marrow cells had been stored from 2007 to 2010 at point of first diagnosis were included in this study. Hematological diagnoses and subtyping were reconfirmed according to the 2008 WHO classification and clinicohematologic datas were collected from patient records. Direct sequencing for TET2(exon3–11) and JAK2 (exons 12 and 14) were performed using an ABI 3730XL DNA analyzer. The JAK2V617F allele burdens were determined by pyrosequencing for samples available and MPL was analyzed by allele-specific PCR. Results: The overall TET2 mutational frequency was 12.1%, and disease-specific mutational frequencies were 22.2% in PV, 9.7% in ET and 18.2% in PMF. The found mutations included 11 mutations, 7 frame-shift (p.Lys95AsnfsX18, p.Gln967AsnfsX40, p.Lys1022GlufsX4, p.Asp1314MetfsX49, p.Gln1534AlafsX43, p.Tyr1618LeufsX4, p.Leu1609GlufsX45), 1 nonsense (p.Gly1735X), 1 missense (Q599R) and 2 splicing mutations (c.3409+1G>T, c.4044+2insT). Those mutations most frequently involved exon 3(four mutations) and exon 11(four mutaions), and rarely intron 3, intron 8 and exon 7. None of the mutations were associated with a karyotypically apparent 4q24 rearrangement. All patients were also screened for JAK2 V617F, and the overall JAK2 V617F positive rate was 68%(94.4% in PV, 69.4% in ET, 45.5% in PMF and 37.5% in MPN, unclassified). All TET2 mutations occurred in JAK2 V617F positive cases. JAK2 exon12 mutation was not found in all patients. MPL W515L was found in one ET patient who also carried JAK2V617F, but not TET2 mutation. Information on JAK2 V617F allele burden was available in 78 patients. Considering all 99 patients, the patient age, hematologic indexes (leukocyte count, neutrophil fraction, lymphocyte fraction, monocyte fraction, Hb, Hct and platelet count), the frequency of organomegaly, marrow fibrosis or thrombotic/hemorrhagic complications were not different according to carrying TET2 mutation. However, TET2 mutation was more frequently found in JAK2 V617F carriers than non-carriers (P=0.008), but JAK2 V617F allele burden did not correlated with the presence of mutant TET2. When analysis was performed for each PV, ET, and PMF (no TET2 mutation in MPN-unclassifiable patients), correlation between TET2 and JAK2 V617F mutational status was not found in each subtypes (P=0.078 in PV, P=0.099 in ET and P=0.182 in PMF). However, the JAK2 V617F allele burden was significantly higher in PMF harboring TET2 mutation than PMF patients did not (88.0 ± 4.3% vs 19.1 ± 28.7%, P=0.034). In statistical analysis for the correlations of clinicohematologic parameters with TET2 mutation in each PV, ET and PMF patients, only a few statistically significant results were identified. The presence of TET2 mutation was correlated with high Hct in PMF (47.4 ± 5.4 vs 25.5 ± 6.2, P=0.037), and TET2 positive ET patients showed relatively higher frequency of organomegaly compared to ET patients without TET2 mutation (50% vs 19.6%, P=0.018). Conclusions: The overall and disease-specific frequencies of TET2 mutation in our study are similar with previous studies, and frame-shift mutation is the most frequent mutation type. There is no specific relationship between JAK2 V617F and TET2 mutation occurrence, but TET2 mutant PMF has higher JAK2 V617F allele burden than non-mutant. TET2 mutation is also associated with a higher Hct in PMF and higher frequency of organomegaly in ET. Larger scale studies involving more MPN patients are needed. Disclosures: No relevant conflicts of interest to declare.

Loss of Wild-Type Jak2 Allele Enhances Myeloid Cell Expansion and Accelerates Myelofibrosis in Jak2V617F Knock-in Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 809-809
Author(s):  
Hajime Akada ◽  
Saeko Akada ◽  
Dongqing Yan ◽  
Robert Hutchison ◽  
Golam Mohi
Keyword(s):  
Polycythemia Vera ◽  
Cell Expansion ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Myeloid Cell ◽  
Negative Regulator ◽  
Jak2v617f Mutation ◽  
Common Mutation ◽  
Wild Type

Abstract Abstract 809 The activating JAK2V617F mutation is the most common mutation found in Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs), which include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Although a majority of MPN patients carry heterozygous JAK2V617F mutation, loss of heterozygosity (LOH) on chromosome 9p involving JAK2 has been observed in ∼30% of patients with MPNs particularly in PV and PMF. JAK2V617F homozygosity through 9pLOH has been linked to more severe MPN phenotype. However, the contribution of 9pLOH in the pathogenesis of MPNs remains unclear. To investigate the role of wild-type JAK2 in MPNs induced by JAK2V617F, we have utilized conditional Jak2 knock-out and Jak2V617F knock-in alleles and generated heterozygous, hemizygous and homozygous Jak2V617F mice. Whereas heterozygous Jak2V617F expression results in a polycythemia vera-like disease in mice, loss of wild-type Jak2 allele in hemizygous or homozygous Jak2V617F mice results in a significantly greater increase in reticulocytes, white blood cells, neutrophils and platelets in the peripheral blood and larger spleen size. We also have found that hemizygous or homozygous Jak2V617F expression significantly increased megakaryocyte-erythroid progenitors in the bone marrow and spleens and marked infiltration of neutrophils in the liver compared with heterozygous Jak2V617F. More importantly, hemizygous or homozygous Jak2V617F mice show accelerated myelofibrosis compared with heterozygous Jak2V617F-expressing mice. Thus, loss of wild type Jak2 allele increases myeloid cell expansion and enhances the severity of the MPN. Together, these results suggest that wild-type Jak2 serves as a negative regulator of MPN induced by Jak2V617F. Disclosures: No relevant conflicts of interest to declare.

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