Search Results (122)

Background/Objectives: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders driven by somatic mutations, most commonly those in JAK2, CALR, and MPL. While conventional molecular testing often focuses on these canonical mutations, emerging data suggest that additional mutations and low-variant-allele-frequency (VAF) subclones may contribute to disease progression and prognosis. Methods: We applied ultra-deep targeted sequencing with an error-correction algorithm to analyze bone marrow and peripheral blood samples from 134 patients with essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), secondary myelofibrosis (MF), or post-MPN acute leukemia. Targeted sequencing panels were used to detect disease-associated and clonal driver mutations. Matched germline controls were not systematically available. Results: Low-VAF variants (<5%) were identified in 4/16 (25%) CALR, 3/7 (43%) MPL, and 9/11 (82%) TP53 mutations. In contrast, all TP53 mutations identified at leukemic transformation had VAFs > 5%, suggesting clonal expansion during progression. Paired sequencing at initial MPN diagnosis and leukemic transformation was available for three patients. JAK2 p.V617F VAFs differed according to treatment timing (Kruskal–Wallis test, p = 0.0138), with lower VAFs observed in untreated patients; however, this association may be influenced by treatment-selection confounding. Mutations in ASXL1 and SRSF2 were occasionally observed in ET and secondary MF, although their prognostic significance remains uncertain. Progression analyses were exploratory because of the limited number of events and longitudinally sampled patients, and formal survival or prognostic modeling was not performed. Conclusions: Ultra-deep error-corrected sequencing enables sensitive detection of low-VAF mutations in MPNs, including subclonal events potentially missed by less sensitive assays. These findings demonstrate the potential utility of high-sensitivity panel-based sequencing for molecular characterization of MPN, while larger longitudinal studies are required to establish the prognostic and clinical significance of these findings. Full article

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated premalignant state defined by somatic mutations in hematopoietic cells at a variant allele frequency (VAF) ≥2% in the absence of overt hematologic malignancy. Among CHIP-associated mutations, JAK2 V617F is of particular interest because it occupies a dual biological and clinical role: it is both the principal driver of BCR::ABL1-negative myeloproliferative neoplasms (MPNs) and a clonal hematopoiesis variant conferring approximately 12-fold cardiovascular risk in selected cohorts, exceeding that reported for common DTA CHIP variants. Quantitative assessment of JAK2 V617F allele burden is therefore clinically relevant across the full disease continuum—from subclinical clonal expansion to MPN diagnosis, prognostic stratification, and therapeutic monitoring—as VAF thresholds correlate with disease phenotype, thrombotic risk, molecular response, and fibrotic progression. Digital PCR platforms, including droplet digital PCR (ddPCR) and chip-based digital PCR, have emerged as highly sensitive and reproducible methods for absolute JAK2 V617F quantification without the need for standard curves, with reported limits of detection as low as 0.01%. In this review, we synthesize current evidence on the molecular biology of JAK2-driven clonal hematopoiesis, the clinical significance of allele burden quantification, and the analytical performance of digital PCR compared with quantitative PCR and next-generation sequencing. We interpret these findings through a systems biology lens that draws together JAK-STAT signaling networks and thrombo-inflammatory pathways including inflammasome-dependent IL-1 signaling, clonal architecture, and bone marrow microenvironmental remodeling. We also discuss published quantitative models in which JAK2 V617F allele burden is treated as a dynamic state variable, while emphasizing that the present review offers a conceptual synthesis rather than a new computational model. We provide a structured comparative synthesis of published digital PCR analytical performance data, a stage-adapted proposal for clinical monitoring, and schematic models to guide future implementation. Overall, the evidence supports digital PCR as a precision tool for monitoring JAK2 V617F clonal dynamics across the CHIP–MPN spectrum, and points to several priorities: assay standardization, harmonized reporting, external quality assessment, and prospective clinical validation. Full article

Background and objectives: Myeloproliferative neoplasms (MPNs) are blood cancers characterized by elevated blood cell counts, bone marrow fibrosis (BMF), and chronic inflammation, which drives disease progression. BMF results from disrupted collagen turnover in the bone marrow extracellular matrix (ECM), making its reduction or stabilization a key therapeutic goal. Non-invasive biomarkers reflecting collagen turnover could potentially improve early detection of BMF and monitor disease activity. Methods: We evaluated serum biomarkers of collagen turnover in 130 MPN patients (MPN subtypes: ET = 49, PV = 60, pre-PMF = 8, PMF = 13) included in the DALIAH trial (ClinicalTrials.gov identifier: #NCT01387763). Type I and type III collagen formation (PRO-C1 and PRO-C3) and MMP-degraded type I, III, and IV collagens (C1M, C3M, and C4M) were measured by ELISA in serum. Biomarker levels were compared to age- and sex-matched healthy individuals and were assessed according to disease subtypes, somatic driver mutations, JAK2V617F VAF, and fibrosis grade. Furthermore, we studied correlations between the biomarker levels and conventional hematological markers for disease activity, such as hemoglobin, white blood cell count (WBCs), platelet counts, and lactate dehydrogenase (LDH). Results: Baseline PRO-C3 (p = 0.0005) and C1M (p = 0.0102) were elevated in MPN patients compared to healthy individuals, whereas C3M was decreased (p < 0.0001). Patients with primary myelofibrosis (PMF) had higher levels of PRO-C3 compared to patients with ET (p = 0.0041) and PV (p = 0.0172), correlated with higher JAK2V617F VAF (≥50%) (p = 0.0069) and advanced fibrosis grade (p = 0.0002). In addition, PRO-C3 was positively correlated to LDH, which is a biomarker of disease activity in MPNs (r = 0.5754, p < 0.0001). Conclusions: Taken together, these findings emphasize the role of ECM remodeling in MPN pathophysiology and the potential of soluble ECM neoepitopes as biologically plausible disease markers. Full article

Background: Precise quantification of JAK2 V617F variant allele frequency (VAF) is clinically important in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). This study evaluated the analytical performance and clinical utility of a laboratory-developed chip-based real-time digital PCR (dPCR) assay for JAK2 V617F and compared it with a commercial quantitative real-time PCR (qPCR) assay. Methods: Residual DNA extracts from 76 JAK2 V617F-positive clinical specimens collected from patients with suspected MPNs were analyzed using both qPCR and dPCR. Analytical performance was assessed according to CLSI-based approaches, including limit of blank (LoB), limit of detection (LoD), precision, linearity, and method comparison. Associations between VAF and hematologic parameters, as well as diagnostic groups, were also examined. Results: Both methods showed a LoB of 0. The LoD was 0.1167% for qPCR and 0.0846% for dPCR, and dPCR demonstrated lower variability than qPCR across high-, intermediate-, and low-concentration samples, with the largest difference observed at low VAF levels. Linearity was excellent for both assays (R² = 0.988 for qPCR and 0.999 for dPCR), although dPCR showed less low-concentration bias. The two methods were highly correlated (Pearson r = 0.9789, R² = 0.958), but dPCR yielded slightly higher VAF values overall. VAF was significantly higher in polycythemia vera than in essential thrombocythemia, and both qPCR- and dPCR-based VAFs were positively correlated with white blood cell count. Conclusions: The chip-based laboratory-developed dPCR assay showed high concordance with qPCR while providing lower LoD and better precision at low allele burden. These findings support its potential utility as a sensitive alternative for JAK2 V617F quantification in clinical laboratories, particularly in settings requiring accurate low-level detection and follow-up monitoring. Full article

Background: Polycythemia vera (PV) is characterized by mutation JAK2 V617F, elevated blood counts, and risk of thrombosis. Ropeginterferon alfa-2b (ropeg) approved for PV at a low-starting dose and slow-titration schema with efficacy at 12 months with assessment visits every three months. This period might be at thrombotic risk resulting from inadequate control of hematological parameters and JAK2. The study was aimed at assessing its efficacy at less than 12 months with assessment visits every two weeks. Methods: Thirteen patients with Hydroxyurea (HU)/Intolerance (HU/I) high-risk PV and pruritus were treated with ropeg at a low-starting dose and slow-titration schema with assessment visits every two weeks. The primary endpoint was the complete hematological response (CHR) at less than 12 months. The secondary endpoints were the CHR rates, CHR dose, durable CHR, and reduction in JAK2V617F variant allele frequency (VAF). Results: The CHR of patients was 8 weeks in 30.7% (4/13), 16 weeks in 30.7% (4/13), and 24 weeks in 38.4% (5/13), respectively, with a mean time of 4.15 months. Durable CHR was at 20, 28, and 36 weeks, respectively, with a mean time of 6.55 months. JAK2 VAF continuously declined from 43.38% at baseline to 12.96% at durable CHR. Eleven patients (85%) achieved partial molecular response (PMR) and two (15.38%) complete molecular responses (CMRs) and all patients resolved the pruritus. No adverse event (AE) or thrombosis occurred. Conclusions: We report that ropeg is efficacious under the low-starting dose and slow-titration regimen in obtaining CHR and molecular response (MR) at less than 12 months. Full article

Background: Molecular testing for myeloproliferative neoplasms (MPNs) without defined clinical criteria can lead to inefficient laboratory utilization without proportional diagnostic benefit. Methods: We evaluated the impact of implementing clinical acceptance criteria, including unexplained abnormal blood counts, unusual-site thrombosis, unexplained hepatosplenomegaly, and/or leukoerythroblastic blood film for gene (JAK2, CALR, MPL and/or BCR::ABL1) testing of patients with suspected MPNs in Hamilton, Canada and surrounding areas. The impact of testing criteria on ordering practices and diagnostic yields was assessed by retrospective examination of 3590 MPNs test requests submitted between 1 January and 31 December 2025; including 5.5 months of permissive testing (pre-implementation period), 2 months with a transition in testing criteria (grace period) and 4.5 months with restricted testing (post-implementation period). During the post-implementation period, the Laboratory also transitioned from sequential single-gene PCR-based assays to an MPN next-generation sequencing (NGS) panel for DNA-based MPN testing. Results: Our results show that test volumes decreased significantly from 1835 in the pre-implementation period to 1050 post-implementation, while the positivity rate increased from 12% to 17% (χ² = 12.26, p = 0.001). Patients with elevated platelet counts (237 of 1050 tested) demonstrated the highest positivity rate of 35% (n = 83/237). JAK2 V617F represented the highest proportion of all detected mutations at 73% (n = 127/174). Conclusions: These findings show that implementing appropriate pre-test clinical criteria significantly improved MPN test utilization and diagnostic yield. Full article

Background: The coexistence of systemic prothrombotic disorders, chronic thromboembolic pulmonary hypertension (CTEPH), chronic hypoxia, and cerebrovascular thrombosis creates complex diagnostic and therapeutic challenges. Case summary: We report the case of a 52-year-old woman with JAK2V617F-positive polycythemia vera, inherited thrombophilic abnormalities, recurrent pulmonary thromboembolism progressing to severe CTEPH, chronic hypoxemia, cerebral venous sinus thrombosis, and right vertebral artery occlusion. Management challenge: The case illustrates persistent thrombotic risk despite anticoagulation, the need for disease-directed cytoreduction, limited access to CTEPH-directed interventional treatment, neurological vulnerability despite preserved brain parenchymal integrity, and the narrow therapeutic margin created by the combined use of anticoagulant, cytoreductive, and pulmonary vasodilator therapy. Particular emphasis is placed on the competing risks of recurrent thrombosis and hemorrhagic complications, especially in the cerebrovascular territory. Conclusion: This case highlights the need for repeated multidisciplinary reassessment in patients with overlapping hematological, pulmonary, and neurological vascular disease. Improved survival in patients with severe multisystemic conditions may increase the clinical relevance of complex presentations requiring coordinated management. Further evidence is needed to support safer, more standardized treatment strategies for patients requiring simultaneous control of thrombosis, pulmonary vascular disease, myeloproliferation, hypoxia, and treatment-related bleeding risk. Full article

Objective: This study examined whether HFE H63D carriers living at moderate-to-high altitude have a stronger secondary polycythemia phenotype than non-carriers from the same region. Methods: This retrospective cohort study included 59 patients with HFE gene mutation (heterozygous n = 49, homozygous n = 10) and 51 controls without HFE mutation (total N = 110). JAK2 V617F negativity was confirmed in all participants. Serum erythropoietin (EPO) levels were assessed in the HFE mutation group to support secondary, non-clonal erythrocytosis. Results: Hemoglobin (17.32 ± 1.29 vs. 15.11 ± 0.95 g/dL (p < 0.001), hematocrit (median 51.50 vs. 45.20; p < 0.001), and erythrocyte count (p < 0.001) were significantly higher in the HFE mutation group. Transferrin saturation was higher in the HFE mutation group than in controls (64.56 ± 2.03% vs. 36.30 ± 1.58%; p < 0.001; Cohen’s d = 0.95). Serum iron was higher and total iron-binding capacity was lower in the HFE mutation group, respectively (127.58 ± 44.10 vs. 93.62 ± 29.55 µg/dL and 194.32 ± 72.41 vs. 243.36 ± 40.82 µg/dL; both p < 0.001). CRP levels were also significantly elevated (p < 0.001). No significant differences were observed between the heterozygous and homozygous HFE mutation subgroup. Conclusions: HFE H63D carriers had higher erythrocytosis-related parameters and transferrin saturation than controls. These findings suggest that HFE-related changes in iron handling may strengthen the erythrocytosis phenotype at moderate-to-high altitude. Larger prospective studies should test this association. Full article

Background/Objectives: Immune surveillance is increasingly recognized as a modifier of myeloproliferative neoplasm (MPN) initiation and evolution, yet the contribution of the NKG2D receptor and its ligands MICA/MICB to CALR-mutated disease remains unclear. Methods: We performed high-resolution next-generation sequencing genotyping of MICA and MICB in 43 patients with CALR-mutated MPN (WHO 2022 criteria) and compared the allele and haplotype distributions with those of 156 healthy Bulgarian controls and 85 patients with JAK2 V617F-positive MPN. Associations were tested using age- and sex-adjusted additive generalized linear models; bi-locus haplotypes were evaluated using haplotype score methods. In a genotyped subgroup (35 CALR-mutated MPN patients and 105 controls), functional KLRK1 (NKG2D) polymorphisms were analyzed for haplotype-level associations. We also performed 700 ns molecular dynamics simulations of selected MICA variants in complex with NKG2D and reanalyzed publicly available single-cell RNA-sequencing data (GSE117826) and RNA-sequencing data from CRISPR/Cas9-edited CALR-mutant iPSC-derived megakaryocytes to evaluate MICA/MICB expression. Results: MICA*004:001 was significantly associated with CALR-mutated MPN versus controls (p = 0.004; Bonferroni-adjusted p = 0.047), while MICB*008:001 showed only nominal association. Exploratory haplotype analyses identified a MICA*009:01-MICB*004:001 haplotype associated with CALR-mutated status (p = 0.008) and a KLRK1 G-A-G-T haplotype (rs1049174-rs2617160-rs2246809-rs2617170) associated with increased CALR-mutated MPN risk (OR = 3.61; p = 0.029). Transcriptomic reanalysis indicated a higher fraction of CALR-mutant stem and progenitor cells expressing detectable MICA/MICB transcripts, and heterozygous CALR-mutant megakaryocytes exhibited higher MICA expression than the wild type. Conclusions: Together, these data support an exploratory immunogenetic and transcriptomic link between the NKG2D-MICA/MICB axis and CALR-mutated MPN, but direct protein-level and functional studies are required before mechanistic or therapeutic conclusions can be drawn. Full article

Background/Objectives: IL23R encodes a pivotal component of the IL-23/Th17 signaling axis and represents a validated genetic susceptibility locus for inflammatory bowel disease (IBD), psoriasis, and ankylosing spondylitis. Despite extensive GWAS data, the functional consequences of the full spectrum of IL23R missense single-nucleotide variants (SNVs) have not been systematically characterized. This study aimed to identify high-risk missense SNVs through a multi-tool in silico pipeline. Methods: A total of 723 missense SNVs from NCBI dbSNP were verified against transcript NM_144701.3/Q5VWK5-1 (629 aa) using Ensembl VEP (GRCh38). Sequential filtering was performed using applied SIFT, PolyPhen-2, PROVEAN, E-SNPs&GO, MutPred2, and ConSurf (grade ≥ 7); AlphaMissense and FATHMM-MKL were used as independent annotation layers. Protein stability was assessed with MuPro and DynaMut2 (AlphaFold2 AF-Q5VWK5-F1-v6; pLDDT = 68.19); structural characterization was performed with Project HOPE, and interaction networks were constructed using STRING and GeneMANIA. Results: Sequential filtering identified 37 high-risk missense variants. MuPro predicted destabilizing effects for 36/37 variants, with concordant DynaMut2 results for 35/37. Project HOPE identified disulfide bond disruption in 11 variants, charge-altering substitutions in 8, and glycine/proline backbone conformational changes in 11. STRING analysis identified IL12RB1 (0.999), IL23A (0.999), JAK2 (0.995), IL12B (0.986), and STAT3 (0.980) as the leading IL23R interactors. The protective variant R381Q was appropriately characterized as neutral by PROVEAN (−1.16) and AlphaMissense (likely_benign), supporting the specificity of the pipeline. Conclusions: Comprehensive in silico analysis identified 37 high-risk IL23R missense candidates with convergent computational evidence of predicted deleteriousness, predominantly involving cysteine bridge disruption, charge alteration, and glycine/proline backbone conformational changes. These variants are presented as prioritized candidates for future functional validation and may inform subsequent investigations of IBD susceptibility and IL-23 pathway pharmacogenomics. Full article

Indolent systemic mastocytosis (ISM) is an under-recognised cause of secondary osteoporosis, and skeletal fragility may be the only presenting feature, delaying diagnosis. We describe four adults referred to a tertiary endocrinology service for unexplained osteoporosis or low-trauma fractures, in whom systemic mastocytosis (SM) was identified during work-up. All had elevated basal serum tryptase (41.4–87.0 µg/L), bone-marrow biopsy showing atypical mast cells and the KIT D816V variant; cutaneous lesions were absent in every case. Three patients fulfilled WHO 2022 criteria for ISM. The fourth had coexistent JAK2 V617F-positive post-essential-thrombocythaemia myelofibrosis and was classified as SM with associated haematological neoplasm (SM-AHN); his mast cell clone (tryptase 43.7 µg/L; KIT D816V VAF 0.391%) behaved indolently and contributed clinically through osteoporosis alone, illustrating that an indolent mast cell component can be overlooked when a chronic myeloid neoplasm dominates the picture. Presentations ranged from an isolated low-energy L5 fracture in a 55-year-old man, to multiple vertebral compression fractures despite denosumab in a 71-year-old woman with primary hyperparathyroidism, to severe wasp-sting anaphylaxis in a 43-year-old man. After multidisciplinary review, all received intravenous zoledronic acid with vitamin D repletion; KIT-targeted therapy is under consideration in selected patients. Although causal inferences cannot be drawn from four retrospectively identified cases, the series illustrates how ISM may be missed in unexplained or treatment-refractory osteoporosis—particularly in younger men, those with prior severe anaphylaxis, and those fracturing on antiresorptive therapy—and supports combining basal serum tryptase with high-sensitivity peripheral-blood KIT D816V testing, in line with the WHO/ICC/AIM-ECNM 2022–2024 criteria. Prospective studies are needed. Full article

Background/Objectives: Somatic CALR gene insertions/deletions in exon 9, causing frameshift, are a diagnostic sign of myeloproliferative neoplasms (MPNs). Besides the most common somatic mutations of type I (52 bp deletion) and type II (5 bp insertion), there are rare ones whose significance is not always clear. This study evaluates the frequency of rare mutations and demonstrates a germline rather than somatic nature for some of them. Methods: A retrospective analysis of 8417 blood samples subjected to molecular diagnosis of myeloproliferative neoplasm (MPN) was performed. Cases suspected as germline variants were sequenced, and paired samples (when available) of buccal epithelium were analyzed. Results: We have identified 632 CALR gene mutation-positive cases. Most of the cases were typical insertions/deletions (5 bp/52 bp). Non-type I/II frameshift or nonframeshift mutations were observed in 68 cases (11%). The buccal swab samples obtained from 4 patients confirmed the germline nature of these variants. It is worth noting that the MPN diagnosis for three of these patients was made considering the presence of the JAK2 V617F mutation (two cases) or BCR::ABL1 translocation (one case). In one case, the diagnosis of MPN was reclassified to CML. Conclusions: Non-type I/II CALR mutations, according to our data, could be found in 0.8% of MPN-suspected cases, and may not be associated with the diagnosis. The detection of a non-standard CALR mutation with an allelic frequency close to 50% should raise suspicion of the possibility of a germline CALR variant, and such cases should be investigated further. Full article

Polycythemia vera (PV) is a JAK2V617F-driven myeloproliferative neoplasm characterized by erythroid expansion, increased thrombotic risk, and heterogeneous clinical outcomes. Although prior studies have described key transcriptional abnormalities—including Janus kinase–signal transducer and activator of transcription (JAK–STAT) hyperactivation and chronic myeloinflammation—most have examined single hematopoietic compartments. A multi-compartment approach may reveal conserved and lineage-specific disease-associated transcriptional programs. Here, an integrated, multi-compartment transcriptomic analysis of publicly available microarray datasets was performed, spanning bone marrow (BM) CD34+ progenitors, peripheral blood (PB) CD34+ progenitors, and whole blood from PV patients and healthy controls, with independent validation in neutrophils. Differential gene expression, pathway enrichment, and protein–protein interaction network analyses were used to delineate conserved versus compartment-specific transcriptional programs and to evaluate persistence of progenitor-derived signatures into mature myeloid cells. Across compartments, PV demonstrated consistent enrichment of inflammatory, interferon, and JAK–STAT-associated pathways despite limited overlap at the individual gene level, indicating that core disease processes are maintained through lineage- and differentiation-stage-specific transcriptional reprogramming. Network analysis identified highly connected hub genes, which were used to derive a single-sample gene set enrichment (ssGSEA) signature. This signature showed strong diagnostic performance across cohorts; remained enriched in PV neutrophils; and correlated with platelet count, indolent disease status, and reduced levels in post-splenectomy patients. Together, these findings support a model in which PV is driven by stable, progenitor-derived inflammatory programs that persist across myeloid differentiation while incorporating compartment-specific adaptations, and highlight the value of multi-compartment, network-based approaches for translational biomarker development. Full article

Background/Objectives: The increasing sensitivity of molecular diagnostic techniques has led to the frequent detection of low-level JAK2 V617F mutations in individuals without overt myeloproliferative neoplasms (MPNs), creating uncertainty regarding their biological and clinical significance. This study aimed to evaluate the clinical relevance, thrombotic risk, and hematologic evolution associated with low JAK2 V617F allele burden. Methods: We conducted a retrospective single-center study including adult patients tested for JAK2 V617F between January 2016 and December 2023. Patients with a variant allele frequency (VAF) <2% who did not meet WHO or 2022 International Consensus Classification diagnostic criteria for MPN at baseline were included. Clinical characteristics, laboratory parameters, molecular findings, thrombotic events, and longitudinal ou--comes were analyzed. Results: Among two-thousand-three-hundred-seventy-two tested subjects, 55 patients (9.2% of JAK2-positive cases) harbored a low-level JAK2 V617F mutation (median VAF 0.35%). Over a median follow-up of 31.7 months, 12 patients (21.8%) progressed to overt MPN. Baseline VAF was significantly higher in patients who evolved to MPN compared to non-progressors. Thrombotic events occurred in 30.9% of patients and were associated with higher VAF values irrespective of MPN diagnosis. Serial molecular analyses showed stable persistence of the mutant clone over time. Conclusions: Low-burden JAK2 V617F mutations represent clinically relevant clonal events associated with thrombotic risk and potential disease evolution. These findings support the need for structured clinical and molecular follow-up even in the absence of initial diagnostic criteria. Full article

Background/Objectives: Thoracic aortic aneurysms have long been associated with germline mutations such as FBN1, TGFBR2, and COL3A1, which predispose to Marfan, Loeys–Dietz, and Ehlers–Danlos syndromes, respectively. However, recent research has identified a correlation between the JAK2 V617F somatic mutation and thoracic aortic aneurysm formation. This review aims to synthesize the current evidence on the relationship between JAK2 V617F and TAA development. Methods: A literature review was conducted using PubMed reviewed articles up to June 2025. Search terms included “thoracic aortic aneurysm”, “somatic mutations” and “JAK2 V617F”. Relevant clinical datasets and population-based cohort studies were identified and evaluated. Results: The available studies demonstrated a consistent association between JAK2 V617F and thoracic aortic aneurysm formation, with JAK2 V617F variant allele frequency (VAF) being a valuable biomarker of aneurysm risk. The mutation is accompanied by the onset of increased cytokine production, pro-inflammatory leukocytes, and elevated expression levels of MMPs—all of which drive elastin degradation and are classically associated with thoracic aortic aneurysm development. Conclusions: Compelling emerging evidence supports an association between the JAK2 V617F somatic mutation and the formation of thoracic aortic aneurysms, with VAF acting as a valuable biomarker for aneurysm risk. However, no studies have evaluated whether increasing VAF influences aneurysm growth rate, highlighting the need for future clinical research. Full article