Search Results (108)

Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), which are clonal hematopoietic disorders caused by somatic gene mutations in the JAK2, CALR, or MPL genes. Mutations activate the JAK–STAT pathway and disrupt NF-κB signaling, leading to a chronic inflammatory state caused by pro-inflammatory cytokines and reactive oxygen species (ROS). This altered microenvironment causes serious clinical features of the disease, such as bone marrow fibrosis, splenomegaly, vascular niche remodeling, and a greater probability of thrombosis or secondary leukemic transformation. Concurrently, MPNs cause both severe immune dysregulation and tumor evasion, as evidenced by progressive lymphopenia, T and B cell exhaustion, Natural Killer cell maturation arrest, and the accumulation of myeloid-derived suppressor cells. Although FDA-approved JAK1/JAK2 inhibitors ruxolitinib, fedratinib pacritinib and momelotinib effectively reduce splenomegaly and symptom burden and have demonstrated survival benefits in clinical trials, their ability to eliminate malignant clones or induce durable disease modification remains limited, and disease progression continues to occur in most patients. Finally, this review assesses the complex immunological dysfunction and chronic inflammatory dysregulation that characterize Ph-negative MPNs, as well as emerging therapeutic strategies, emphasizing the importance of fully understanding these intricate microenvironmental mechanisms for the identification and development of novel precision treatment targets. Full article

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

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/Objectives: BCR::ABL1-negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are clonal hematopoietic stem cell disorders characterized by chronic systemic inflammation and elevated thrombotic risk. Osteoarthritis (OA), the most prevalent joint disease globally, is common in MPNs and shares a common proinflammatory cytokine milieu with MPNs. However, whether symptomatic OA may independently impact MPN-related symptom burden and thrombotic outcomes remains unexplored. Methods: In this prospective two-center study conducted in Croatia (2021–2023), 107 consecutive MPN patients diagnosed by 2016 World Health Organization criteria underwent orthopedic evaluation and completed the MPN Symptom Assessment Form (MPN-SAF) at enrolment. Symptomatic OA was defined as radiographic grade ≥1 (Kellgren–Lawrence) with concordant symptoms. Patients were subsequently followed for thrombotic events. Multiple linear regression and Cox proportional hazards regression were used for multivariable analyses. Results: Symptomatic OA was identified in 64 patients (59.8%). The total symptom score (TSS) was significantly higher in OA patients (p < 0.001), and in multivariable analysis, OA independently predicted higher TSS (β 10.12, 95% confidence interval-CI 5.38–14.86, p < 0.001), alongside female sex and arterial hypertension. Over a median follow-up of 44 months, 10 thrombotic events occurred. Patients with symptomatic OA had significantly worse time to thrombosis (hazard ratio-HR 3.61, 95% CI 1.02–12.8, p = 0.046). In multivariable Cox regression, OA remained associated with thrombosis (HR 15.55, p = 0.002), while female sex (HR 0.17, p = 0.042) and aspirin use (HR 0.15, p = 0.019) were protective. Conclusions: Symptomatic OA may be associated with higher symptom burden and, in this preliminary analysis, with higher thrombotic risk in MPNs. These findings support systematic OA evaluation in MPNs and multidisciplinary management strategies targeting this frequent and burdensome comorbidity. Full article

Background: The detection of JAK2 exon 12 mutations is important for the differential diagnosis of myeloproliferative neoplasms (MPN) and is included in the World Health Organization’s diagnostic criteria for polycythemia vera (PV). We developed and evaluated a pyrosequencing-based technique to detect somatic mutations in JAK2 exon 12 and tested the method in a group of PV patients. Methods: PCR and pyrosequencing primers were designed for region JAK2 exon 12; PCR conditions were optimized for subsequent qualitative and quantitative detection by pyrosequencing. Diagnostic specificity and sensitivity were determined using plasmid controls. Genomic DNA from 145 MPN patients was used to validate the method. Results: The analytical characteristics of the method were as follows: the limit of blank was 1.2–7.4% and the limit of detection was 3.4–9.9% depending on mutation type. DNA samples from Russian patients with clinical evidence of MPNs were analyzed. In 7 of 145 cases (4.8%) JAK2 exon 12 mutations were detected. One patient had the mutation I540-E543insdelTCAGAAATG<AAA. The A-homopolimer insertion in this complex mutation type could not be clearly identified by pyrosequencing, and Sanger confirmation was required. For another patient with N542-E543delAATGAA mutation, we observed the mutant allele burden growing from 15 to 55% between 2014 and 2018 and further reduction during treatment to 11%. Conclusions: The developed pyrosequencing-based method presents a simple solution to qualitative and quantitative JAK2 exon 12 mutations detection. However, some complex mutation types may require manual interpretation and Sanger confirmation. Full article

Background/Objectives: Chronic myeloid leukemia (CML), essential thrombocythemia (ET), primary myelofibrosis (PMF), and polycythemia vera (PV) are myeloproliferative neoplasms (MPNs) that require precise molecular characterization. Although driver mutations such as BCR-ABL1 and JAK2 are diagnostically important, they do not fully explain disease heterogeneity. The NanoString nCounter^® system enables direct multiplex gene expression analysis without RNA amplification and is suitable for degraded bone marrow specimens. This study aimed to analyze cytokine gene expression in bone marrow mononuclear cells of patients with MPNs and controls using NanoString technology, identify differentially expressed genes (DEGs) among MPN subtypes, and investigate their biological significance. Methods: Bone marrow aspirates were collected from 19 patients with MPNs (CML, ET, PMF, and PV) and 6 control patients. Mononuclear cells were isolated, and RNA expression of a 40-gene cytokine panel was analyzed using the NanoString nCounter^® system with strict quality control and normalization. DEGs were identified for each MPN subtype, followed by Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analyses. Results: CML and PV demonstrated 20 and 12 DEGs, respectively. In contrast, ET showed only one DEG (IRAK2), and PMF showed none. Functional analyses revealed enrichment of cytokine signaling, Toll-like receptor (TLR), and JAK-STAT pathways in CML, indicating immune and inflammatory dysregulation. PV DEGs were associated with TLR signaling, IL-17 pathways, and cytokine–cytokine receptor interactions, suggesting active cytokine-mediated inflammation. Conclusions: CML and PV exhibited distinct cytokine-driven transcriptional signatures, whereas ET and PMF exhibited minimal alterations. These findings support the clinical utility of NanoString technology for bone marrow specimens and highlight disease-specific immune pathways as potential diagnostic biomarkers in MPNs. Full article

Myeloproliferative neoplasms (MPNs) are a heterogenous group of myeloid disorders including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). All these conditions can be associated with significant morbidity including increased risk of thrombotic events as well as reduced survival. Selecting therapy is dependent on patients’ risk assessment and thus prognostication is vital in the management of these conditions. There have been significant developments in prognostic and risk stratification models for MPNs over the last few years, including incorporation of molecular markers. This narrative review article aims to summarize these prognostic models and provide practical advice on how clinicians can utilize these tools to develop personalized treatment strategies for MPN patients. 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: Myeloproliferative neoplasms (MPNs)—including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET)—are clonal stem-cell disorders driven by JAK–STAT pathway activation within an inflammatory microenvironment. Ruxolitinib (RUX), a JAK1/2 inhibitor, improves splenomegaly and symptom burden in myelofibrosis and serves as second-line therapy in hydroxyurea-resistant/intolerant PV. However, real-world data from Middle Eastern populations remains scarce. This study evaluates the effectiveness, safety, and dosing practices of RUX in a heterogeneous Omani MPN cohort. Methods: Electronic records were reviewed for adults diagnosed with MF, PV, or ET who received RUX at Sultan Qaboos University Hospital or the National Hematology and BMT Center between 2018 and 2025. Only patients with at least six months of follow-up were included. Clinical variables, laboratory results, dosing information, and data on treatment responses and toxicities were extracted. Outcomes focused on spleen size changes, symptom improvement, hematologic responses, adverse events, and reasons for treatment discontinuation. Results: Twenty-eight patients were included (71% PMF; mean age 52.6 years). The median time from diagnosis to RUX initiation was 28 months. Among MF patients, mean spleen size decreased by 35% (p = 0.003); 28% achieved ≥35% reduction. Symptomatic improvement was reported by 60%. LDH levels remained unchanged. PV patients showed spleen control in 75% and symptom benefit in all cases, while ET responses were limited. Cytopenias (21%) and infections (11%) were the most common toxicities; discontinuation occurred in 8/28 of patients, and two patients died while on therapy. Initial dosing was frequently inappropriate, particularly underdosing in MF and overdosing in PV. Conclusions: RUX provided meaningful spleen and symptom improvement in MF and PV; however, toxicity, delayed initiation, and inconsistent dosing practices limited overall outcomes. Enhanced guideline-based dosing, proactive toxicity management, and structured multidisciplinary follow-up are essential to optimize RUX use in regional MPN practice. Full article

Background and Clinical Significance: Polycythemia vera (PV) is a myeloproliferative neoplasm associated with a markedly increased risk of arterial and venous thrombosis. Superior mesenteric artery (SMA) thrombosis is an exceptionally rare but potentially fatal complication. Case Presentation: We report the case of a 25-year-old man with previously diagnosed, JAK2-negative PV who presented with acute abdominal pain, nausea, vomiting, abdominal distension, and absence of stool and flatus, consistent with clinical features of intestinal obstruction. Laboratory testing revealed marked leukocytosis, elevated inflammatory markers, and subtherapeutic anticoagulation (INR 1.2) despite ongoing oral therapy. Multislice computed tomography demonstrated occlusion of the SMA with developed collateral circulation and features of small-bowel ischemia. Due to progression to an acute abdomen, emergency laparotomy was performed, revealing jejunal perforation with preserved viability of the remaining bowel. Primary closure was carried out, followed by peritoneal lavage and drainage. The postoperative course was uneventful. After correction of anticoagulation and therapeutic INR monitoring, no recurrent thrombotic events were observed during follow-up. Conclusions: This case underscores the importance of strict anticoagulation control, early imaging, and prompt surgical intervention in patients with PV, even in young individuals and in atypical vascular territories. Full article

Background and Clinical Significance: Polycythemia vera is a myeloproliferative neoplasm associated with a high thrombotic risk. Although this association is well recognized, acute coronary syndrome as the initial manifestation of polycythemia vera is rare. Case Presentation: We report the case of a previously healthy 57-year-old male with no conventional cardiovascular risk factors who presented with an anterior ST-elevation myocardial infarction. Coronary angiography revealed a subocclusive lesion in the left anterior descending artery, which was successfully treated with primary percutaneous coronary intervention. Initial laboratory testing showed markedly elevated hemoglobin (209 g/L) and hematocrit (64.9%), together with thrombocytosis (438 × 10⁹/L). In the absence of conventional risk factors, the combination of a single-vessel coronary lesion and marked hematologic abnormalities raised suspicion for polycythemia vera as a major contributor to coronary thrombosis. Subsequent work-up confirmed polycythemia vera based on the presence of a JAK2 V617F mutation and suppressed erythropoietin levels. The patient underwent therapeutic phlebotomy shortly after angioplasty and was subsequently started on hydroxyurea to maintain a hematocrit below 45%, together with dual antiplatelet therapy. Conclusions: This case highlights acute myocardial infarction as a rare initial presentation of polycythemia vera. It underscores the importance of considering polycythemia vera in patients presenting with acute coronary syndrome and unexplained erythrocytosis, while acknowledging that, in the absence of intracoronary imaging, a definitive causal link between PV and the coronary event cannot be established. Full article

Background: The prevalence and the prognostic impact of chronic obstructive pulmonary disease (COPD) and asthma in patients with myeloproliferative neoplasms (MPNs) are unknown. Methods: This retrospective multicenter cohort analyzed the prevalence and prognostic implications of COPD and asthma in 246 patients with essential thrombocythemia (ET) and polycythemia vera (PV). Results: A total of 6.5% and 1.6% patients had COPD or asthma, respectively, without statistically significant differences with respect to disease phenotype. The presence of COPD/asthma was more frequently associated with active/prior smoking (p = 0.021) and constitutional symptoms (p = 0.001). After the median follow-up of 47.5 months, the presence of COPD/asthma was univariately associated with an inferior time to thrombosis (TTT; median 135 vs. 190 months, 95% confidence interval (CI) 1.8–29.5, hazard ratio-HR 7.75, p = 0.005), mainly driven by venous (HR 37.3, 95% CI 3.2–43.6, p = 0.003) and not arterial events (HR 1.77, 95% CI 0.40–7.78, p = 0.445, p = 0.445). Statistically significant interactions existed between COPD/asthma, female sex (HR 3.94, 95% CI 1.01–11.02), ET phenotype (HR 7.1, 95% CI 15.3–16.7), JAK2 positive status (HR 4.17, 95% CI 1.04–6.9), hydroxyurea use (HR 4.67, 95% CI 1.10–7.43), and the presence of other cardiovascular risk factors (HR 8.1, 95% CI 1.55–10.72) with overall thrombotic risk (interaction p < 0.050 for all analyses). Finally, the negative effect of COPD/asthma on TTT persisted in the multivariate analysis (HR 6.54, p = 0.010) independently of older (>60 years) age (p = 0.030) when being adjusted for other clinically meaningful variables. There was no effect of COPD/asthma on overall survival. Conclusions: These results provide an important signal regarding the potentially inferior outcomes in ET/PV patients presenting with these common respiratory disorders and may help to further personalize MPN management. Full article

Leukemia stem cells (LSCs) in numerous hematologic malignancies are generally believed to be responsible for disease initiation, progression/relapse and resistance to chemotherapy. It has been shown that non-leukemic hematopoietic cells are affected molecularly and biologically by leukemia cells in the same bone marrow environment where both non-leukemic hematopoietic stem cells (HSCs) and LSCs reside. We believe the molecular and biological changes of these non-leukemic HSCs should be accompanied by the morphological changes of these cells. On the other hand, the quantity of these non-leukemic HSCs with morphological changes should reflect disease severity, prognosis and therapy responses. Thus, identification of non-leukemic HSCs in the leukemia bone marrow environment and monitoring of their quantity before, during and after treatments will potentially provide valuable information for correctly handling treatment plans and predicting outcomes. However, we have known that these morphological changes at the stem cell level cannot be extracted and identified by microscopic visualization with human eyes. In this study, we chose polycythemia vera (PV) as a disease model (a type of human myeloproliferative neoplasms derived from a hematopoietic stem cell harboring the JAK2V617F oncogene) to determine whether we can use artificial intelligence (AI) deep learning to identify and quantify non-leukemic HSCs obtained from bone marrow of JAK2V617F knock-in PV mice by analyzing single-cell images. We find that non-JAK2V617F-expressing HSCs are distinguishable from LSCs in the same bone marrow environment by AI with high accuracy (>96%). More importantly, we find that non-JAK2V617F-expressing HSCs from the leukemia bone marrow environment of PV mice are morphologically distinct from normal HSCs from a normal bone marrow environment of normal mice by AI with an accuracy of greater than 98%. These results help us prove the concept that non-leukemic HSCs undergo AI-recognizable morphological changes in the leukemia bone marrow environment and possess unique morphological features distinguishable from normal HSCs, providing a possibility to assess therapy responses and disease prognosis through identifying and quantitating these non-leukemic HSCs in patients. Full article

Objective: This study investigated the prevalence of arterial stiffness among individuals diagnosed with myeloproliferative neoplasms (MPNs), specifically essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Methods: We performed a cross-sectional study at Chiang-Mai University Hospital, Thailand, defining arterial stiffness as a mean cardio-ankle vascular index (CAVI) ≥8.0. Patients were compared to age-, sex-, and Thai cardiovascular (CV) risk score-matched controls with CV risk factors. Additional outcomes included the 10-year CV risk in MPN patients, estimated by the Thai CV risk score, and the correlation between plasma C-reactive protein (CRP) levels and CAVI. Results: Eighty participants were included (50 with PV, 24 with ET, 6 with PMF; median age: 63.5 years). Arterial stiffness was present in 63.8% of MPN patients overall, with respective rates for ET, PV, and PMF being 70.8%, 60.0%, and 66.7% (p = 0.655). When compared to matched non-MPN controls with CV risk, prevalence of arterial stiffness did not differ significantly (65.2% vs. 60.9%, p = 0.539). The median estimated 10-year CV risk for patients with MPNs was 13.6% (range 0.7–30.0). No significant association was observed between CRP levels and mean CAVI (R = 0.208, p = 0.073). Conclusions: Arterial stiffness was detected in 63.8% of individuals with MPNs, a prevalence like that of matched non-MPN patients with CV risk factors. Full article

Myeloproliferative neoplasms (MPNs) encompass three principal subtypes: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These hematologic malignancies originate from clonal hematopoietic stem cells (HSCs) and exhibit pathological overproduction of myeloid lineage cells. Recent advances in molecular diagnostics, particularly the precise detection of core driver mutations (JAK2 V617F, CALR, and MPL) and non-driver mutations (ASXL1, TET2, SRSF2), has refined diagnostic precision and risk stratification. A variety of prognostic models for MPNs provide guidance for treatment. Treatment methods mainly include bloodletting therapy, low-dose aspirin anticoagulant therapy, cytoreductive therapy, and allogeneic hematopoietic stem cell transplantation (HSCT). JAK inhibitors (such as ruxolitinib) remain the basic therapeutic drugs. However, emerging strategies targeting epigenetic dysregulation and the interaction in the immune microenvironment (such as interferon-α) show promise in reducing drug resistance. New methods, including combination therapy (combination of JAK inhibitors and BCL-XL inhibitors) and mutation-independent immunotherapy, are under investigation. This review summarizes the latest advancements in the diagnosis and treatment of MPNs, highlighting the importance of molecular mechanisms in guiding therapeutic approaches and the potential for precision medicine in the future. Full article