Search Results (147)

Background/Objectives: Erythrocytosis is a common laboratory abnormality affecting approximately 4% of males and 0.4% of females. The JAKPOT score was recently developed to differentiate primary from secondary erythrocytosis without molecular testing. JAKPOT+ patients meet any of the following criteria: erythrocytes > 6.45 × 1012/L, platelets > 350 × 109/L, or neutrophils > 6.2 × 109/L. We aimed to validate this score and identify predictors of JAK2-positive erythrocytosis in a retrospective cohort. Methods: We identified 213 patients (50 female, mean age 57 years) with undifferentiated erythrocytosis, serum erythropoietin (EPO) and JAK2 molecular testing (V617F or exon 12) at a tertiary care center in Hamilton, Canada, between 2017 and 2022. Charts were manually reviewed for laboratory data, comorbidities, demographics, and medications. We evaluated the diagnostic accuracy of EPO, JAKPOT, and a combination of low EPO and JAKPOT (EPO-JAKPOT) for predicting JAK2 mutant erythrocytosis. Multivariate logistic regression analysis was performed to detect predictors of JAK2 mutant erythrocytosis. Results: Forty patients (19%) had JAK2 mutations. Older age (p < 0.01), higher platelet count (p < 0.01), and lower EPO (p < 0.01) were associated with JAK2 mutant erythrocytosis in a multivariate analysis. JAKPOT+ status had a sensitivity of 0.88 (95% CI, 0.73–0.94). Combining low EPO or JAKPOT+ status into a new score (EPO-JAKPOT) increased sensitivity to 0.95 (95% CI, 0.83–0.98). Restricting JAK2 testing to only EPO-JAKPOT+ patients would have led to 55% fewer molecular tests in our cohort. Conclusions: The EPO-JAKPOT score shows promise in excluding JAK2 mutant erythrocytosis without molecular testing, but further prospective validation is warranted. Full article

Classical BCR-ABL-negative myeloproliferative neoplasms are a heterogeneous group of hematologic malignancies, including essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Monocytes, immune cells derived from hematopoietic stem cells, exhibit significant heterogeneity and contribute to immune regulation through cytokine secretion and differentiation into dendritic cells and macrophages. Aberrant monocytes are associated with the prognosis of MPNs, particularly PMF. Furthermore, these altered monocytes play a critical role in the pathogenesis and progression of MPNs. This review aims to explore the heterogeneity of different monocyte subsets during homeostasis and focuses on the potential mechanisms by which monocytes contribute to the development and progression of MPNs. Full article

Hepatosplenomegaly can occur in extrahepatic diseases such as Philadelphia-negative chronic myeloproliferative neoplasms (MPNs), which may involve the liver and vasculature. In myelofibrosis, extramedullary hematopoiesis can be present in the liver, even within hepatic sinusoids. Liver biopsies in MPN patients have shown platelet aggregates obstructing these sinusoids. Both liver and spleen stiffness are significantly higher in myelofibrosis, correlating with the severity of bone marrow fibrosis. Spleen stiffness is also elevated in myelofibrosis and polycythemia Vera compared to essential thrombocythemia. MPNs are a leading cause of splanchnic vein thrombosis in the absence of cirrhosis or local malignancy, especially in the presence of the JAK2V617F mutation. This mutation promotes thrombosis through endothelial dysfunction and inflammation. It is found in endothelial cells, where it enhances leukocyte adhesion and upregulates thrombogenic and inflammatory genes. Hepatic sinusoidal microthromboses in MPNs may contribute to portal hypertension and liver dysfunction. MPN therapies can also affect liver function. While hepatocytolysis has been reported, agents such as Hydroxycarbamide and Ruxolitinib exhibit antifibrotic hepatic effects in experimental models. Overall, MPNs are linked to chronic inflammation, increased thrombotic risk—particularly splanchnic thrombosis—and atherogenesis. Full article

Myeloproliferative neoplasms, particularly the Philadelphia chromosome-negative (Ph-negative) subtypes such as essential thrombocythemia, polycythemia vera, and primary myelofibrosis, present diagnostic challenges due to overlapping morphological features and clinical heterogeneity. Traditional diagnostic approaches, including imaging and histopathological analysis, are often limited by interobserver variability, delayed diagnosis, and subjective interpretations. To address these limitations, we propose a novel framework that integrates handcrafted and automatic feature extraction techniques for improved classification of Ph-negative myeloproliferative neoplasms. Handcrafted features capture interpretable morphological and textural characteristics. In contrast, automatic features utilize deep learning models to identify complex patterns in histopathological images. The extracted features were used to train machine learning models, with hyperparameter optimization performed using Optuna. Our framework achieved high performance across multiple metrics, including precision, recall, F1 score, accuracy, specificity, and weighted average. The concatenated probabilities, which combine both feature types, demonstrated the highest mean weighted average of 0.9969, surpassing the individual performances of handcrafted (0.9765) and embedded features (0.9686). Statistical analysis confirmed the robustness and reliability of the results. However, challenges remain in assuming normal distributions for certain feature types. This study highlights the potential of combining domain-specific knowledge with data-driven approaches to enhance diagnostic accuracy and support clinical decision-making. Full article

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow. These disorders arise from acquired genetic driver mutations, with or without underlying genetic predispositions, resulting in the uncontrolled production of red blood cells, white blood cells, or platelets. The excessive cell production and abnormal signaling from driver mutations cause chronic inflammation and a higher risk of blood clots and vascular complications. The primary goals of MPN treatment are to induce remission, improve quality of life and survival, as well as to reduce the risk of complications such as thrombosis, vascular events, and leukemic transformation. This review provides a comprehensive update on the diagnosis and therapeutic advancements in major MPN subtypes, including chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It examines these complex diseases from a molecular and evolutionary perspective, highlighting key clinical trials’ long-term follow-up and therapies targeting driver mutations that have transformed treatment strategies. Additionally, several important advancements in addressing challenges such as anemia in myelofibrosis, along with promising emerging therapies, are also discussed. Full article

Erythropoiesis is increased in polycythemia vera (PV), with proliferation of erythroid precursors, and macrophages from erythroblastic islands play a key role in this process. Circulating monocytes were shown to perform some of the macrophage’s functions in normal conditions, but their participation during stress erythropoiesis, as in PV, is yet to be determined. In this study, we evaluated the monocytes from the blood of healthy donors or PV patients regarding their phenotype, involvement in the clearance of erythroid cells, and their expression of iron-related molecules. We showed that circulating monocytes from PV patients contained red blood cell-derived material, which correlated with a reduction in Sirp-ɑ expression, indicating that they play a role in erythroid cell clearance in PV. Both PV monocytes and PV erythroid cells seem to influence the increase in erythrophagocytosis. The enhanced expression of heme-oxygenase-1 and ferroportin post-phagocytosis suggests their capability for heme degradation and externalization of residual iron. Moreover, PV monocytes presented higher expression of CD169, CD163, and VCAM-1, which are involved with erythroid adhesion, and they influenced in vitro erythroid cell line differentiation, suggesting that they may interfere with erythropoiesis in PV. Our findings highlight the similarities between PV monocytes and macrophages of erythroblastic islands. These insights contribute to a deeper understanding of erythrophagocytosis and erythropoiesis in the disease, offering new perspectives for advances in the field. Full article

Translational control is crucial for maintaining cellular homeostasis, yet the distinct features and regulatory requirements governing protein synthesis during erythropoiesis remain unclear. Here, we reveal that erythroid cells exhibit an extraordinarily high demand for protein synthesis, which is required for their differentiation but also implies the need for tight regulation to prevent excessive erythropoiesis. Notably, we identify significant phosphorylation of eukaryotic elongation factor 2 (eEF2) at threonine 56 during erythroid differentiation, which reduces protein synthesis and acts as a molecular brake to limit unchecked erythropoiesis. This is evidenced by elevated red blood cell counts in peripheral blood and increased incidence of blood hyperviscosity and thrombosis in eEF2_T56M mice, which are deficient in eEF2 phosphorylation. Mechanistic studies demonstrate that eEF2 phosphorylation selectively regulates the translation of a subset of proteins, including NFE2, which partially mediates the effects of eEF2 modification. Collectively, our findings highlight a previously unappreciated role for translational control in achieving efficient and balanced erythropoiesis, with eEF2 phosphorylation serving as a critical protective mechanism against hyperactive erythropoiesis and offering a potential therapeutic target for hematologic disorders such as polycythemia vera. Full article

The Janus kinase 2 (JAK2) protein fulfills an important role in hematopoiesis via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, as it provides the genetic driver of BCR::ABL1-negative myeloproliferative neoplasms (MPNs), which are clinically manifested as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The most common cause of MPNs is the mutation of JAK2 V617F in the JAK2 gene, which results in increased cell proliferation. However, both the pathogenesis and treatment regimen of BCR::ABL1-negative MPNs remain poorly understood. The aim of the present study was to establish K562 cell lines with a point mutation in exon 14 (JAK2p.V617F) using CRISPR/Cas9 technology. The modified JAK2 V617F cell lines were examined for the gene mutation using droplet digital PCR (DDPCR), and the presence of the mutation was confirmed by DNA sequencing. Modified cells were characterized by measuring JAK2 gene expression and the extent of cell proliferation. Interferon α2a (IFN-α2a) and arsenic trioxide were also administered to the cells to explore their potential effects. The JAK2 V617F-mutated cells were found to exhibit a higher level of JAK2 gene expression compared with the wild type. Interestingly, a significant increase in the proliferation rate was observed with the modified cells compared with the wild type cells (p < 0.001), as assessed from the JAK2 gene expression levels. Furthermore, the treatments with IFN-α2a and arsenic trioxide led to the preferential suppression of the cell proliferation rate of the K562 expressing mutant JAK2 cells compared with the wild type cells, and this suppression occurred in a dose-dependent manner(p < 0.01). Moreover, the modified cells were able to differentiate into megakaryocyte-like cells following stimulation with phorbol 12 myristate 13 acetate (PMA). Taken together, the results of the present study have shown that the CRISPR/Cas9-modified JAK2 V617F model may be used as a disease model in the search of novel therapies for MPNs. Full article

Background/Objectives: Overt primary myelofibrosis (PMF), secondary post-polycythemia vera (post-PV), and post-essential thrombocythemia (post-ET) myelofibrosis (SMF) are chronic myeloproliferative neoplasms (MPN) that sometimes present with extreme thrombocytosis (ExTh, platelet count > 1000 × 10⁹/L), a phenomenon of uncertain clinical significance since there are no published data available. Methods: We retrospectively investigated the clinical correlations and associated outcomes of ExTh in a cohort of 172 patients with overt myelofibrosis diagnosed in six Croatian hematology centers. Results: ExTh was present in 5.8% of patients and was associated with post-ET etiology of myelofibrosis, older age, smaller spleen size, and the presence of arterial hypertension (p < 0.05 for all analyses). No significant associations were observed with sex, degree of bone marrow fibrosis, or driver mutation status. Over the follow-up period, patients with ExTh experienced a favorable course regarding survival (p < 0.001) and bleeding risk (p = 0.034), whereas no significant association with thrombotic risk was observed (p = 0.682). Conclusions: In contrast to its context in ET, ExTh in overt fibrotic MPN does not appear to confer higher bleeding or thrombotic risk. Instead, it is associated with more favorable survival outcomes and reduced bleeding risk. Full article

Janus kinase 2 (JAK2) is an important intracellular mediator of cytokine signaling. Mutations in the JAK2 gene are associated with myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV) and essential thrombocythemia (ET), while aberrant JAK2 activity is also associated with a number of immune diseases. The acquired somatic mutation JAK2 V617F (95% of cases of PV and in 55–60% of cases of ET), which constitutively activates the JAK2, is the most common molecular event in MPN. The development of specific JAK2 inhibitors is therefore of considerable clinical importance. Ruxolitinib is a JAK inhibitor recently approved by the FDA/EMA and effective in relieving symptoms in patients with MPN. Ruxolitinib binds to the JAK2 last domain, namely JH1; its action on the dynamics of the domain is still only partially known. Using Molecular Dynamics simulations, we have analyzed the JH1 domain in four different states as follows: (i) alone, (ii) with one phosphorylation, (iii) adding Ruxolitinib, and (iv) with five phosphorylations and Ruxolitinib. The ligand induces a dynamic behavior similar to the inactive form of JH1, with a less flexible state than the phosphorylated active form of JH1. This study highlights the inhibitory effect of Ruxolitinib on the JH1 domain, demonstrating the importance of dynamics in regulating JH1 activation. Full article

Myeloproliferative neoplasms are clonal hematological neoplasms characterized by excessive proliferation of cells of erythroid, granulocytic, and megakaryocytic lineage. The genetic mechanisms underlying this group of blood diseases are now known, but new perspectives have recently emerged in the field of epigenetics and particularly related to the possible role of DNA methylation in disease development and progression. DNA methylation regulates different cellular processes, such as proliferation, differentiation, and apoptosis. In myeloproliferative neoplasms, a link has been found between abnormal methylation patterns, such as hypermethylation of tumor suppressors or, conversely, oncogenes hypomethylation, with the progression of the disease, spreading important prognostic and therapeutic implications. This review aims to investigate the relationship between methylation alterations and myeloproliferative neoplasms, emphasizing the ways by which epigenetic dysregulation promotes disease biology. Full article

Background: Hydroxyurea (HU) is a widely used chemotherapeutic agent for myeloproliferative disorders, yet its long-term use can rarely trigger a dermatomyositis-like (DM-like) eruption characterized solely by cutaneous manifestations without muscle involvement or serologic markers. This study presents a case of HU-induced DM-like eruption and reviews the literature regarding this rare occurrence. Methods: A 77-year-old woman with polycythemia vera on long-term HU therapy developed a progressively worsening, erythematous, scaly, and crusted eruption on the face, neck, and anterior thorax. Comprehensive clinical evaluations, laboratory tests (including normal muscle enzymes and negative autoimmune panels), and skin biopsies were performed. In parallel, a systematic literature review was conducted using databases such as PubMed, Scopus, and Google Scholar, incorporating case reports and series published prior to January 2025 that provided detailed individual clinical data. Results: The patient exhibited hallmark DM-like cutaneous features—interface dermatitis with basal vacuolar degeneration and prominent dermal mucin deposition—without evidence of muscle weakness or positive myositis-specific antibodies. The literature review of 23 cases revealed a median latency of 5 years from HU initiation to skin eruption, with the dorsal hands most frequently affected. HU discontinuation, often combined with systemic and topical corticosteroids (and, in some cases, steroid-sparing agents), resulted in lesion resolution in over 90% of cases, with a median healing time of approximately 3 months. Conclusions: HU-induced DM-like eruption, though infrequent, is a distinct clinical entity requiring prompt recognition and management. The main treatment is the discontinuation of HU, which, when supplemented by appropriate corticosteroid therapy, leads to significant clinical improvement. Ongoing dermatologic surveillance is recommended for patients on long-term HU therapy due to the potential risk of premalignant skin changes. Full article

Background/Objectives: Chronic myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are hematopoietic stem cell disorders characterized by increased proliferation of mature myeloid cells, a chronic inflammatory state, and high cardiovascular risk. The diagnostic and therapeutic landscape in the field of MPNs is rapidly evolving. Therefore, it is important to assess the behavior of physicians involved in the management of MPN patients to gain insight into how they embrace the current diagnostic and treatment landscape in real-life settings. Methods: An online anonymous survey consisting of 50 questions regarding their MPN practice and divided into four major domains (physician characteristics, diagnostic procedures, therapeutic decisions, and patient follow-up) was sent through the Croatian Cooperative Group for Hematologic Diseases’ (KROHEM’s) e-mailing list to all Croatian hematologists. Results: Thirty-one out of ninety adult hematologists (34.4% response rate) from KROHEM responded to this survey. There was a very high rate of self-proclaimed abidance to current international diagnostic and therapeutic recommendations, with no major differences among academic and community practices. However, some areas of uncertainty have been highlighted, especially in the frequency of cytogenetic and molecular testing, as well as very low implementation of the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) questionnaire in everyday practice. Conclusions: This study provides an important snapshot of the current MPN practice in Croatia. Similar studies from other countries are needed to provide a more detailed overview of real-life MPN practice globally. Full article

Introduction: Polycythemia is a rare condition that can be either primary or secondary. We report a case of an adolescent with progressive hydronephrosis-induced polycythemia and low erythropoietin levels, along with a thorough literature review. Report of a Case: A 17-year-old girl with epilepsy had progressively elevated hemoglobin levels and low erythropoietin levels. Initial investigations, including genetic surveys and bone marrow studies, showed no evidence of polycythemia vera or myeloproliferative disorders. Further imaging studies revealed severe hydronephrosis on the left side caused by ureteropelvic junction stenosis. Following nephroureterectomy, her hemoglobin levels gradually returned to normal. Conclusions: This case highlights the potential association between hydronephrosis and polycythemia, even with low erythropoietin levels. Renal abnormalities should be considered in the differential diagnosis of pediatric patients with polycythemia, even in the absence of elevation of erythropoietin. Further research is needed to clarify this association and its pathophysiology. Full article

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic cancers characterized by hyperproliferation of the myeloid lineages. These clonal marrow disorders are extremely rare in pediatric patients. MPN is reported to occur 100 times more frequently in adults, and thus research is primarily focused on this patient group. At present, modern diagnostic techniques, primarily genetic, facilitate the identification of the biology of these diseases. The key genes are JAK2, MPL, and CALR, namely, driver mutations, which are present in approximately 90% of patients with suspected MPN. Moreover, there are more than 20 other mutations that affect the development of these hematological malignancies, as evidenced by a review of the literature. The pathogenic mechanism of MPNs is characterized by the dysregulation of the JAK/STAT signaling pathway (JAK2, MPL, CALR), DNA methylation (TET2, DNMT3A, IDH1/2), chromatin structure (ASXL1, EZH2), and splicing (SF3B1, U2AF2, SRSF2). Although rare, myeloproliferative neoplasms can involve young patients and pose unique challenges for clinicians in diagnosis and therapy. The paper aims to review the biological markers of MPNs in pediatric populations—a particular group of patients that has been poorly studied due to the low frequency of MPN diagnosis. Full article