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Introduction: The disruption of the JAK/STAT signaling pathway is a defining feature of myelofibrosis (MF). The introduction of JAK inhibitors (JAKi) has transformed the therapeutic approach to MF, becoming essential to treatment and reshaping the management landscape. While JAKi are now the preferred first-line treatment for most patients, various management options are available for those who do not respond to initial therapy., Areas Covered: This review focuses on management options for patients with MF, with particular emphasis on therapeutic strategies following the failure of first-line JAKi. It provides a comprehensive overview of the current treatment landscape, including alternative JAKi and other approaches. The review is based on an extensive literature search using available databases (PubMed, Cochrane …) and relevant web resources (clinicaltrials.gov)., Expert Opinion: Ruxolitinib benefits in MF often diminish after 3-4 years, with complications like thrombocytopenia and anemia. Three newer JAKi offer alternatives with similar efficacy and varied side effects. Stem cell transplantation is a curative option for a minority, ideally timed at peak response to JAKi. Research aims to enhance first-line treatments and restore responses in resistant patients. Future therapies may include novel combinations or immunotherapies targeting specific mutations, requiring collaboration between patient, clinical, and pharmaceutical communities.

Hepatoid thymic carcinoma (HTC) is an extremely rare variant of primary epithelial tumor of the thymus morphologically resembling hepatocellular carcinoma Herein, we report an additional case of HTC diagnosed in a 40-years-old man affected by polycythemia vera and treated with ropeginterferon alfa 2-b, for the first time deeply analyzing the molecular profile of this distinctive thymic malignancy. By immunohistochemistry, tumor cells were positive for cytokeratin 7-19, GLUT1, and Hep-Par-1, whereas AFP tested negative. Whole exome sequencing revealed loss of function mutations in TP53, STK11, PBRM1, SMAD3, FN1, NTRK1, and FANCD2, as well as gain of function mutations in MTOR, BCL11A and COL1A1, along with amplification of CCND3 and MDM2. This mutational landscape halfway between thymic carcinoma (TP53, PBRM1) and hepatoid variant carcinoma of other sites (STK11) suggests that, at some point during carcinogenesis, a switch occurred from an epithelial thymic phenotype to a hepatoid-like one., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Alessandro Maria Vannucchi reports financial support was provided by Italian Association for Cancer Research. Alessandro Maria Vannucchi reports a relationship with Novartis that includes: consulting or advisory and speaking and lecture fees. Alessandro Maria Vannucchi reports a relationship with Incyte Corporation that includes: consulting or advisory and speaking and lecture fees. Alessandro Maria Vannucchi reports a relationship with AOP Orphan Pharmaceuticals GmbH that includes: consulting or advisory and speaking and lecture fees. All the other authors declare no conflict of interest to report., (Copyright © 2024. Published by Elsevier GmbH.)

Higher neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been associated with increased risk of thrombosis, cardiovascular mortality, but their role in myeloproliferative neoplasms (MPN) remains unclear. We analyzed NLR and PLR as prognostic markers for thrombosis and overall survival (OS) in the study that included 461 consecutive MPN patients who were diagnosed from 2018 to 2022 at University center. Twenty age-matched patients without hematological disorder were used as controls. NLR and PLR were significantly increased in whole MPN group compared to controls. NLR was highest in PV > PMF > ET (p < 0.001) while PLR was highest in ET > PMF > PV (p < 0.001). Thrombosis occurrence during follow-up correlated with NLR, NLR ≥ 4.5, presence of ≥ 2 CV factors and previous thrombosis. Arterial thrombosis was associated with previous thrombosis, NLR and NLR ≥ 4.5. Similarly in venous thrombosis previous thrombosis was risk factor, together with NLR, NLR ≥ 4.5, PLR, but also secondary malignancy and female gender. In multivariate Cox model, most important factors for thrombosis development during follow-up were previous thrombosis, NLR ≥ 4.5 and PLR ≥ 500; for arterial thrombosis, NLR ≥ 4.5 and previous thrombosis; for venous thrombosis PLR ≥ 500 and previous thrombosis. Patients with pre-PMF had significantly higher NLR than ET patients. In multivariate Cox regression model, most important factors associated with survival were NLR ≥ 4.5 and PLR ≥ 500. This study highlights strong prognostic correlation of NLR ≥ 4.5 and PLR ≥ 500 with development of thrombosis and OS in MPN. Besides previous thrombosis, most important factor associated with development of arterial thrombosis is NLR ≥ 4.5 and for venous PLR ≥ 500. Our results revealed that NLR ≥ 4.5 could be used as additional marker to distinguish ET from prePMF., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In previous research, we created a C. elegans model with homozygous mutations in calreticulin similar to those found in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), two myeloproliferative neoplasms (MPNs). This model, lacking JAK orthologs, enabled us to examine the transcriptomic effects caused by mutant calreticulin without the influence of JAK/STAT activation, the primary pathogenic mechanism associated with calreticulin mutations known to date. Most of the gene expression changes observed seemed to be due to a partial loss of protein function, with the alteration of the extracellular matrix being particularly notable. In this study, our aim was to determine whether this model exhibited any phenotype related to these transcriptomic alterations. The results demonstrate that these strains exhibit multiple phenotypes related to the alteration of the extracellular matrix, fat levels, and fertility, which could be a possible consequence of a partial loss of calreticulin function. These phenotypes resemble some of the clinical and molecular characteristics described in patients with MPNs, but they had never before been linked to a loss of protein function in humans. Thus, these results collectively suggest that CALR mutations could have significant effects on MPNs due to loss of protein function. Delving deeper into these effects to develop innovative therapies for these patients offers considerable potential and interest, given that targeted therapies for these patients have not yielded very promising results so far.

Myelofibrosis (MF) is a complex myeloproliferative neoplasm characterized by abnormal hematopoietic stem cell proliferation and subsequent bone marrow (BM) fibrosis. First documented in the late 19th century, MF has since been extensively studied to unravel its pathophysiology, clinical phenotypes, and therapeutic interventions. MF can be classified into primary and secondary forms, both driven by mutations in genes such as JAK2, CALR, and MPL, which activate the JAK-STAT signaling pathway. These driver mutations are frequently accompanied by additional non-driver mutations in genes like TET2, SRSF2, and TP53, contributing to disease complexity. The BM microenvironment, consisting of stromal cells, extracellular matrix, and cytokines such as TGF-β and TNF-α, plays a critical role in fibrosis and aberrant hematopoiesis. Clinically, MF manifests with symptoms ranging from anemia, splenomegaly, and fatigue to severe complications such as leukemic transformation. Splenomegaly, caused by extramedullary hematopoiesis, leads to abdominal discomfort and early satiety. Current therapeutic strategies include JAK inhibitors like Ruxolitinib, which target the JAK-STAT pathway, alongside supportive treatments such as blood transfusions, erythropoiesis-stimulating agents and developing combinatorial approaches. Allogeneic hematopoietic stem cell transplantation remains the only curative option, though it is limited to younger, high-risk patients. Recently approved JAK inhibitors, including Fedratinib, Pacritinib, and Momelotinib, have expanded the therapeutic landscape. Spatially Resolved Transcriptomics (SRT) has revolutionized the study of gene expression within the spatial context of tissues, providing unprecedented insights into cellular heterogeneity, spatial gene regulation, and microenvironmental interactions, including stromal-hematopoietic dynamics. SRT enables high-resolution mapping of gene expression in the BM and spleen, revealing molecular signatures, spatial heterogeneity, and pathological niches that drive disease progression. These technologies elucidate the role of the spleen in MF, highlighting its transformation into a site of abnormal hematopoietic activity, fibrotic changes, and immune cell infiltration, functioning as a "tumor surrogate." By profiling diverse cell populations and molecular alterations within the BM and spleen, SRT facilitates a deeper understanding of MF pathophysiology, helping identify novel therapeutic targets and biomarkers. Ultimately, integrating spatial transcriptomics into MF research promises to enhance diagnostic precision and therapeutic innovation, addressing the multifaceted challenges of this disease., (© 2024. The Author(s).)

Myeloid neoplasms include myeloproliferative and myelodysplastic neoplasms and acute myeloid leukaemia. Historically, these diseases have been diagnosed based on clinicopathological features with sometimes arbitrary thresholds that have persisted even as molecular features were gradually incorporated into their classification. As such, although current diagnostic approaches can classify the majority of myeloid neoplasms accurately using a combination of molecular and clinicopathological features, some areas of overlap persist and occasionally pose diagnostic challenges. These include overlap across BCR::ABL1-negative myeloproliferative neoplasms; between clonal cytopenia of undetermined significance and myelodysplastic neoplasms; myelodysplastic/myeloproliferative neoplasms; and, detection of KIT mutations in myeloid neoplasms other than mastocytosis, raising the prospect of systemic mastocytosis. Molecular testing has become state of the art in the diagnostic work-up of myeloid neoplasms, and molecular patterns can inherently help to classify overlapping entities if considered within a framework of haematological presentations. For future development, molecular testing will likely include whole genome and transcriptome sequencing, and primarily molecular classifications of myeloid neoplasms have already been suggested. As such, genetically defined groups should still constitute the basis for our understanding of disease development from early onset to progression, while clinicopathological features could then be used to describe the stage of the disease rather than the specific type of myeloid neoplasm., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Background: Myeloproliferative neoplasms (MPN) are a heterogeneous group of disorders characterized by the cellular proliferation of one or more hematologic cell lines. Patients with MPN who are Philadelphia-negative such as those with Polycythemia Vera (PV), Essential Thrombocytosis (ET), or Myelofibrosis (MF) experience a cluster of symptoms related to the disease activity which can affect their quality of life., Objectives: This study aimed to explore the symptoms and symptom experience as well as lived experience of Filipino patients with MPN using a qualitative phenomenological approach to get a deeper understanding of the disease symptomatology., Methods: Twenty-three patients with myeloproliferative neoplasms were purposively selected according to: 1) type of MPN (PV, ET, MF) 2) status of MPN disease (newly diagnosed vs. chronic) 3) age (≤50 years old; >50 years) and 4) sex (male vs. female). The investigators conducted key informant interviews using a semi-structured interview guide. Interview scripts and narratives were transcribed and analyzed using categorical aggregation and thematic analysis., Results: Twenty patients proceeded with the interview (8 PV, 6 ET, 6 MF). The meta-themes identified were 1) symptom experience and 2) disease perception. Three sub-themes under symptom experience were a) heterogenous and complex symptomatology; b) dynamic nature of symptoms; c) living and coping with symptoms. Three sub-themes under disease perception were a) struggle with the concept of the disease; b) anxiety and uncertainty; c) acceptance and hope. The most common symptoms experienced by the patients were fatigue, bone pain, and abdominal discomfort. Vascular symptoms specifically headache, numbness, and problems in concentration were commonly reported by patients with PV. Fever and weight loss were the least common. Sources of anxiety/uncertainty include the unpredictability of symptom occurrence and blood counts, the burden of taking maintenance medications, the financial burden of living with MPN, and the unpredictability of disease and complications., Conclusion: Patients with MPN had heterogenous, co-occurring, and dynamic symptoms which affected their overall productivity both at home and at work. Patients with MF had the most symptom burden while patients with ET had the least. This study provided valuable insights on disease perceptions, sources of anxiety, and coping mechanisms of patients with MPN. A deeper understanding of the symptom experience and disease perceptions of the patients will enhance the physician-patient interaction especially when discussing management options., Competing Interests: All authors declared no conflicts of interest., (© 2024 Acta Medica Philippina.)

The most common causes of morbidity and mortality in the myeloproliferative neoplasms (MPNs), with the exception of myelofibrosis, are venous and arterial thrombosis, as well as more recently discovered cardiovascular disease (CVD). Clonal hematopoiesis of indeterminate potential (CHIP) is the subclinical finding in an individual of somatic mutations that are also found in clinically overt MPNs and other myeloid malignancies. The prevalence of "silent" CHIP increases with age. CHIP can transform into a clinically overt MPN at an estimated rate of 0.5 to 1% per year. It is likely, therefore, but not proven, that many, if not all, MPN patients had antecedent CHIP, possibly for many years. Moreover, both individuals with asymptomatic CHIP, as well as clinically diagnosed patients with MPN, can develop thrombotic complications. An unexpected and remarkable discovery during the last few years is that even CHIP (as well as MPNs) are significant, independent risk factors for CVD. This review discusses up-to-date information on the types of thrombotic and cardiovascular complications that are found in CHIP and MPN patients. A systemic inflammatory state (that is often subclinical) is most likely to be a major mediator of adverse reciprocal bone marrow-cardiovascular interplay that may fuel the development of progression of MPNs, including its thrombotic and vascular complications, as well as the worsening of cardiovascular disease, possibly in a "vicious cycle". Translating this to clinical practice for hematologists and oncologists who treat MPN patients, attention should now be paid to ensuring that cardiovascular risk factors are controlled and minimized, either by the patient's cardiologist or primary care physician or by the hematologist/oncologist herself or himself. This review is intended to cover the clinical aspects of thrombosis and cardiovascular complications in the MPN, accompanied by pathobiological comments.

Myeloproliferative neoplasms (MPNs) are characterized by an increased production of blood cells due to the acquisition of mutations such as JAK2 V617F . TGF-β, whose secretion is increased in MPN patients, is known to negatively regulate haematopoietic stem cell (HSC) proliferation. Using an isogenic JAK2 V617F or JAK2 wild-type UT-7 cell line we observed that JAK2 V617F cells resist to TGF-β antiproliferative activity. Although TGF-β receptors and SMAD2/3 expressions are similar in both cell types, TGF-β-induced phosphorylation of SMAD2/3 is reduced in UT-7 JAK2 V617F cells compared with JAK2 WT cells. We confirmed that JAK2 V617F mutated cells are resistant to the antiproliferative effect of TGF-β in a competitive assay as we observed a positive selection of JAK2 V617F cells when exposed to TGF-β. Using cell lines, CD34-positive cells from MPN patients and bone marrow cells from JAK2 V617F knock-in mice we identified a down regulation of the SHP-1 phosphatase, which is required for the regulation of HSC quiescence by TGF-β. The transduction of SHP-1 cDNA (but not a phosphatase inactive cDNA) restores the antiproliferative effect of TGF-β in JAK2 V617F mutated cells. Finally, SC-1, a known agonist of SHP-1, antagonized the selection of JAK2 V617F mutated cells in the presence of TGF-β. In conclusion, we show a JAK2-dependent down regulation of SHP-1 in MPN patients' cells which is related to their resistance to the antiproliferative effect of TGF-β. This may participate in the clonal selection of cancer cells in MPNs., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Opinion Statement: Myeloproliferative neoplasms (MPN) are a heterogenous group of disorders of clonal hematopoiesis characterized by constitutive activation of the JAK/STAT signaling pathway leading to proliferation of blood cells. Cardiovascular disease (CVD) contributes significantly to the morbidity and mortality of patients with MPN. Particularly well-known CVD complications of MPNs are arterial and venous thrombotic events. However, MPNs are also associated with other forms of CVD including atrial fibrillation, heart failure, and pulmonary hypertension. Recent studies have characterized outcomes of patients with MPN and CVD, including acute myocardial infarction (AMI), heart failure, atrial fibrillation, and pulmonary hypertension. Additionally, optimal cardiovascular disease prevention strategies in patients with MPN are not yet clear. Further investigation is warranted to improve CVD outcomes in patients with MPN. Clinicians should be aware of cardiovascular complications of MPN, including thrombotic as well as non-thrombotic complications (heart failure, arrhythmias, pulmonary hypertension)., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Recently, an antibody which inhibits the glycoprotein A repetitions predominant (GARP)-mediated release of active transforming growth factor beta (TGFβ) from the TGFβ propeptide latency-associated peptide (LAP) showed preclinical activity in a murine model of the chronic myeloproliferative neoplasms (MPN). Consequently, we investigated the expression of the immunosuppressive molecules LAP and GARP on peripheral blood lymphocytes from 56 MPN patients and 11 healthy donors (HD). We found that lymphocytes from patients with MPN express higher levels of LAP and GARP with no strong differences found between the different MPN diagnoses. The impact of clinical parameters on the expression of LAP and GARP by lymphocytes showed that patients with calreticulin (CALR)mut MPN have increased expression compared with HD and patients with the Januskinase2 (JAK2) mutation. The fraction of lymphocytes bound to activated platelets (aPLT) strongly correlate to LAP and GARP expression suggesting that it is not the lymphocytes themselves but aPLT, which confer the increased expression of GARP and LAP on MPN patient lymphocytes. Notably, no differences in neither platelet counts nor anti-thrombotic therapy was identified between patients with JAK2- and CALRmut patients. Analysis of platelet gene expression failed to identify differences in expression of relevant genes between JAK2- and CALRmut patients., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Patients with myeloproliferative neoplasms (MPNs) face chronic symptom burden. Online symptom assessment studies allow for recruitment of large numbers of motivated patients, but patient self-selection can lead to sampling bias. This study evaluated how gender representativeness in MPN symptom surveys and trials impacted symptom score mean estimates, using data from 4825 survey respondents and 291 trial participants with MPNs. The survey data showed that men participated at a rate roughly 50% less than what would be expected based on prevalence, and women reported higher scores than men on average for six of 10 symptoms. Together, this led to potential over estimation in six of 10 symptom score means (ranging from 5.8% to 15.3% overestimated). The trial data showed less gender-based sampling bias compared to the survey data. Studies utilizing online symptom surveys should implement study design features to recruit more men, assess for gender participation imbalances, and provide weighted estimates where appropriate.

Introduction: Artificial intelligence (AI) is a rapidly growing field of computational research with the potential to extract nuanced biomarkers for the prediction of outcomes of interest. AI implementations for the prediction for clinical outcomes for myeloproliferative neoplasms (MPNs) are currently under investigation., Areas Covered: In this narrative review, we discuss AI investigations for the improvement of MPN clinical care utilizing either clinically available data or experimental laboratory findings. Abstracts and manuscripts were identified upon querying PubMed and the American Society of Hematology conference between 2000 and 2023. Overall, multidisciplinary researchers have developed AI methods in MPNs attempting to improve diagnostic accuracy, risk prediction, therapy selection, or pre-clinical investigations to identify candidate molecules as novel therapeutic agents., Expert Opinion: It is our expert opinion that AI methods in MPN care and hematology will continue to grow with increasing clinical utility. We believe that AI models will assist healthcare workers as clinical decision support tools if appropriately developed with AI-specific regulatory guidelines. Though the reported findings in this review are early investigations for AI in MPNs, the collective work developed by the research community provides a promising framework for improving decision-making in the future of MPN clinical care.

DNA methyltransferase 3 A mutations (DNMT3A MT ) are frequent in myeloid neoplasia (MN) and mostly heterozygous. However, cases with multiple DNMT3A MT can be also encountered but their clinical and genetic landscape remains unexplored. We retrospectively analyzed 533 cases with DNMT3A MT identified out of 5,603 consecutive MNs, of whom 8.4% had multiple DNMT3A MT hits. They were most frequent in acute myeloid leukemia (AML) with R882 variant accounting for 13.3% of the multi-hits. Multiple DNMT3A MT more likely coincided with IDH2 (P = 0.005) and ETV6 (P = 0.044) mutations compared to patients with single DNMT3A MT . When the sum of variant allele frequencies (VAFs) for multiple DNMT3A MT exceeded 60%, we found a significant positive clonal burden correlation of the two DNMT3A variants (P < 0.0001) suggesting that they occurred in biallelic configuration. AML patients with biallelic DNMT3A inactivation (n = 52) presented with older age (P = 0.029), higher leukocytes (P < 0.0001) and peripheral blast counts (P = 0.0001) and significantly poorer survival rate (5.6% vs. 47.6% at 2 years; P = 0.002) than monoallelic DNMT3A MT . Multivariate analysis identified biallelic DNMT3A MT (HR 2.65; P = 0.001), male gender (HR 2.05; P = 0.014) and adverse genetic alteration according to the European LeukemiaNet 2022 classification (HR 1.84; P = 0.028) as independent adverse factors for survival, whereas intensive chemotherapy (HR 0.47; P = 0.011) favorably influenced outcomes. Longitudinal molecular analysis of 12 cases with biallelic DNMT3A MT demonstrated that such clones persisted or expanded in 9 relapsed or transformed cases (75%) suggesting the early origin of biallelic hits with strong leukemogenic potential. Our study describes the likelihood that biallelic DNMT3A MT , while rare, are indeed compatible with clonal expansion and thus questions the applicability of synthetic lethality strategies., (© 2024. The Author(s).)

Motivation: By accounting for variants within measured transcripts, it is possible to evaluate the status of somatic variants using single-cell RNA-sequencing (scRNA-seq) and to characterize their clonality. However, the sparsity (very few reads per transcript) or bias in protocols (favoring 3' ends of the transcripts) makes the chance of capturing somatic variants very unlikely. This can be overcome by targeted sequencing or the use of mitochondrial variants as natural barcodes for clone identification. Currently, available computational tools focus on genotyping, but do not provide functionality for combined analysis of somatic and mitochondrial variants and functional analysis such as characterization of gene expression changes in detected clones., Results: Here, we propose SIGURD (SIngle cell level Genotyping Using scRna Data) (SIGURD), which is an R-based pipeline for the clonal analysis of scRNA-seq data. This allows the quantification of clones by leveraging both somatic and mitochondrial variants. SIGURD also allows for functional analysis after clonal detection: association of clones with cell populations, detection of differentially expressed genes across clones, and association of somatic and mitochondrial variants. Here, we demonstrate the power of SIGURD by analyzing single-cell data of colony-forming cells derived from patients with myeloproliferative neoplasms., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: Thrombosis and bleeding significantly affect morbidity and mortality in myeloproliferative neoplasms (MPNs). The efficacy and safety of direct oral anticoagulants (DOACs) in MPN patients remain uncertain., Materials and Methods: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service database from 2010 to 2021., Results: Out of the 368 MPN patients included in the final analysis, 62.8% were treated with DOACs for atrial fibrillation (AF), and 37.2% for venous thromboembolism (VTE). The AF group was statistically older with higher CHA2DS2-VASc scores compared to the VTE group. Antiplatelet agents were used in 51.1% of cases, and cytoreductive drugs in 79.3%, with hydroxyurea being the most common (64.9%). The median follow-up was 22.3 months, with one-year cumulative incidence rates of thrombosis and bleeding at 11.1% and 3.7%, respectively. Multivariate analysis identified CHA2DS2-VASc scores ≥ 3 (HR=3.48), concomitant antiplatelet use (HR = 2.57), and cytoreduction (HR=2.20) as significant thrombosis risk factors but found no significant predictors for major bleeding., Conclusion: Despite the limitations of retrospective data, DOAC treatment in MPN patients seems effective and has an acceptable bleeding risk.

Myeloproliferative neoplasms (MPNs) are characterized by increased proliferation of myeloid lineages in the bone marrow. Calreticulin ( CALR ) 52 bp deletion and CALR 5 bp insertion have been identified in essential thrombocythemia (ET) and primary myelofibrosis (PMF). There is not much data on the crosstalk between mutated CALR and MPN-related signaling pathways, such as JAK/STAT, PI3K/Akt/mTOR, and Hedgehog. Calreticulin, a multifunctional protein, takes part in many cellular processes. Nevertheless, there is little data on how mutated CALR affects the oxidative stress response and oxidative stress-induced DNA damage, apoptosis, and cell cycle progression. We aimed to investigate the role of the CALR 52 bp deletion and 5 bp insertion in the pathogenesis of MPN, including signaling pathway activation and functional analysis in CALR -mutated cells. Our data indicate that the JAK/STAT and PI3K/Akt/mTOR pathways are activated in CALR -mutated cells, and this activation does not necessarily depend on the CALR and MPL interaction. Moreover, it was found that CALR mutations impair calreticulin function, leading to reduced responses to oxidative stress and DNA damage. It was revealed that the accumulation of G2/M- CALR -mutated cells indicates that oxidative stress-induced DNA damage is difficult to repair. Taken together, this study contributes to a deeper understanding of the specific molecular mechanisms underlying CALR -mutated MPNs.

The central role of the control of apoptosis in the pathophysiology of Philadelphia chromosome-negative myeloproliferative neoplasms has recently been reinforced in genetic and pharmacological studies. The inhibitor of apoptosis protein family has eight members and plays an important role in apoptosis, with the most studied being survivin (BIRC5) and X-linked inhibitor of apoptosis (XIAP). YM155 is a small molecule with antineoplastic potential that has been described as a suppressant of survivin and XIAP. In the present study, BIRC5 expression was significantly increased in primary myelofibrosis patients compared to healthy donors. On the other hand, XIAP expression was reduced in myeloproliferative neoplasms patients. In JAK2 V617F cells, YM155 reduces cell viability and autonomous clonal growth and induces apoptosis, cell cycle arrest, and autophagy. HEL cells that show greater malignancy are more sensitive to the drug than SET2 cells. In the molecular scenario, YM155 modulates apoptosis-, cell cycle-, DNA damage- and autophagy-related genes. Protein expression analysis corroborates the observed cellular phenotype and exploratory gene expression findings. In summary, our results indicate that survivin/BIRC5 and XIAP are differently expressed in myeloproliferative neoplasms and YM155 has multiple antineoplastic effects on JAK2 V617F cells suggesting that inhibitor of apoptosis proteins may be a target for pharmacological interventions in the treatment of these diseases., Competing Interests: Conflicts of interest The authors declare no competing interests., (Copyright © 2024 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.)

The JAK2 V617F is a prevalent driver mutation in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph - MPNs), significantly affecting disease progression, immunophenotype, and patient outcomes. The World Health Organization (WHO) guidelines highlight the JAK2 V617F mutation as one of the key diagnostic criterions for Ph - MPNs. In this study, we analyzed 283 MPN samples with the JAK2 V617F mutation to assess the effectiveness of three detection technologies: chip-based digital PCR (cdPCR), real-time quantitative PCR (qPCR), and next-generation sequencing (NGS). Additionally, we investigated the relationship between JAK2 V617F mutant allele burden (% JAK2 V617F) and various laboratory characteristics to elucidate potential implications in MPN diagnosis. Our findings demonstrated high conformance of cdPCR with qPCR/NGS for detecting % JAK2 V617F, but the mutant allele burdens detected by qPCR/NGS were lower than those detected by cdPCR. Moreover, the cdPCR exhibited high sensitivity with a limit of detection (LoD) of 0.08% and a limit of quantification (LoQ) of 0.2% for detecting % JAK2 V617F in MPNs. Clinical implications were explored by correlating % JAK2 V617F with various laboratory characteristics in MPN patients, revealing significant associations with white blood cell counts, lactate dehydrogenase levels, and particularly β2-microglobulin (β2-MG) levels. Finally, a case report illustrated the application of cdPCR in detecting low-allele burdens in a de novo chronic myeloid leukemia (CML) patient with a hidden JAK2 V617F subclone, which expanded during tyrosine kinase inhibitor (TKI) treatment. Our findings underscore the superior sensitivity and accuracy of cdPCR, making it a valuable tool for early diagnosis and monitoring clonal evolution., (© 2024. The Author(s).)

The influence of demographic characteristics and social determinants on cancer outcomes is widely recognized in various malignancies but remains understudied in myelofibrosis (MF). This study aims to investigate social and demographic variables associated with MF survival. We retrospectively reviewed data of biopsy-proven MF patients from the Surveillance, Epidemiology and End Results (SEER) database (2000-2021) and Montefiore Medical Center (2000-2023), an underserved inner-city hospital. The SEER cohort included 5,403 MF patients and was predominantly Non-Hispanic (NH) White (82%) with a median age of 69 years. The age-adjusted incidence rate of MF was 0.32 cases per 100,000 person-years, increasing annually by 1.3% from 2000 to 2021. Two- and five- year overall survival rates were 69% and 42%, respectively. Worse cause-specific survival was associated with older age, male sex, and diagnosis before 2011 (year of Ruxolitinib approval). NH-Black ethnicity, unmarried status and lower median income were independent predictors of worse overall survival. The single-center analysis included 84 cases, with a median age of 66 years. NH-White patients comprised 37% of the sample, followed by NH-Black (28.5%). Two- and five- year overall survival rates were 90% and 61%, respectively, with NH-Black patients exhibiting the lowest median survival, although the difference was not statistically significant. Age was a significant predictor of worse survival in this cohort. NH-Black and Hispanic patients lived in areas with higher socioeconomic and demographic stress compared to NH-White patients. Overall, this study highlights the association of social and demographic factors with MF survival and emphasizes the need for equitable healthcare and further exploration of social-demographic factors affecting MF survival., (© 2024. The Author(s).)

Background: Outcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF., Methods: We conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021 to 2024., Results: The cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (n = 9) receiving > 4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3 per cycle., Conclusions: This report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial., Competing Interests: Disclosures D.T. receives contracted research funding paid to his institution from Sobi, Astellas Pharma, Gilead and Cogent Biosciences and consulting fees from Novartis, AbbVie, Sierra Oncology, GSK and Cogent Biosciences. J.M. receives research funding paid to his institution from Incyte, Novartis, BMS, CTI/Sobi, Abbvie, Geron, Kartos and PharmaEssentia. Consulting fees paid to me by Incyte, Novartis, CTI/Sobi, Abbvie, Karyopharm, Kartos, Geron, GSK, Sumitomo, BMS, MorphoSys, Galecto, Pfizer, Merck, Roche and PharmaEssentia. R.H. received research grant funding through his institution from the following sources: Citi BioPharma Corp, Curis, Inc., Dexcel Pharma Technologies Ltd. Genentech, Kartos Therapeutics, Karyopharm Therapeutics, Inc., Kymera Therapeutics, OncoMyx Therapeutics, Novartis, Protagonist Therapeutics, Repare Therapeutics, Translational Drug Development (TD2), Turning Point Therapeutics, and the NIH/NCI. Additionally, he has received funding as an advisor/consultant from the following sources: AbbVie, Ionis Pharmaceuticals, Protagonist Therapeutics, Silence Therapeutics, GlycoMimetics, Dexcel Pharma Technologies LTD, Sumitomo Pharma Oncology, and Cellenkos, Inc. Finally, he holds a share of a patent filed by Dompé farmaceutici S.p.A. Y.Z.G. received research grant funding through her institution from the following sources: Protagonist Therapeutics, Repare Therapeutics, and the NIH/NIDDK. YZG has received funding as an advisor/consultant from the following sources: Bay Clinical, Takeda, Denali, Ionis Pharmaceuticals, Protagonist Therapeutics. No other relevant financial disclosures for other authors., (Copyright © 2024. Published by Elsevier Inc.)

Background: Myeloproliferative neoplasms (MPNs) are hematological disorders characterized by abnormal production of myeloid cells due to genetic mutations. Since 2013, researchers have identified somatic mutations in the Calreticulin (CALR) gene, primarily insertions or deletions, in two Philadelphia chromosome-negative MPNs; essential thrombocytosis (ET) and primary myelofibrosis (PMF), and occasionally in chronic myelomonocytic leukemia (CMML). This study aims to identify the various types of CALR mutations and their impact on CALR-positive MPN patients' clinical manifestations and outcomes., Methods: A single-center retrospective study was conducted. The data was collected from pre-existing records. The study was carried out on Philadelphia-negative MPN patients who were being followed up on at the NCCCR (National Center for Cancer Care and Research) to assess the clinical manifestation and outcome of disease treatment. All patients included, were followed in our center between January 1, 2008, and November 20, 2021., Results: A total of 50 patients with CALR -positive MPN were reviewed with a median follow-up of three years (1-11). This cohort included 31 (62%) patients with ET, 10 (20%) patients with PMF, and 9 (18%) patients with prefibrotic myelofibrosis (pre-MF). The study involved 38 (76%) male and 12 (24%) female patients. There were 16 (32%) patients diagnosed before the age of 40, 24 (48%) patients diagnosed between the ages of 40 and 60; and 10 (20%) patients diagnosed after the age of 60. Molecular analysis showed 24 (48%) patients with CALR type 1, 21 (42%) patients with CALR type 2, and 5 (10%) patients with none Type 1, none Type 2 CALR mutations. Two patients have double mutations; 1(2%) with none Type 1, none Type 2 CALR and JAK2 mutations, and 1(2%) with CALR type 1 and MPL mutations. The thrombotic events were 3 (6%) venous thromboembolisms, 3 (6%) abdominal veins thromboses, 2 (4%) strokes, and 4 (8%) ischemic cardiac events. Only 4 (8%) patients progressed to Myelofibrosis and were carrying CALR 1 mutations, and 1 (2%) patient progressed to AML with CALR 2 mutation., Conclusion: The data shows a significant rise in CALR-positive MPN diagnoses in younger people, emphasizing the need for a better assessment tool to improve disease management and reduce complications.

Objectives: Constitutive activation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription (STAT) signaling pathway is central to the pathogenesis of myeloproliferative neoplasms (MPNs). Long noncoding RNAs (lncRNAs) regulate diverse biological processes. However, the role of lncRNAs in MPN pathogenesis is not well studied., Methods: The expression of lnc-AC004893 in MPN patients was measured by quantitative real-time PCR (qRT-PCR). Gene-specific short hairpin RNAs (shRNAs) were designed to inhibit the expression of lnc-AC004893, and western blot was performed to explore the role of lnc-AC004893 via regulating the JAK2/STAT5 signaling pathway. Furthermore, co-IP was performed to determine the binding ability of lnc-AC004893 and STAT5 protein. Finally, the BaF3-JAK2V617F-transplanted mouse model was used to assess the biological role of lnc-ac004893 in vivo ., Results: We report that lnc-AC004893, a poorly conserved pseudogene-209, is substantially upregulated in MPN cells compared with normal controls (NCs). Knockdown of lnc-AC004893 by specific shRNAs suppressed cell proliferation and decreased colony formation. Furthermore, the knockdown of lnc-AC004893 reduced the expression of p-STAT5 but not total STAT5 in HEL and murine IL-3-dependent Ba/F3 cells, which present constitutive and inducible activation of JAK2/STAT5 signaling. In addition, inhibition of murine lnc-ac004893 attenuated BaF3-JAK2V617F-transplanted phenotypes and extended the overall survival. Mechanistically, knockdown of lnc-AC004893 enhanced the binding ability of STAT5 and protein tyrosine phosphatase SHP1. Furthermore, knockdown of lnc-AC004893 decreased STAT5-lnc-AC004893 interaction but not SHP1-lnc-AC004893 interaction., Conclusion: Lnc-AC004893 regulates STAT5 phosphorylation by affecting the interaction of STAT5 and SHP1. Lnc-AC004893 might be a potential therapeutic target for MPN patients.

Transcription factor 3 (TCF3) is a DNA transcription factor that modulates megakaryocyte development. Although abnormal TCF3 expression has been identified in a range of hematological malignancies, to date, it has not been investigated in myelofibrosis (MF). MF is a Philadelphia-negative myeloproliferative neoplasm (MPN) that can arise de novo or progress from essential thrombocythemia [ET] and polycythemia vera [PV] and where dysfunctional megakaryocytes have a role in driving the fibrotic progression. We aimed to examine whether TCF3 is dysregulated in megakaryocytes in MPN, and specifically in MF. We first assessed TCF3 protein expression in megakaryocytes using an immunohistochemical approach analyses and showed that TCF3 was reduced in MF compared with ET and PV. Further, the TCF3-negative megakaryocytes were primarily located near trabecular bone and had the typical "MF-like" morphology as described by the WHO. Genomic analysis of isolated megakaryocytes showed three mutations, all predicted to result in a loss of function, in patients with MF; none were seen in megakaryocytes isolated from ET or PV marrow samples. We then progressed to transcriptomic sequencing of platelets which showed loss of TCF3 in MF. These proteomic, genomic and transcriptomic analyses appear to indicate that TCF3 is downregulated in megakaryocytes in MF. This infers aberrations in megakaryopoiesis occur in this progressive phase of MPN. Further exploration of this pathway could provide insights into TCF3 and the evolution of fibrosis and potentially lead to new preventative therapeutic targets.

Objectives: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study., Methods: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma., Results: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n  = 8; essential thrombocythemia, n  = 14; and primary myelofibrosis, n  = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed ( n  = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy., Conclusion: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

The Myeloproliferative Neoplasm Symptom Assessment Total Symptom Score (MPN-SAF TSS) is a surrogate marker for symptom evaluation in chronic myeloproliferative neoplasms (MPNs). However, insufficient data are available regarding the relationship among the MPN-SAF TSS, JAK2 mutation allele burden, and thrombosis. In this retrospective analysis, we aimed to determine the genetic burdens, clinical features, and relationships with MPN-SAF TSS in MPN patients. One hundred thirty JAK2 V617F-positive patients with MPNs were included in our study. We calculated the MPN-SAF TSS for all patients and compared it with their clinical characteristics. Patients with higher JAK2 V617F mutation allele burden had higher MPN-SAF TSS values (p=0.008). Patients with thrombosis had higher MPN-SAF TSS than patients without thrombosis (p=0.003). The mean MPN-SAF TSS was higher in patients with primary myelofibrosis compared to those with polycythemia vera and essential thrombocythemia. Thrombosis was associated with increased symptom severity in several domains, including fatigue, abdominal discomfort, inactivity, night sweats, pruritus, weight loss, and early satiety. Additionally, an increase in JAK2 allele burden was observed with higher symptom scores. The MPN-SAF TSS proved to be a reliable tool for assessing symptom burden in Turkish MPN patients. Furthermore, the significant association between thrombosis occurrence and symptom severity suggests that thrombotic events may contribute to symptom development. Notably, increasing JAK2 allele burden was correlated with more severe symptoms, highlighting its potential role in predicting disease burden. This study emphasizes the importance of symptom assessment in MPN patients and supports the incorporation of the MPN-SAF TSS in routine clinical practice to enhance patient care and management., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (©Copyright 2024 by Turkish Society of Hematology Turkish Journal of Hematology, Published by Galenos Publishing House.)

Objective: It has been shown that clonal mutations occur in hematopoietic stem cells with advancing age and increase the risk of death due to atherosclerotic vascular diseases, similarly to myeloproliferative neoplasms. Endothelial cells (ECs) and hematopoietic stem cells develop from common stem cells called hemangioblasts in the early embryonic period. However, the presence of hemangioblasts in the postnatal period is controversial. In this study, JAK2 gene variants were examined in patients with atherosclerotic carotid disease and without any hematological malignancies., Materials and Methods: Ten consecutive patients (8 men and 2 women) with symptomatic atherosclerotic carotid stenosis were included in this study. ECs (CD31 + CD45 - ) were separated from tissue samples taken by carotid endarterectomy. JAK2 variants were examined in ECs, peripheral blood mononuclear cells, and oral epithelial cells of the patients with next-generation sequencing., Results: The median age of the patients was 74 (range: 58-80) years and the median body mass index value was 24.44 (range: 18.42-30.85) kg/m 2 . Smoking history was present in 50%, hypertension in 80%, diabetes in 70%, and ischemic heart disease in 70% of the cases. The JAK2 V617F mutation was detected in the peripheral blood mononuclear cells of 3 of the 10 patients, and 2 patients also had the JAK2 V617F mutation in their ECs. The JAK2 V617F mutation was not found in the oral epithelial cells of any of the patients., Conclusion: In this study, for the first time in the literature, we showed that the JAK2 V617F mutation was found somatically in both peripheral blood cells and ECs in patients with atherosclerosis. This finding may support that ECs and hematopoietic cells originate from a common clone or that somatic mutations can be transmitted to ECs by other mechanisms. Examining the molecular and functional changes caused by the JAK2 V617F mutation in ECs may help open a new avenue for treating atherosclerosis., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (©Copyright 2024 by Turkish Society of Hematology Turkish Journal of Hematology, Published by Galenos Publishing House.)

Myeloproliferative neoplasms (MPNs) are a group of rare chronic progressive blood cancers that vary widely in clinical presentation, yet all patients have a risk of disease progression and thrombotic complications. Diseases include primary myelofibrosis, polycythemia vera, and essential thrombocythemia. With current treatment approaches, most patients live a prolonged life, but many experience a complex of symptoms that negatively influence their functional status and quality of life. Although significant advances have been made in preventing arterial and venous complications while mitigating inflammatory processes, comprehensive palliative care can help address unmet complex physical and psychosocial needs on a long-term basis. This article, created by a multidisciplinary group of providers, offers an overview of MPNs so palliative care clinicians can better support patients with these hematologic cancers.

Background: Blast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia., Case Presentation: The patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 10 9 /L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 10 9 /L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 10 9 /L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes., Conclusions: To our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia., (© 2024. The Author(s).)

Philadelphia-Negative Myeloproliferative neoplasms (MPNs) are a diverse group of blood cancers leading to excessive production of mature blood cells. These chronic diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), can significantly impact patient quality of life and are still incurable in the vast majority of the cases. This review examines the mechanobiology within a bone marrow niche, emphasizing the role of mechanical cues and the primary cilium in the pathophysiology of MPNs. It discusses the influence of extracellular matrix components, cell-cell and cell-matrix interactions, and mechanosensitive structures on hematopoietic stem cell (HSC) behavior and disease progression. Additionally, the potential implications of the primary cilium as a chemo- and mechanosensory organelle in bone marrow cells are explored, highlighting its involvement in signaling pathways crucial for hematopoietic regulation. This review proposes future research directions to better understand the dysregulated bone marrow niche in MPNs and to identify novel therapeutic targets.

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.

Chronic neutrophilic leukemia (CNL) is a rare type of myeloproliferative neoplasm (MPN). Due to its nonspecific clinical symptoms and lack of specific molecular markers, it was previously difficult to distinguish it from other diseases with increased neutrophils. However, the discovery of the CSF3R mutation in CNL 10 years ago and the update of the diagnostic criteria by the World Health Organization (WHO) in 2016 brought CNL into a new era of molecular diagnosis. Next-generation sequencing (NGS) technology has led to the identification of numerous mutant genes in CNL. While CSF3R is commonly recognized as the driver mutation of CNL, other mutations have also been detected in CNL using NGS, including mutations in other signaling pathway genes (CBL, JAK2, NARS, PTPN11) and chromatin modification genes (ASXL1, SETBP1, EZH2), DNA methylation genes (DNMT3A, TET2), myeloid-related transcription factor genes (RUNX1, GATA2), and splicing and RNA metabolism genes (SRSF2, U2AF1). The coexistence of these mutated genes and CSF3R mutations, as well as the different evolutionary sequences of clones, deepens the complexity of CNL molecular biology. The purpose of this review is to summarize the genetic research findings of CNL in the last decade, focusing on the common mutated genes in CNL and their clinical significance, as well as the clonal evolution pattern and sequence of mutation acquisition in CNL, to provide a basis for the appropriate management of CNL patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Myeloproliferative neoplasms (MPN) are hematological diseases associated with genetic driver mutations in the JAK2, CALR, and MPL genes and exacerbated oncoinflammatory status . Analyzing public microarray data from polycythemia vera (n = 41), essential thrombocythemia (n = 21), and primary myelofibrosis (n = 9) patients' peripheral blood by in silico approaches, we found that pro-inflammatory and monocyte-related genes were differentially expressed in MPN patients' transcriptome. Genes related to cell activation, secretion of pro-inflammatory and pro-angiogenic mediators, activation of neutrophils and platelets, coagulation, and interferon pathway were upregulated in monocytes compared to controls. Together, our results suggest that molecular alterations in monocytes may contribute to oncoinflammation in MPN.

Background: Chronic pruritus affecting primary non-lesional skin (CPNL) manifests as a common symptom across a spectrum of diseases spanning various medical specialties. Given the diverse etiological factors involved, diagnosing the underlying condition poses a significant challenge., Objectives: To provide a comprehensive overview of clinical, laboratory, and imaging diagnostics for CPNL., Materials and Methods: A thorough literature search on the diagnostics of chronic pruritus was conducted using PubMed with specific keywords "chronic pruritus AND non-lesional skin", "chronic itch AND non-lesional skin", "chronic pruritus AND diagnostics", "chronic itch AND diagnostics", "CKD-aP", "hepatic pruritus", "cholestatic pruritus", and "myeloproliferative neoplasms AND pruritus"., Results: A systematic diagnostic approach is recommended for patients with CPNL, guided by the prevalence of pruritus-associated diseases. Initial basic diagnostics facilitate a cost-effective and focused evaluation during the initial medical assessment. Information pertaining to underlying diseases can be further refined through specialized diagnostic procedures., Conclusions: CPNL often presents a diagnostic dilemma. Adopting a stepwise diagnostic strategy facilitates the identification of underlying etiologies, which is crucial for recognizing diseases and administering pruritus-specific pharmacotherapy., (© 2024. The Author(s).)

Background : This study aimed to evaluate the clinical and prognostic associations of the systemic inflammatory index (SII) in polycythemia vera (PV) patients. SII integrates information on absolute neutrophil (ANC), lymphocyte (ALC), and platelet counts into one index (calculated as ANCxALC/platelet count) and was previously shown to predict thrombotic and mortality risks in the general population. Methods : A total of 279 PV patients treated in several hematologic centers in Croatia and Serbia was retrospectively evaluated. Results : The median SII for the overall cohort was 1960. Higher SII stratified at the specific cut-off points was significantly associated with shorter time to thrombosis (TTT; p = 0.004) driven by arterial thrombotic events, and shorter overall survival (OS; p < 0.001). Higher SII was able to refine the European Leukemia Net-defined high-risk patient subgroup for both thrombotic and survival risks, especially in individuals over 60 years of age. SII and all other evaluated CBC components and indices (leukocytes, ANC, ALC, platelets, neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR)) demonstrated low-to-modest prognostic properties, whereas SII outperformed other parameters with respect to TTT and OS prognostications. Discussion : The presented results complement prior studies evaluating the prognostic performance of different CBC components for thrombotic and survival risk predictions and offer more options to personalize PV treatments.

Myelofibrosis (MF) is a clonal disorder of hematopoietic stem cells characterized by altered bone marrow function and fibrosis. The aim of this narrative review is to report on the most recent epidemiologic data and to discuss features of MF and current strategies for the management of this condition in clinical practice. MF features covered by our review will include: characteristics of patients with MF; myeloproliferative and myelodepletive phenotypes; MF-associated thrombosis and bleeding; risk of infections; prefibrotic and overt PMF; secondary MF. Finally, we will discuss a few aspects of MF management in clinical practice and suggest strategies for its optimization and standardization. The focus of our paper is on Italy, but relevant data from other countries will also be reviewed., Competing Interests: MC and MBe are AbbVie employees and may own AbbVie stocks/options. MBr honoraria by Novartis, Pfizer, Incyte, BMS, AOP, AbbVie, Jazz. VS received honoraria for advisory board from AOP Health, Argenx, Bristol Myers Squibb, Glaxo Smith Kline, Grifols, Novartis, SOBI, and Takeda; speaker fees from AbbVie, Alexion, Amgen, Bristol Myers Squibb, Grifols, Leo Pharma, Novartis, Novo Nordisk, Sanofi, and Takeda; research grants from Alexion and Novartis. FP consultancy and honoraria from Novartis, Celgene, AbbVie, AOP, Sierra Oncology, Sobi, and CTI. GP received honoraria from AbbVie, AOP, AstraZeneca, BMS, GSK, Incyte, MorphoSys and Novartis. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.​. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Breccia, Palandri, Polverelli, Caira, Berluti, Palumbo and De Stefano.)

DARS, encoding for aspartyl-tRNA synthetase, is implicated in the pathogenesis of various cancers, including renal cell carcinoma, glioblastoma, colon cancer, and gastric cancer. Its role in BCR/ABL1-negative myeloproliferative neoplasms (MPNs), however, remains unexplored. This study aimed to elucidate the expression of DARS in patients with MPNs (PV 23, ET 19, PMF 16) through immunohistochemical analysis and to examine the profiles of circulating immune cells and cytokines using flow cytometry. Our findings indicate a significant overexpression of DARS in all MPNs subtypes at the protein level compared to controls (P < 0.05). Notably, elevated DARS expression was linked to splenomegaly in MPNs patients. The expression of DARS showed a negative correlation with CD4+ T cells (R = - 0.451, P = 0.0004) and CD4+ T/CD8+ T cell ratio (R = - 0.3758, P = 0.0040), as well as with CD68+ tumor-associated macrophages (R = 0.4037, P = 0.0017). Conversely, it was positively correlated with IL-2 (R = 0.5419, P < 0.001), IL-5 (R = 0.3161, P = 0.0166), IL-6 (R = 0.2992, P = 0.0238), and IFN-γ (R = 0.3873, P = 0.0029). These findings underscore a significant association between DARS expression in MPNs patients and specific clinical characteristics, as well as immune cell composition. Further investigation into the interplay between DARS and the immune microenvironment in MPNs could shed light on the underlying mechanisms of MPNs pathogenesis and immune dysregulation., (© 2024. The Author(s).)

Introduction: The hallmark discovery of hyperactivation of the janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway was a sentinel moment in the history of myeloproliferative neoplasms (MPNs). This finding paved the way for the development of JAK inhibitors, which now represent the foundation of myelofibrosis therapy. With four JAK inhibitors now approved for myelofibrosis, awareness of their clinical efficacy and safety data and recognition of their unique pharmacologic attributes are of critical importance. Additionally, ruxolitinib represents an integral part of the therapeutic arsenal for polycythemia vera., Areas Covered: This review provides a broad overview of the published literature supporting JAK inhibitor therapy for MPNs. Primarily focusing on myelofibrosis, each of the four available JAK inhibitors is reviewed in detail, including pharmacology, efficacy, and safety data. Failure of JAK inhibitors and future directions in JAK inhibitor therapy are also discussed., Expert Opinion: JAK inhibitors revolutionized the treatment of MPNs and have dramatically improved patient outcomes. However, data informing selection between currently available JAK inhibitors is limited. These agents are not curative and eventually fail most patients with myelofibrosis. Combining JAK inhibitors with novel targeted agents appears to be the most promising path to further improve outcomes.

Ropeginterferon-alfa2b (ropegIFNα2b) is a long-acting IFN formulation with broad FDA/EMA approval as a therapy of polycythemia vera (PV) with no symptomatic splenomegaly. There is currently lack of information on the real-world patient selection, including the impact of local reimbursement policies, and drug management, particularly: type/timing of screening and follow-up tests; absolute/relative contraindications to therapy; ropegIFNα2b dose and combinations with hydroxyurea. As a sub-analysis of the PV-ARC retrospective study (NCT06134102), we here report our monocenter experience with ropegIFNα2b in the period from January 2021, corresponding to drug availability outside clinical trial, and December 2023. Among the 149 patients with EMA/FDA indication, only 55 (36.9%) met the local reimbursement criteria and 18 (12.1%) received ropegIFNα2b. Thanks to appropriate screening, relative/absolute contraindications to ropegIFNα2b were detected and managed in a multidisciplinary manner. Efficacy and safety of ropegIFNα2b was confirmed, with 3 cases of early molecular response. General use of low ropegIFNα2b dose, with frequent need for hydroxyurea combinations, was noted. This real-world experience suggests a significant impact of local regulations on drug prescription and the need for greater real-world data collection on ropegIFNα2b in PV patients. Also, it describes appropriate multidisciplinary screening and monitoring procedures during ropegIFNα2b therapy., (© 2024. The Author(s).)

Background: Patients with myeloproliferative neoplasms (MPN) are exposed to a higher risk of cardiovascular disease, especially cardiovascular calcification. The present research aimed to analyze the clinical features and coronary artery calcium score (CACS) in MPN patients, and construct an effective model to predict acute coronary syndrome (ACS) in MPN patients., Materials and Methods: A total of 175 MPN patients and 175 controls were recruited from the First Affiliated Hospital of Ningbo University. Based on cardiovascular events, the MPN patients were divided into the ACS group and the non-ACS group. Multivariate Cox analysis was completed to explore ACS-related factors. Furthermore, ROC curves were plotted to assess the predictive effect of CACS combined with white blood cells (WBC) and platelet for ACS in MPN patients., Results: The MPN group exhibited a higher CACS than the control group (133 vs. 55, P  < 0.001). A total of 16 patients developed ACS in 175 MPN patients. Compared with non-ACS groups, significant differences in age, diabetes, smoking history, WBC, percentage of neutrophil, percentage of lymphocyte, neutrophil count, hemoglobin, hematocrit, platelet, lactate dehydrogenase, β 2 -microglobulin, and JAK2V617F mutation were observed in the ACS groups. In addition, the CACS in the ACS group was also significantly higher than that in the non-ACS group (374.5 vs. 121, P  < 0.001). The multivariable Cox regression analysis identified WBC, platelet, and CACS as independent risk factors for ACS in MPN patients. Finally, ROC curves indicated that WBC, platelet, and CACS have a high predictive value for ACS in MPN patients (AUC = 0.890)., Conclusion: CACS combined with WBC and platelet might be a promising model for predicting ACS occurrence in MPN patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Huang, Zhang, Shen, Zheng, Ding, Pan and Ruan.)

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., Competing Interests: The authors declare no conflicts of interest.

Myeloproliferative neoplasms (MPN) are blood cancers that appear after acquiring a driver mutation in a hematopoietic stem cell. These hematological malignancies result in the overproduction of mature blood cells and, if not treated, induce a risk of cardiovascular events and thrombosis. Pegylated IFN$\alpha $ is commonly used to treat MPN, but no clear guidelines exist concerning the dose prescribed to patients. We applied a model selection procedure and ran a hierarchical Bayesian inference method to decipher how dose variations impact the response to the therapy. We inferred that IFN$\alpha $ acts on mutated stem cells by inducing their differentiation into progenitor cells; the higher the dose, the higher the effect. We found that the treatment can induce long-term remission when a sufficient (patient-dependent) dose is reached. We determined this minimal dose for individuals in a cohort of patients and estimated the most suitable starting dose to give to a new patient to increase the chances of being cured., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.)

The presence of steatotic liver disease (SLD) is associated with an increased cardiovascular risk in the general population. Chronic myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET) and polycythemia vera (PV), are characterized by clonal myeloproliferation, chronic inflammatory state, and increased cardiovascular morbidity and mortality. The aim of this single-center study was to analyze clinical associations and the potential prognostic impact of SLD in ET and PV patients. We retrospectively included 108 patients (64 ET and 44 PV); median age was 70.5 years (range 21-92), 68 (63 %) were females, and the median follow-up time was 69 months. Baseline SLD presence was defined ultrasonographically and was detected in 25 (23.1 %) patients. There were no associations of SLD with any of the clinical and laboratory patient characterictics. Also, baseline ultrasonographic presence of SLD did not have an impact on future thrombotic, bleeding and disease transformation risk, nor patient survival. None of the patients experienced signs of liver failure during the follow-up. In conclusion, the presence of SLD in ET and PV patients does not seem to have major clinical implications. Therefore, patients may be advised about the generally harmless nature of SLD when occurring in the MPN context., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Patients with myeloproliferative neoplasms (MPNs) experience a high disease-related symptom burden. A specific instrument to evaluate quality of life (QoL), i.e., the MPN Symptom Assessment Form Total Symptom Score (MPN-SAF TSS; MPN-10), was developed. We conducted the translation, cultural adaptation, and validation into Romanian of the MPN-10. Methods: We translated the MPN-10 and tested its psychometric properties. Results: We recruited 180 MPN patients: 66 polycythemia vera (36.67%), 61 essential thrombocythemia (33.89%), 51 primary and secondary myelofibrosis (SMF) (28.33%), and 2 MPN-unclassifiable (1.11%). The mean TSS was 19.51 ± 16.51 points. Fatigue, inactivity, and concentration problems were the most cumbersome symptoms. We detected scoring differences between MPN subtypes regarding weight loss ( p < 0.001), fatigue ( p = 0.006), early satiety ( p = 0.007), night sweats ( p = 0.047), pruritus ( p = 0.05), and TSS ( p = 0.021). There were strong positive associations between TSS and inactivity, fatigue, and concentration problems, and moderate negative correlations between QoL scores and all MPN-10 items. Cronbach's α internal consistency coefficient was 0.855. The Kaiser-Meyer-Olkin construct validity test result was 0.870 and the Bartlett Sphericity Test was significant ( p < 0.001). Symptom scores were loaded into one single factor according to the exploratory factor analysis. Conclusions: The Romanian MPN-10 version displayed excellent psychometric properties and is a reliable instrument for assessing symptom burden and QoL in Romanian MPN patients.

Chronic myeloid leukemia is defined by the presence of the Philadelphia translocation t (9; 22) resulting in the BCR::ABL1 fusion. The other myeloproliferative neoplasms (MPN) subtypes also carry typical chromosomal abnormalities, which however are not pathognomonic for a specific entity of MPN. According to the WHO classification the distinction between these entities is still based on the integration of cytological, histopathological and molecular findings. Progression of CML into accelerated and blastic phase is usually driven by additional chromosome abnormalities and ABL1 kinase mutations. In the other MPN subtypes the additional mutations besides driver gene mutations in JAK2, MPL and CALR have a decisive impact on the propensity for progression. In addition, the sequence in which the driver mutations and risk conveying additional mutations have been acquired appears to play an important role. Here, we review cytogenetic and molecular changes in CML and MPN that should be evaluated during diagnosis and disease monitoring., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Hannover Medical School. Published by Elsevier Ltd.. All rights reserved.)