Search Results (57)

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

Philadelphia-negative myeloproliferative neoplasms (Ph-MPNs) are clonal hematologic malignancies characterized not only by driver mutations such as JAK2V617F, CALR, and MPL but also by a profoundly dysregulated immune microenvironment. Chronic inflammation and immune remodeling sustain malignant hematopoiesis and contribute to disease progression from essential thrombocythemia (ET) and polycythemia vera (PV) to overt myelofibrosis (MF). Pro-inflammatory cytokines and chemokines—including IL-2, IFN-α, IL-23, and TNF-α—drive abnormal T cell polarization, favoring a pathogenic Th17 phenotype. Lymphocyte subset analysis reveals a predominance of exhausted PD-1⁺ T cells, reflecting impaired immune surveillance. Concurrently, alterations in neutrophil apoptosis lead to persistent inflammation and stromal activation. GRO-α (CXCL1) is elevated in ET but reduced in MF, suggesting a subtype-specific role in disease biology. Fibrosis-promoting factors such as TGF-β and IL-13 mediate bone marrow remodeling and megakaryocyte expansion, while VEGF and other angiogenic factors enhance vascular niche alterations, particularly in PV. These immunopathologic features underscore novel therapeutic vulnerabilities. In addition to JAK inhibition, targeted strategies such as CXCR1/2 antagonists, anti-TGF-β agents, and immune checkpoint inhibitors (PD-1/PD-L1 blockade) may offer disease-modifying potential. Understanding the interplay between cytokine signaling and immune cell dysfunction is crucial for developing precision immunotherapies in MPNs. 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

Background and Objectives: Philadelphia (Ph)-negative myeloproliferative neoplasms can exhibit defects in Janus kinase 2 (JAK2), Calreticulin (CalR), and MPL genes. It is possible that the presence of other driver mutations may influence diagnosis and prognosis in patients who do not have a JAK2 gene mutation. The purpose of this study was to assess the frequency of CalR and MPL gene mutations and the clinical effects of these mutations in JAK2 gene-unmutated MPN patients from a single center. Materials and Methods: We examined 46 patients (ET/PMF: 34/12) diagnosed with MPNs regarding their genetic conditions, diagnoses, and complications. Results: CalR Type 1 gene mutation was detected in 26.1% of cases, CalR Type 2 gene mutation in 13.0%, MPL-L gene mutation in 2.2%, and MPL-K gene mutation in 6.5%. In total, 56.5% of patients were triple-negative. The presence of CalR Type 1 and Type 2 mutations was significantly more prevalent in patients with essential thrombocytosis (ET), although the difference did not reach statistical significance (p = 0.51, p = 0.57). In contrast, MPL mutations were only observed in patients with primary myelofibrosis (PMF). Conclusions: We found no correlation between thrombosis, leukemic transformation, and driver mutations. MPL gene mutation was present in only myelofibrosis patients, and CALR gene mutation was present in one of the three cases of leukemic transformation. The triple-negative group had a lower survival rate, but this difference was not statistically significant (110.3 months vs. 121.4 months, respectively, p = 0.53). However, the sample size was quite small. Our limited observations suggest a possible trend that requires confirmation. Full article

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

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

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

Myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis, and primary myelofibrosis are a unique group of clonal hematopoietic stem cell neoplasms that share somatic, gain-in-function driver mutations in JAK2, CALR, and MPL. As a consequence, these disorders exhibit similar phenotypic features, the most common of which are the ceaseless production of normal erythrocytes, myeloid cells, platelets alone or in combination, extramedullary hematopoiesis, myelofibrosis, and a potential for leukemic transformation. In the case of polycythemia vera and essential thrombocytosis, however, prolonged survival is possible. With an incidence value in the range of 0.5–2.0/100,000, myeloproliferative neoplasms are rare disorders, but they are not new disorders, and after a century of scrutiny, their clinical features and natural histories are well-defined, though their individual management continues to be controversial. With respect to polycythemia vera, there has been a long-standing dispute between those who believe that the suppression of red blood cell production by chemotherapy is superior to phlebotomy to prevent thrombosis, and those who do not. With respect to essential thrombocytosis, there is a similar dispute about the role of platelets in veinous thrombosis, and the role of chemotherapy in preventing thrombosis by suppressing platelet production. Linked to these disputes is another: whether therapy with hydroxyurea promotes acute leukemia in disorders with a substantial possibility of longevity. The 21st century revealed new insights into myeloproliferative neoplasms with the discovery of their three somatic, gain-of-function driver mutations. Almost immediately, this triggered changes in the diagnostic criteria for myeloproliferative neoplasms and their therapy. Most of these changes, however, conflicted with prior well-validated, phenotypically driven diagnostic criteria and the management of these disorders. The aim of this review is to examine these conflicts and demonstrate how genomic discoveries in myeloproliferative neoplasms can be used to effectively complement the known phenotypic features of these disorders for their diagnosis and management. Full article

Diagnosis of myeloid neoplasm is currently performed according to the presence of a predetermined set of clinical, morphological, and molecular diagnostic criteria agreed upon by a consensus of experts. Even strictly adhering to these criteria, it is possible to encounter patients who present features that are not easily ascribable to a single disease category. This is the case, e.g., of patients with de novo myeloid neoplasms with features intermediate between primary myelofibrosis (PMF) and chronic myelomonocytic leukemia (CMML). In this study, we retrospectively searched the pathological database of IRCCS Humanitas Research Hospital to identify cases of chronic myeloid neoplasm with monocytosis with a driver mutation of classic myeloproliferative neoplasms (MPN) and showing morphological MPN features. For each case, we assessed all epidemiological, clinical, histopathological, and molecular data. Then, we carried out a literature review, searching for cases with features similar to those of our patients. We retrieved a total of 13 cases presenting such criteria (9 from the literature review and 4 from our institution); in all of them, there was a coexistence of clinical, histopathological, and molecular myelodysplastic and myeloproliferative features. To date, according to current classifications (World Health Organization and International Consensus Classification), given the presence/absence of essential features for PMF or CMML, these patients should be formally diagnosed as myelodysplastic/myeloproliferative neoplasm unclassified/not otherwise specified (U/NOS). This review aims to summarize the features of these difficult cases and discuss their differential diagnosis and their classification according to the novel classifications and the existing literature on overlapping myeloid neoplasms. 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

Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation sequencing in clinical laboratories, have revolutionized the diagnosis, classification, and clinical decision making of myelofibrosis. Driver mutations involving JAK2, CALR, and MPL induce hyperactivity in the JAK-STAT signaling pathway, which plays a central role in cell survival and proliferation. Approximately 80% of myelofibrosis cases harbor additional mutations, frequently in the genes responsible for epigenetic regulation and RNA splicing. Detecting these mutations is crucial for diagnosing myeloproliferative neoplasms (MPNs), especially in cases where no mutations are present in the three driver genes (triple-negative MPNs). While fibrosis in the bone marrow results from the disturbance of inflammatory cytokines, it is fundamentally associated with mutation-driven hematopoiesis. The mutation profile and order of acquiring diverse mutations influence the MPN phenotype. Mutation profiling reveals clonal diversity in MF, offering insights into the clonal evolution of neoplastic progression. Prognostic prediction plays a pivotal role in guiding the treatment of myelofibrosis. Mutation profiles and cytogenetic abnormalities have been integrated into advanced prognostic scoring systems and personalized risk stratification for MF. Presently, JAK inhibitors are part of the standard of care for MF, with newer generations developed for enhanced efficacy and reduced adverse effects. However, only a minority of patients have achieved a significant molecular-level response. Clinical trials exploring innovative approaches, such as combining hypomethylation agents that target epigenetic regulators, drugs proven effective in myelodysplastic syndrome, or immune and inflammatory modulators with JAK inhibitors, have demonstrated promising results. These combinations may be more effective in patients with high-risk mutations and complex mutation profiles. Expanding mutation profiling studies with more sensitive and specific molecular methods, as well as sequencing a broader spectrum of genes in clinical patients, may reveal molecular mechanisms in cases currently lacking detectable driver mutations, provide a better understanding of the association between genetic alterations and clinical phenotypes, and offer valuable information to advance personalized treatment protocols to improve long-term survival and eradicate mutant clones with the hope of curing MF. Full article

Myeloproliferative neoplasms (MPN) are rare hematologic disorders characterized by clonal hematopoiesis. Familial clustering is observed in a subset of cases, with a notable proportion exhibiting heterozygous germline mutations in DNA double-strand break repair genes (e.g., BRCA1). We investigated the therapeutic potential of targeting BRCA1 haploinsufficiency alongside the JAK2V617F driver mutation. We assessed the efficacy of combining the PARP inhibitor olaparib with interferon-alpha (IFNα) in CRISPR/Cas9-engineered Brca1^+/− Jak2V617F-positive 32D cells. Olaparib treatment induced a higher number of DNA double-strand breaks, as demonstrated by γH2AX analysis through Western blot (p = 0.024), flow cytometry (p = 0.013), and confocal microscopy (p = 0.071). RAD51 foci formation was impaired in Brca1^+/− cells compared to Brca1^+/+ cells, indicating impaired homologous recombination repair due to Brca1 haploinsufficiency. Importantly, olaparib enhanced apoptosis while diminishing cell proliferation and viability in Brca1^+/− cells compared to Brca1^+/+ cells. These effects were further potentiated by IFNα. Olaparib induced interferon-stimulated genes and increased endogenous production of IFNα in Brca1^+/− cells. These responses were abrogated by STING inhibition. In conclusion, our findings suggest that the combination of olaparib and IFNα presents a promising therapeutic strategy for MPN patients by exploiting the synthetic lethality between germline BRCA1 mutations and the JAK2V617F MPN driver mutation. Full article

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) arise due to acquired somatic driver mutations in stem cells and develop over 10–30 years from the earliest cancer stages (essential thrombocythemia, polycythemia vera) towards the advanced myelofibrosis stage with bone marrow failure. The JAK2V617F mutation is the most prevalent driver mutation. Chronic inflammation is considered to be a major pathogenetic player, both as a trigger of MPN development and as a driver of disease progression. Chronic inflammation in MPNs is characterized by persistent connective tissue remodeling, which leads to organ dysfunction and ultimately, organ failure, due to excessive accumulation of extracellular matrix (ECM). Considering that MPNs are acquired clonal stem cell diseases developing in an inflammatory microenvironment in which the hematopoietic cell populations are progressively replaced by stromal proliferation—“a wound that never heals”—we herein aim to provide a comprehensive review of previous promising research in the field of circulating ECM fragments in the diagnosis, treatment and monitoring of MPNs. We address the rationales and highlight new perspectives for the use of circulating ECM protein fragments as biologically plausible, noninvasive disease markers in the management of MPNs. Full article

JAK2 V617F is the predominant driver mutation in patients with Philadelphia-negative myeloproliferative neoplasms (MPN). JAK2 mutations are also frequent in clonal hematopoiesis of indeterminate potential (CHIP) in otherwise “healthy” individuals. However, the period between mutation acquisition and MPN diagnosis (known as latency) varies widely between individuals, with JAK2 mutations detectable several decades before diagnosis and even from birth in some individuals. Here, we will review the current evidence on the biological factors, such as additional mutations and chronic inflammation, which influence clonal expansion and may determine why some JAK2-mutated individuals will progress to an overt neoplasm during their lifetime while others will not. We will also introduce several germline variants that predispose individuals to CHIP (as well as MPN) identified from genome-wide association studies. Finally, we will explore possible mutation screening or interventions that could help to minimize MPN-associated cardiovascular complications or even delay malignant progression. Full article

Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell-derived disorders characterized by uncontrolled proliferation of differentiated myeloid cells. Two main groups of MPN, BCR::ABL1-positive (Chronic Myeloid Leukemia) and BCR::ABL1-negative (Polycythemia Vera, Essential Thrombocytosis, Primary Myelofibrosis) are distinguished. For many years, cytomorphologic and histologic features were the only proof of MPN and attempted to distinguish the different entities of the subgroup BCR::ABL1-negative MPN. World Health Organization (WHO) classification of myeloid neoplasms evolves over the years and increasingly considers molecular abnormalities to prove the clonal hematopoiesis. In addition to morphological clues, the detection of JAK2, MPL and CALR mutations are considered driver events belonging to the major diagnostic criteria of BCR::ABL1-negative MPN. This highlights the preponderant place of molecular features in the MPN diagnosis. Moreover, the advent of next-generation sequencing (NGS) allowed the identification of additional somatic mutations involved in clonal hematopoiesis and playing a role in the prognosis of MPN. Nowadays, careful cytomorphology and molecular biology are inseparable and complementary to provide a specific diagnosis and to permit the best follow-up of these diseases. Full article