Search Results (53)

(1) Background: Chronic myeloid leukemia (CML) is a myeloproliferative disorder driven by the BCR::ABL oncoprotein. During the chronic phase, Philadelphia chromosome-positive hematopoietic stem cells generate proliferative myeloid cells with various stages of maturation. Despite this expansion, leukemic stem cells (LSCs) retain self-renewal capacity via asymmetric cell divisions, sustaining the stem cell pool. Quiescent LSCs are known to be resistant to tyrosine kinase inhibitors (TKIs), potentially through BCR::ABL-independent signaling pathways. We hypothesize that dysregulation of genes governing asymmetric division in LSCs contributes to disease progression, and that their expression pattern may serve as a prognostic marker during the chronic phase of CML. (2) Methods: Genes related to asymmetric cell division in the context of hematopoietic stem cells were extracted from the PubMed database with the keyword “asymmetric hematopoietic stem cell”. The collected relative gene set was tested on two independent bulk transcriptome cohorts and the results were confirmed by single-cell RNA sequencing. (3) Results: The expression of genes involved in asymmetric hematopoietic stem cell division was found to discriminate disease phases during CML progression in the two independent transcriptome cohorts. Concordance between cohorts was observed on asymmetric molecules downregulated during blast crisis (BC) as compared to the chronic phase (CP). This downregulation during the BC phase was confirmed at single-cell level for SELL, CD63, NUMB, HK2, and LAMP2 genes. Single-cell analysis during the CP found that CD63 is associated with a poor prognosis phenotype, with the opposite prediction revealed by HK2 and NUMB expression. The single-cell trajectory reconstitution analysis in CP samples showed CD63 regulation highlighting a trajectory cluster implicating HSPB1, PIM2, ANXA5, LAMTOR1, CFL1, CD52, RAD52, MEIS1, and PDIA3, known to be implicated in hematopoietic malignancies. (4) Conclusion: Regulation of CD63, a tetraspanin involved in the asymmetric division of hematopoietic stem cells, was found to be associated with poor prognosis during CML progression and could be a potential new therapeutic target. Full article

Background: Myeloproliferative neoplasms (MPN), a group of chronic hematologic neoplasms, are driven by inflammatory mechanisms that influence disease initiation and progression. Emerging evidence highlights the gut microbiome and plasma metabolome as pivotal immunomodulators, yet their causal roles in MPN pathogenesis remain uncharacterized. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to systematically evaluate causal relationships between 196 gut microbial taxa, 526 plasma metabolites, and MPN risk. Instrumental variables were derived from genome-wide association studies (GWASs) of microbial/metabolite traits. Validation utilized 16S rRNA sequencing data from NCBI Bioproject PRJNA376506. Mediation and multivariable MR analyses elucidated metabolite-mediated pathways linking microbial taxa to MPN. Results: Our MR analysis revealed that 7 intestinal taxa and 17 plasma metabolites are causally linked to MPN. External validation confirmed the three taxa’s differential abundance in MPN cohorts. Mediation analysis revealed two mediated relationships, of which succinylcarnitine mediated 14.5% of the effect, and lysine 27.9%, linking the Eubacterium xylanophilum group to MPN. Multivariate MR analysis showed that both succinylcarnitine (p = 0.004) and lysine (p = 0.040) had a significant causal effect on MPN. Conclusions: This study identifies novel gut microbiota–metabolite axes driving MPN pathogenesis through immunometabolic mechanisms. The validated biomarkers provide potential therapeutic targets for modulating inflammation in myeloproliferative disorders. 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

Malignant hematologic diseases, also referred to as hematologic tumors, encompass a series of malignant proliferative disorders of the lymphopoietic system, including leukemia, lymphoma, multiple myeloma, and myeloproliferative neoplasms. The dysregulation of inflammatory factors or chronic inflammatory responses plays an indispensable role in the onset and progression of these tumors. The C-X-C motif chemokine receptor (CXCR) serves as a key mediator of immune-inflammatory responses. Through its specific regulatory mechanisms, CXCR is involved in the transduction and activation of various signaling pathways, thereby mediating the malignant biological characteristics of blood tumor cells, such as uncontrolled proliferation, differentiation, invasion, migration, autophagy, and apoptosis. In the bone marrow microenvironment, CXCR plays a pivotal role. This review systematically analyzes and elucidates the roles and mechanisms of the CXCR family in hematologic malignancies, aiming to provide new insights into the biological mechanisms and clinical significance of these diseases. The CXCR family holds great potential as a molecular marker for both fundamental research and the clinical diagnosis and treatment of hematologic malignancies. Full article

Hydroxyurea (HU), a cornerstone treatment for myeloproliferative disorders, is associated with a wide range of cutaneous side effects, from xerosis and hyperpigmentation to more severe conditions like dermatomyositis-like eruptions (DM-LE) and nonmelanoma skin cancers (NMSC), particularly squamous cell carcinoma (SCC). In this review, we present a unique case of HU-induced DM-LE with histological evidence of keratinocyte dysplasia and p53 overexpression, followed by a systematic analysis of similar cases. Our findings reveal that the clinical presentation of DM-LE, while typically considered benign, shares clinical and histological features with hydroxyurea-associated squamous dysplasia (HUSD), a precancerous condition that may progress to SCC in chronically exposed patients. Key insights include the characteristic histopathological findings of DM-LE, the role of chronic HU therapy and UV-induced damage in promoting p53 overexpression, and the overlap between DM-LE and HUSD. Regular dermatologic monitoring, patient education on photoprotection, and the careful assessment of skin lesions in long-term HU users are essential for the early detection and prevention of malignancies. This review underscores the importance of distinguishing between DM-LE, HUSD, and SCC to optimize management and minimize risks associated with HU therapy. 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

Erythroleukemia, a complex myeloproliferative disorder presenting as acute or chronic, is characterized by aberrant proliferation and differentiation of erythroid cells. Although nootkatone, a sesquiterpene derived from grapefruit peel and Alaska yellow cedar, has shown anticancer activity predominantly in solid tumors, its effects in erythroleukemia remain unexplored. This study aimed to investigate the impact of nootkatone and its derivatives on erythroleukemia. Our results demonstrate that the nootkatone derivative nootkatone-(E)-2-iodobenzoyl hydrazone (N2) significantly inhibited erythroleukemia cell proliferation in a concentration- and time-dependent manner. More importantly, N2 induced megakaryocytic differentiation, as evidenced by significant morphological changes, and upregulation of megakaryocytic markers CD41 and CD61. In vivo, N2 treatment led to a marked increase in platelet counts and megakaryocytic cell counts. Mechanistically, N2 activated a crosstalk between the JAK2/STAT3 and PKCδ/MAPK signaling pathways, enhancing transcriptional regulation of key factors like GATA1 and FOS. Network pharmacology and experimental validation confirmed that N2 targeted JAK2, and knockdown of JAK2 abolished N2-induced megakaryocytic differentiation, underscoring JAK2’s critical role in erythroleukemia differentiation. In conclusion, N2 shows great promise as a differentiation therapy for erythroleukemia, offering a novel approach by targeting JAK2-mediated signaling pathways to induce megakaryocytic differentiation. Full article

Background: Chronic Myelomonocytic Leukemia (CMML) is a rare and aggressive form of leukemia with characteristics of both myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDSs). This study aims to explore the clinical features, survival outcomes, and prognostic factors in CMML patients over the past 20 years using a large sample. Methods: The study data from 4124 patients diagnosed with CMML between 2000 and 2017 were sourced from the SEER database. Demographic and clinical characteristics, along with overall and cancer-specific mortality, were examined. Factors with a p-value < 0.01 in univariate Cox regression were included in the multivariate Cox model to identify independent prognostic factors, with hazard ratios (HRs) greater than one indicating adverse outcomes. Results: The majority of the cohort were male (61.57%), and most diagnoses occurred between ages 60–79 (55.16%), with a small percentage under 40 (1.41%). Non-Hispanic whites represented the largest racial group (79.03%). Multivariate analysis showed higher mortality in males, those aged 80+, residents in metropolitan areas with populations between 250,000 and 1 million, single or widowed individuals, and those who underwent chemotherapy. Conversely, lower mortality was associated with an annual income of $75,000+. Conclusions: CMML remains a rare and highly aggressive hematologic disorder. This U.S.-based retrospective cohort study identified male gender, advanced age, single or widowed status, and chemotherapy as independent poor prognostic factors. While it is expected that older patients and those requiring chemotherapy would have a poorer prognosis, the higher mortality risk in single or widowed patients, as well as males, warrants further investigation. The early involvement of family and community support may help reduce mortality in these groups, suggesting a need for larger prospective studies to explore these associations further. Full article

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. Full article

Myeloproliferative neoplasms (MPNs), namely, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal stem cell disorders defined by an excessive production of functionally mature and terminally differentiated myeloid cells. MPNs can transform into secondary acute myeloid leukemia (sAML/blast phase MPN) and are linked to alterations in the redox balance, i.e., elevated concentrations of reactive oxygen species and markers of oxidative stress (OS), and changes in antioxidant systems. We evaluated OS in 117 chronic phase MPNs and 21 sAML cases versus controls by measuring total antioxidant capacity (TAC) and 8-hydroxy-2′-deoxy-guanosine (8-OHdG) concentrations. TAC was higher in MPNs than controls (p = 0.03), particularly in ET (p = 0.04) and PMF (p = 0.01). MPL W515L-positive MPNs had higher TAC than controls (p = 0.002) and triple-negative MPNs (p = 0.01). PMF patients who had treatment expressed lower TAC than therapy-free subjects (p = 0.03). 8-OHdG concentrations were similar between controls and MPNs, controls and sAML, and MPNs and sAML. We noted associations between TAC and MPNs (OR = 1.82; p = 0.05), i.e., ET (OR = 2.36; p = 0.03) and PMF (OR = 2.11; p = 0.03), but not sAML. 8-OHdG concentrations were not associated with MPNs (OR = 1.73; p = 0.62) or sAML (OR = 1.89; p = 0.49). In conclusion, we detected redox imbalances in MPNs based on disease subtype, driver mutations, and treatment history. Full article

Chronic myeloid leukemia (CML) is an oncological myeloproliferative disorder that accounts for 15 to 20% of all adult leukemia cases. The molecular basis of this disease lies in the formation of a chimeric oncogene BCR–ABL1. The protein product of this gene, p210 BCR–ABL1, exhibits abnormally high constitutive tyrosine kinase activity. Over recent decades, several targeted tyrosine kinase inhibitors (TKIs) directed against BCR–ABL1 have been developed and introduced into clinical practice. These inhibitors suppress BCR–ABL1 activity through various mechanisms. Furthermore, the advent of RNA interference technology has enabled the highly specific inhibition of BCR–ABL1 transcript expression using small interfering RNA (siRNA). This experimental evidence opens avenues for the development of a novel therapeutic strategy for CML, termed siRNA therapy. The review delves into molecular genetic mechanisms underlying the pathogenesis of CML, challenges in CML therapy, potential molecular targets for drug development, and the latest results from the application of siRNAs in in vitro and in vivo CML models. Full article

Background: Sjögren’s disease (SjD) is a common systemic autoimmune disease that affects mainly women. Key pathologic features include the infiltration of exocrine glands by lymphocytes and the activation of B lymphocytes with the production of autoantibodies. We aimed to analyze the transcriptome of circulating B cells from patients with SJD and healthy controls to decipher the B-cell-specific contribution to SJD. Methods: RNA from peripheral blood B cells of five untreated female patients with SjD and positive ANA, positive anti-SSA (both Ro-52 and Ro-60), positive anti-SSB and positive rheumatoid-factor, and five healthy controls was subjected to whole-transcriptome sequencing. A false discovery rate of < 0.1 was applied to define differentially expressed genes (DEG). Results: RNA-sequencing identified 56 up and 23 down DEG. Hierarchal clustering showed a clear separation between the two groups. Ingenuity pathway analysis revealed that these genes may play a role in interferon signaling, chronic mycobacterial infection, and transformation to myeloproliferative disorders. Conclusions: We found upregulated expression of type-I and type-II interferon (IFN)-induced genes, as well as genes that may contribute to other concomitant conditions, including infections and a higher risk of myeloproliferative disorders. This adds insight into the autoimmune process and suggests potential targets for future functional and prognostic studies. Full article

Background: Philadelphia-negative chronic myeloproliferative neoplasms are a group of clonal hematopoietic disorders including polycythemia vera, essential thrombocythemia, and primary myelofi-brosis. These neoplasms are characterized by an increased risk of thrombotic complications. Several studies have highlighted that the study of vessels of the retina offers the opportunity to visualize, in vivo, the damage to microcirculation that is common in various systemic pathologies. Methods: in our study, forty patients underwent an ophthalmological examination, using non-invasive imaging tech-niques, for analyses of their retinal vascularization. The objective was to correlate the findings ob-tained from this study of the retina with different markers of thrombotic risk, to demonstrate the usefulness of studying retinal vessels as a possible new prognostic biomarker of thrombotic risk in patients affected by Philadelphia-negative chronic myeloproliferative neoplasms. Results: retinal imaging demonstrated changes in the microcirculation, with a reduced vascular density of the deep and superficial capillary plexuses with respect to a normal group, and a correlation between retinal changes and blood parameters. Conclusions: additional research will allow us to determine whether retinal changes in individuals with chronic myeloproliferative neoplasms could be predictive of the development of thrombotic events in these subjects. Full article

Background: Portal vein thrombosis (PVT) is a rare disease with an estimated incidence of 2 to 4 cases per 100,000 inhabitants. The most common predisposing conditions for PVT are chronic liver diseases (cirrhosis), primary or secondary hepatobiliary malignancy, major infectious or inflammatory abdominal disease, or myeloproliferative disorders. Methods: PVT can be classified on the basis of the anatomical site, the degree of venous occlusion, and the timing and type of presentation. The main differential diagnosis of PVT, both acute and chronic, is malignant portal vein invasion, most frequently by hepatocarcinoma, or constriction (typically by pancreatic cancer or cholangiocarcinoma). Results: The management of PVT is based on anticoagulation and the treatment of predisposing conditions. The aim of anticoagulation in acute thrombosis is to prevent the extension of the clot and enable the recanalization of the vein to avoid the development of complications, such as intestinal infarction and portal hypertension. Conclusions: The treatment with anticoagulant therapy favors the reduction of portal hypertension, and this allows for a decrease in the risk of bleeding, especially in patients with esophageal varices. The anticoagulant treatment is generally recommended for at least three to six months. Prosecution of anticoagulation is advised until recanalization or lifelong if the patient has an underlying permanent pro-coagulant condition that cannot be corrected or if there is thrombosis extending to the mesenteric veins. Full article

Myeloid neoplasms and acute leukemias include different entities that have been recently re-classified taking into account molecular and clinicopathological features. The myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) category comprises a heterogeneous group of hybrid neoplastic myeloid diseases characterized by the co-occurrence of clinical and pathological features of both myelodysplastic and myeloproliferative neoplasms. The most frequent entity in this category is chronic myelomonocytic leukemia (CMML) which is, after acute myeloid leukemia (AML), the main myeloid disorder prone to develop cutaneous manifestations. Skin lesions associated with myelodysplastic and myeloproliferative neoplasms include a broad clinical, histopathological and molecular spectrum of lesions, poorly understood and without a clear-cut classification in the current medical literature. The aim of this review is to describe and classify the main clinical, histopathological and molecular patterns of cutaneous lesions in the setting of MDS/MPN in order to improve the diagnostic skills of the dermatologists, hematologists and pathologists who deal with these patients. Full article