JAK2V617F Mutation Research Articles

LNK/SH2B3 Loss Exacerbates the Development of Myeloproliferative Neoplasms in CBL-deficient Mice.

Genetic variations of signaling modulator protein LNK (also called SH2B3) are associated with relatively mild myeloproliferative phenotypes in patients with myeloproliferative neoplasms (MPN). However, these variations can induce more severe MPN disease and even leukemic transformation when co-existing with other driver mutations. In addition to the most prevalent driver mutation JAK2V617F, LNK mutations have been clinically identified in patients harboring CBL inactivation mutations, but its significance remains unclear. Here, using a transgenic mouse model, we demonstrated that mice with the loss of both Lnk and Cbl exhibited severe splenomegaly, extramedullary hematopoiesis and exacerbated myeloproliferative characteristics. Moreover, a population of Mac1+ myeloid cells expressed c-Kit in aged mice. Mechanistically, we discovered that LNK could pull down multiple regulatory subunits of the proteosome. Further analysis confirmed a positive role of LNK in regulating proteasome activity, independent of its well-established function in signaling transduction. Thus, our work reveals a novel function of LNK in coordinating with the E3 ligase CBL to regulate myeloid malignancies.

The CHIP-clinic as the catalyst of preventive medicine

Clonal Hematopoiesis of Indeterminate Potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVD) and is a precursor stage to the BCR-ABL negative chronic myeloproliferative neoplasms (MPNs). These diseases are acquired stem cell neoplasms, arising due to mutations in the hematopoietic stem cell. The most prevalent is the JAK2V617F (JAK2) mutation, which potently generates reactive oxygen species (ROS), and accordingly contributes greatly to the chronic inflammatory state and the increased risk of thrombosis in MPNs. The MPNs are largely underdiagnosed blood cancers with a long pre-diagnostic phase of several years, when the elevated blood cell counts are considered reactive to smoking, blood clots, infections or chronic inflammatory diseases. Since the JAK2 mutation as CHIP-JAK2 associates with an increased risk of CVD and an increased risk of hematological and non-hematological cancers there is an urgent need to explore and validate the JAK2 mutation as a novel risk factor for CVD and to establish CHIP-clinics, which in an interdisciplinary collaboration between experts from several disciplines, and ensure timely diagnosis of the undiagnosed MPN patient and associated comorbidities. We envisage studies of the JAK2 mutation in large CVD cohorts to deliver the “Proof of Concept” for the JAK2 mutation to be implemented as a novel, highly important risk factor for CVD. These novel preventive strategies are considered to have the potential of reducing morbidity and mortality in a large population of citizens and patients, carrying the thrombosis- and CVD-promoting JAK2 mutation.

Myeloid neoplasm with concurrent BCR::ABL1 translocation, and JAK2 and SF3B1 co-mutations with severe fibrosis: a case report

Abstract Introduction/Objective Myeloproliferative neoplasms (MPNs) arise from hematopoietic stem cells with somatically altered tyrosine kinase signaling. Classification of MPNs is based on hematologic, histopathologic and molecular characteristics including the presence of BCR::ABL1 and JAK2 V617F. Methods/Case Report We present a 72-year-old male with a myeloid neoplasm and severe fibrosis, with concurrent BCR::ABL1 translocation, and co-mutations in JAK2 and SF3B1. Initially, the patient was diagnosed with anemia, thrombocytosis and folic acid deficiency and was prescribed supplemental folic acid. At follow up, normocytic anemia and thrombocytosis were seen. Bone marrow biopsy showed overtly fibrotic marrow with maturing trilineage hematopoiesis, markedly increased megakaryopoiesis and ring sideroblasts. Chromosome analysis and sequential GTG-fluorescence in situ hybridization (FISH) of metaphases using the dual-fusion three color probe BCR/ABL1- ASS1 revealed abnormal results. A t(9;22)(q34;q11.2) was detected along with an atypical FISH signal pattern with a single BCR::ABL1 fusion on the derivative chromosome 22 instead of the typical two fusions, resulting in loss of one BCR::ABL1 fusion signal including loss of the ASS1 on the derivative chromosome 9. Next-generation sequencing (NGS) analysis detected double driver mutations, JAK2 p. Val617Phe and SF3B1 p. Lys700Glu in the patient. JAK2 V617F mutation was further confirmed by real-time quantitative PCR (qPCR) with variant allele frequencies of 39.7%. Additionally, the patient was positive for BCR::ABL1 p190 fusion transcript (10%). The presence of JAK2 and SF3B1 co-mutations along with ring sideroblasts and the patient’s clinical presentation suggests the diagnosis of myelodysplastic/myeloproliferative neoplasm with thrombocytosis and SF3B1 mutation. Results (if a Case Study enter NA) NA Conclusion Although, the detection of t(9;22) by chromosome analysis is a diagnostic feature of chronic myeloid leukemia (CML), our case adds to the limited information on co-existence of BCR::ABL1 and JAK2 V617F with SF3B1 mutations in severe fibrosis. The frequency of co-occurrence, the temporal order of acquisition and clonal relationship of these alterations is poorly understood, and it is also unclear for this case since there is no prior bone marrow biopsy or diagnostic work up. Literature search of these rare cases show that some patients with similar findings progress to myelofibrosis as in this patient. It is possible that the presence of two mutated tyrosine kinase genes accelerates disease progression.

JAK2 mutational status and the contribution of TERT and JAK2 polymorphisms to the occurrence of myeloproliferative neoplasms in Eastern Morocco

Background: The JAK2 V617F somatic mutation is a hallmark of myeloproliferative neoplasms (MPN) and is present in some patients with splanchnic venous thrombosis (SVT). Objectives: We investigated for the first time in Eastern Morocco the JAK2 mutational status and germline risk factors, such as the TERT and JAK2 polymorphisms, in MPN and SVT patients. Methods: This study included 38 patients with MPN, 24 patients presenting with SVT and 60 healthy donors from the BRO Biobank. JAK2 mutations were analyzed using qPCR and Sanger sequencing. Predisposing polymorphisms to MPN were evaluated using Sanger sequencing. Results: JAK2 V617F mutation was positive in 64.5% of patients with MPN and 20.8% of patients with SVT. The JAK2 V617F allelic burden ranged from 2% to 97.53%. We found a strong association between the JAK2 rs56241661 polymorphism of the JAK2 46/1 haplotype and the development of MPN. However, no association was detected between the TERT rs2736100 polymorpism and MPN. Conclusion: The JAK2 mutational status and its allelic burden in Eastern Morocco are consistent with previous studies. The JAK2 46/1 haplotype was strongly associated with MPN. However, unlike other previously studied populations, the TERT polymorphism rs2736100 has no effect on the occurrence of MPN in our population. Keywords: Myeloproliferative neoplasms; JAK2 V617F; TERT and JAK2 polymorphisms; genetic predisposition; Morocco.

Relation of JAK2 V617F allele burden and coronary calcium score in patients with essential thrombocythemia.

JAK2 V617F (JAK2) mutation is associated with clonal hemopoiesis in myeloproliferative neoplasms as well as with faster progression of cardiovascular diseases. Little is known about the relationship between allele burden and the degree of atherosclerotic alteration of coronary vasculature. We previously reported that carotid artery stiffness progressed faster in patients with JAK2 positive essential thromocythemia (ET) patients. After a four-year follow-up we investigated whether mutation burden of a JAK2 allele correlates with a higher coronary calcium score. Thirty-six patients with JAK2 positive ET and 38 healthy matched control subjects were examined twice within four years. At each visit clinical baseline characteristics and laboratory testing were performed, JAK2 mutation burden was determined, and coronary calcium was measured. JAK2 allele burden decreased in 19 patients, did not change in 5 patients, and increased in 4 patients. The coronary calcium Agatston score increased slightly in both groups. Overall, there was no correlation between JAK2 allele burden and calcium burden of coronary arteries. However, in patients with the JAK2 mutation burden increase, the coronary calcium score increased as well. The average JAK2 allele burden decreased in our patients with high-risk ET during the four-year period. However, in the small subgroup whose JAK2 mutation burden increased the Agatston coronary calcium score increased as well. This finding, which should be interpreted with caution and validated in a larger group, is in line with emerging evidence that JAK2 mutation accelerates atherosclerosis and can be regarded as a non-classical risk factor for cardiovascular disease.

Essential thrombocythemia (ET) presenting as a combined cilioretinal artery occlusion (Cil.RAO) and central retinal vein occlusion (CRVO)

A 35-year-old male presented with sudden vision loss in his left eye for 1 day and was diagnosed with combined cilioretinal artery occlusion (Cil.RAO) and central retinal vein occlusion (CRVO). A multidisciplinary clinical work up was conducted to determine the underlying cause. A full blood count revealed a very high platelet count (1,147,000/mm3), prompting further hematologic investigation. Peripheral blood smear showed abundant platelet clumps, and bone marrow trephine biopsy indicated megakaryocytic hyperplasia and reticulin fibrosis (grade 1). The patient tested heterozygous for the JAK2 V617F mutation, a genetic marker for myeloproliferative disorders, and was diagnosed with essential thrombocythemia (ET). After a month of treatment with hydroxyurea 500 mg daily, his platelet count returned to normal. Thrombocythemia is associated with systemic and ocular thrombotic and embolic complications. A full blood count was pivotal in diagnosing and managing ET in this patient with combined retinal vascular disease.

Reduced Platelet Activation in Triple-Negative Essential Thrombocythemia Compared with JAK2V617F-Mutated Essential Thrombocythemia.

Triple-negative (TN) essential thrombocytopenia (ET) is characterized by the absence of driver mutations while retaining histologic and phenotypic characteristics sufficient for an ET diagnosis. Our understanding of TN-ET and its platelet activation remains incomplete. We carried out a large-scale multicenter clinical analysis to analyze the clinical and molecular characteristics and thrombotic complications of TN-ET. We also related the above characteristics to platelet activation to further explore the thrombosis mechanism of TN-ET. A retrospective multicenter study was conducted on 138 patients with TN-ET and 759 patients with ET with driver mutations from March 1, 2012 to December 1, 2021. The clinical and molecular characteristics of the patients with TN-ET were summarized. Additionally, platelet activation, apoptosis, and reactive oxygen species (ROS) levels were analyzed in 73 patients with TN-ET from this cohort and compared with 41 age- and sex-matched healthy donors. Compared with patients with the JAK2V617F mutation, those with TN mutation were younger (P < 0.001) and exhibited fewer thrombotic events before diagnosis (P < 0.001) and during follow-up (P = 0.039). Patients with TN mutation also presented with significantly reduced CD62P expression in platelets (P = 0.031), slightly reduced calcium concentration in platelets (P = 0.063), increased mitochondrial membrane potential (P = 0.011), reduced phosphatidylserine exposure (P = 0.015), reduced levels of ROS (P = 0.043) and MitoSOX in platelets (P = 0.047). In comparison with JAK2V617F-mutated ET, TN-ET is associated with lower platelet ROS levels, which leads to reduced platelet activation and consequently a lower risk of thrombosis.

Association of JAK2 Haplotype GGCC_46/1 with the Response to Onco-Drug in MPNs Patients Positive for JAK2V617F Mutation

Association of JAK2 Haplotype GGCC_46/1 with the Response to Onco-Drug in MPNs Patients Positive for JAK2V617F Mutation

A comparative retrospective study of pre-fibrotic primary myelofibrosis versus overtly fibrotic stage in Qatar: clinicopathological, genetic landscape, risk stratification and survival data (2008–2021) – a single center experience

ABSTRACT Background In MENA region, there is a lack of evidence on Primary Myelofibrosis (PMF), leading to its underrepresentation in medical literature. This study marks the first comprehensive report on PMF data in Qatar, presenting findings from a single-center study spanning 13 years (2008-2021). Methods Clinicopathological data, genetic features, and disease progression parameters of pre-PMF and overt PMF subgroups were collected. Overall survival (OS), progression-free survival (PFS), DIPSS plus four categories and merged low and high-risk DIPSS scoring groups were assessed. Results Pre-PMF patients showed higher hemoglobin (P < 0.001), and platelet counts (P < 0.05) but lower blast counts, LDH levels, constitutional symptoms (P < 0.0001), and splenomegaly (P < 0.010) than overt PMF patients. JAK2 V617F mutation was more common in pre-PMF (P = 0.059), while unfavorable karyotypes were exclusive to overt PMF (P = 0.028). Median overall survival was significantly longer at 276.9 months (IQR: 315.9, 276.9 months) to what was previously reported. Overt PMF patients predominantly fell into the higher DIPSS risk category (P < 0.001) and showed greater disease progression than pre-PMF (P < 0.0001). Complications including refractory anaemia (P < 0.001) and leukemic transformation (P = 0.043), increased notably in the high-risk group. Furthermore, 86.2% of high-risk patients required treatment versus 59.4% of the lower-risk group (P = 0.020). Conclusions To the best of our knowledge our research represents the first and largest published dataset on PMF in MENA region to be published. Merged DIPSS plus scoring came to be a pragmatic tool for defining high-risk patients who significantly differ in mortality, progression, need for treatment and leukemic transformation.

Differential modulation of mutant CALR and JAK2 V617F-driven oncogenesis by HLA genotype in myeloproliferative neoplasms.

It has been demonstrated previously that human leukocyte antigen class I (HLA-I) and class II (HLA-II) alleles may modulate JAK2 V617F and CALR mutation (CALRmut)-associated oncogenesis in myeloproliferative neoplasms (MPNs). However, the role of immunogenetic factors in MPNs remains underexplored. We aimed to investigate the potential involvement of HLA genes in CALRmut+ MPNs. High-resolution genotyping of HLA-I and -II loci was conducted in 42 CALRmut+ and 158 JAK2 V617F+ MPN patients and 1,083 healthy controls. A global analysis of the diversity of HLA-I genotypes revealed no significant differences between CALRmut+ patients and controls. However, one HLA-I allele (C*06:02) showed an inverse correlation with presence of CALR mutation. A meta-analysis across independent cohorts and healthy individuals from the 1000 Genomes Project confirmed an inverse correlation between the presentation capabilities of the HLA-I loci for JAK2 V617F and CALRmut-derived peptides in both patients and healthy individuals. scRNA-Seq analysis revealed low expression of TAP1 and CIITA genes in CALRmut+ hematopoietic stem and progenitor cells. In conclusion, the HLA-I genotype differentially restricts JAK2 V617F and CALRmut-driven oncogenesis potentially explaining the mutual exclusivity of the two mutations and differences in their presentation latency. These findings have practical implications for the development of neoantigen-based vaccines in MPNs.

New advances in the role of JAK2 V617F mutation in myeloproliferative neoplasms.

The JAK2 V617F mutation is the most common driver gene in myeloproliferative neoplasm (MPN), which means that the JAK/STAT signaling pathway is persistently activated independent of cytokines, and plays an important part in the onset and development of MPN. The JAK inhibitors, although widely used in the clinical practice, are unable to eradicate MPN. Therefore, the unavoidable long-term treatment poses a serious burden for patients with MPN. It is established that the JAK2 V617F mutation, in addition its role in the JAK/STAT pathway, can promote cell proliferation, differentiation, anti-apoptosis, DNA damage accumulation, and other key biologic processes through multiple pathways. Other than that, the JAK2 V617F mutation affects the cardiovascular system through multiple mechanisms. Although JAK inhibitors cannot eradicate MPN cells, the combined use of JAK inhibitors and other drugs may have surprising effects. This requires an in-depth understanding of the mechanism of action of the JAK2 V617F mutation. In this review, the authors explored the role of the JAK2 V617F mutation in MPN from multiple aspects, including the mechanisms of non-JAK/STAT pathways, the regulation of cellular methylation, the induction of cellular DNA damage accumulation, and effects on the cardiovascular system, with the objective of providing valuable insights into multidrug combination therapy for MPN.

A rare case of concurrent JAK2V617F-positive essential thrombocythemia, multiple myeloma, and colorectal adenocarcinoma

ABSTRACT Multiple myeloma (MM), essential thrombocythemia (ET), and colorectal adenocarcinoma (CA) are three distinct diseases. The co-occurrence of MM, ET, and CA in a single patient is exceedingly rare. Our study presents a remarkable case involving a 75-year-old patient who was simultaneously diagnosed with these three diseases. The JAK2V617F mutation was detected in the bone marrow with a variant allele frequency (VAF) of 13.38%, whereas the isolated CD138-positive plasma cells exhibited a significantly lower VAF of 0.38%. This notable difference implies the potential for separate origins of MM and ET. Additionally, the patient responded well to a bortezomib-based treatment regimen, despite the absence of specific therapy for ET. We believe that our findings add new understanding to these rare diseases and encourage further research in this area.

Impaired fibrinolysis in JAK2V617F-related myeloproliferative neoplasms

BackgroundMyeloproliferative neoplasms (MPNs) are characterized by a high rate of thrombotic complications that contribute to morbidity and mortality. MPN-related thrombogenesis is assumed to be multifactorial, involving both procoagulant and proinflammatory processes. Whether impaired fibrinolysis also participates in the prothrombotic phenotype of MPN has been poorly investigated. ObjectivesWe determined whether MPN, particularly JAK2V617F-positive MPN, is associated with fibrinolytic changes. MethodsTissue-type plasminogen activator (tPA)–mediated fibrinolysis was evaluated both in whole blood and plasma from mice with a hematopoietic-restricted Jak2V617F expression compared with wild-type (WT) mice (Jak2WT) using (1) halo clot lysis, (2) front lysis, and (3) plasmin generation assays. tPA clot lysis assay was performed in the plasma from 65 MPN patients (JAK2V617F mutation, n = 50; CALR mutations, n = 9) compared with 28 healthy controls. ResultsIn whole blood from Jak2V617F mice, we observed a decreased fibrinolysis characterized by a significantly lower halo clot lysis rate compared with Jak2WT (95 ± 22 vs 147 ± 39 AU/min; P < .05). Similar results were observed in plasma (halo clot lysis rate, 130 ± 27 vs 186 ± 29 AU/min; front lysis rate, 2.8 ± 1.6 vs 6.1 ± 1.2 μm.min−1; P < .05). Plasmin generation was significantly decreased both in plasma clots and standardized fibrin clots from Jak2V617F mice compared with Jak2WT mice. Among MPN patients, impaired tPA-related fibrinolysis with prolonged clot lysis time was observed in JAK2V617F and CALR patients. Plasminogen activator inhibitor-1 and α2-antiplasmin were significantly increased in plasma from JAK2V617F patients compared with controls. ConclusionOur results suggest that impaired tPA-mediated fibrinolysis represents an important prothrombotic mechanism in MPN patients that requires confirmation in larger studies.

Unmasking Essential Thrombocythemia: Myocardial Infarction as a Rare Complication in a Young Patient

Essential thrombocythemia (ET) is a rare myeloproliferative disorder characterized by elevated platelet counts and seldom presents with myocardial infarction (MI), particularly in younger individuals without traditional cardiovascular risk factors. We report the case of a 41-year-old woman with no significant medical history who presented with acute chest pain and elevated troponin levels. Her laboratory results indicated a markedly high platelet count, and coronary angiography revealed thrombotic stenosis in the proximal left anterior descending artery. Diagnosis of ET was confirmed by JAK2-V617F mutation and bone marrow biopsy. The patient was initially treated with hydroxyurea to reduce platelet levels, allowing for successful angioplasty three weeks later. This case highlights the importance of considering ET in the differential diagnosis of MI, especially in younger patients without other risk factors, and underscores the need for tailored management and close monitoring in such rare presentations.

Decoding Endothelial MPL and JAK2V617F Mutation: Insight Into Cardiovascular Dysfunction in Myeloproliferative Neoplasms.

Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential face a significantly elevated risk of cardiovascular diseases. Endothelial cells carrying the JAK2V617F mutation have been detected in many patients with MPN. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in patients with MPN. We investigated the impact of endothelial JAK2V617F mutation on cardiovascular disease development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines. Our investigations revealed that JAK2V617F mutant endothelial cells promote cardiovascular diseases under stress, which is associated with endothelial-to-mesenchymal transition and endothelial dysfunction. Importantly, we discovered that inhibiting the endothelial TPO (thrombopoietin) receptor MPL (myeloproliferative leukemia virus oncogene) suppressed JAK2V617F-induced endothelial-to-mesenchymal transition and prevented cardiovascular dysfunction caused by mutant endothelial cells. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function. JAK2V617F mutant endothelial cells play a critical role in the development of cardiovascular diseases in JAK2V617F-positive MPNs, and endothelial MPL could be a promising therapeutic target for preventing or ameliorating cardiovascular complications in these patients.

Splenectomy unveils thrombocytosis in underlying myeloproliferative neoplasms with extrahepatic portal vein obstruction.

Extrahepatic portal vein obstruction (EHPVO) is a rare disease with myeloproliferative neoplasm (MPN) as the most common cause. We report that hypersplenic hematologic changes in EHPVO might be eliminated by MPN. Through experience with splenectomy for variceal control with EHPVO, we suspected that spleen might mask MPN-induced thrombocytosis, and that MPN might have a significant influence on excessive thrombocytosis after splenectomy. To clarify the influence of MPN and spleen on platelet trends, we conducted a retrospective hospital database analysis, evaluating 8 EHPVO patients with splenectomy (2 males, 6 females; from 17 years to 64 years, mean 38.3 years). Three (37.5%) of 8 were diagnosed as MPN by JAK2V617F mutation. The perioperative serum platelet counts in EHPVO without MPN were 10.5, 35.4, and 36.6 (x104/μL) preoperatively, after 1 week and 3 weeks, respectively. The platelet counts in EHPVO with MPN were 34.2, 86.4, and 137.0 (x104/μL), respectively. Splenectomy and MPN showed positive interaction on platelet increasing with statistical significance. We also examined the spleen volume index (SpVI: splenic volume (cm3) / body surface area (m2) and postoperative platelet elevations ratio (PER: 3-week postoperative platelet counts / preoperative platelet counts). However, both SpVI and PER showed no significant difference with or without MPN. Histological examination revealed splenic congestion in all 8 EHPVO cases, and splenic extramedullary hematopoiesis in 2 of 3 MPN. In EHPVO with MPN, hypersplenism causes feigned normalization of platelet count by masking MPN-induced thrombocytosis; however, splenectomy unveils postoperative thrombocytosis. Spleen in EHPVO with MPN also participates in extramedullary hematopoiesis.

Transformation into acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 from JAK2-mutated essential thrombocythemia: a case report

BackgroundBlast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia.Case presentationThe patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 109/L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 109/L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 109/L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes.ConclusionsTo our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia.

Cardiovascular Risk in Philadelphia-Negative Myeloproliferative Neoplasms: Mechanisms and Implications-A Narrative Review.

Myeloproliferative neoplasms (MPNs), encompassing disorders like polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are characterized by clonal hematopoiesis without the Philadelphia chromosome. The JAK2 V617F mutation is prevalent in PV, ET, and PMF, while mutations in MPL and CALR also play significant roles. These conditions predispose patients to thrombotic events, with PMF exhibiting the lowest survival among MPNs. Chronic inflammation, driven by cytokine release from aberrant leukocytes and platelets, amplifies cardiovascular risk through various mechanisms, including atherosclerosis and vascular remodeling. Additionally, MPN-related complications like pulmonary hypertension and cardiac fibrosis contribute to cardiovascular morbidity and mortality. This review consolidates recent research on MPNs' cardiovascular implications, emphasizing thrombotic risk, chronic inflammation, and vascular stiffness. Understanding these associations is crucial for developing targeted therapies and improving outcomes in MPN patients.

A 72-year-old Woman with Dyspnea and Thrombocytosis

&lt;p&gt;原發性血小板增多症的臨床表徵並不典型且早期診斷不易，往往多數病人於診斷前已發生動靜脈血栓形成及出血併發症。本個案一位72歲女性，有高血壓及胃食道逆流病史並按時門診追蹤服藥，五天前注射新冠疫苗後，呼吸喘、乾咳併胸悶至診所就醫未改善，於急診初步診斷急性支氣管炎。入院後感心悸且胸悶，藉由病史詢問、檢驗及理學檢查，顯示心肌酵素正常但心電圖呈現陣發性心室上心搏過速，安排冠狀動脈血管攝影攝影後排除急性心肌梗塞，但呼吸急促未見好轉呈現低血氧，經胸腔電腦斷層為肺栓塞。疑似新冠疫苗後引起的免疫併發症，直到右手食指及中指末梢腫、痛且發紺症狀出現，筆者再次重新檢視病史資料，發現血小板異常，透過骨髓穿刺切片是發現巨核細胞（megakaryocyte）增生，病理報告判斷為骨髓增生性腫瘤，基因檢測結果為JAK2V617F 突變，最後確診是原發性血小板增多症併發肺栓塞，接受Hydroxyurea合併口服抗凝血劑治療，症狀改善且血小板數值趨於穩定。藉此案例分享提醒當發現病人有不明血栓產生時須考慮將相關血液疾病列入鑑別診斷，期能及早發現疾病，掌握治療時機。&lt;/p&gt; &lt;p&gt;&amp;nbsp;&lt;/p&gt;&lt;p&gt;The clinical symptoms of essential thrombocythemia are not typical and early diagnosis is difficult.Most patients have arteriovenous thrombosis and bleeding complications before diagnosis. In this case, a 72-year-old woman had a history of hypertension and gastroesophageal reflux and was taking medication regularly at the outpatient clinic. After being injected with the COVID-19 vaccine five days ago, her breathing, dry cough, and chest tightness did not improve when she went to the clinic. She was initially diagnosed with acute bronchitis in the emergency department. After being admitted to the hospital, she felt palpitations and chest tightness. The medical history, examination and physical examination showed that myocardial enzymes were normal, but the electrocardiogram showed Parox-ysmal supraventricular tachycardia. Coronary angiography was arranged to rule out acute myocardial infarction, but the shortness of breath persisted with hypoxemia, and the computed tomography of the chest showed pulmonary embolism. Immune complications caused by the COVID-19 vaccine were suspected, symptoms of swelling, pain and cyanosis appeared in the distal part of the right index fin-ger and middle finger appeared. The author re-examined the medical history data and found abnormal platelets. Through bone marrow aspiration and sectioning, megakaryocyte hyperplasia was found. Pa-thology report determined that the patient suffered from myeloproliferative neoplasm, and the genetic test result was the JAK2V617F mutation. The patient was finally diagnosed with essential thrombocythe-mia complicated by pulmonary embolism. She was treated with Hydroxyurea combined with oral an-ticoagulants. The symptoms improved and the platelet level stabilized. This case serves as a reminder that when a patient is found to have unknown thrombosis, related blood diseases must be considered in the differential diagnosis, so that the disease can be detected early and proper treatments can be pro-vided.&lt;/p&gt; &lt;p&gt;&amp;nbsp;&lt;/p&gt;

Impact of JAK2 V617F mutation on disease profile and prognostic risk factors in primary myelofibrosis (MPN) - A tertiary care experience.

Objective: To evaluate the association between JAK2 mutation status, PMF disease characteristics, and prognostic features as assessed by the DIPSS Plus scoring system. We analyzed clinical and laboratory data from a cohort of PMF patients to determine the influence of JAK2 mutation on disease presentation and progression. Study Design: Cross Sectional study. Setting: Department of Pathology and Oncology, King Edward Medical University/Mayo Hospital, Lahore. Period: December 2022 to December 2023. Methods: Total 27 patients with PMF were enrolled in the study by non-probability consecutive sampling technique. Patients were diagnosed according to WHO 2016 criteria. CBC and serum LDH were performed by automated hematology and chemistry analyzers respectively. Real-time PCR was used to identify the JAK2 mutations. Risk stratification was done by DIPPS criteria. Data was analyzed by Microsoft Excel 2010. Mean and standard deviation was calculated. Student ‘T’ test was used for comparison of mean between two groups with and without JAK2 mutations. Results: Out of 27 patients 66.6% were males and median age was 59 years. Splenomegaly was the dominant clinical feature accounting for 51.4% with mean splenic span of 17.8±2.91cm. Mean LDH levels was 872.5±324. JAK2 positive expression was found to be significantly correlated with increased splenic span and raised LDH levels with P-value of &lt;0.05. Risk stratification showed 11% patients were in high-risk group. Conclusion: Marked enlargement of spleen and raised in serum LDH levels indicate that patients in our settings had clinically advanced stage of the disease. Apart from this manifestation of JAK2 V617F mutated patients indicated a more aggressive phenotype of the disease.