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Annals of Hematology Jul 2023The classic BCR-ABL1-negative myeloproliferative neoplasm (MPN) is a highly heterogeneous hematologic tumor that includes three subtypes, namely polycythemia vera (PV),...
The classic BCR-ABL1-negative myeloproliferative neoplasm (MPN) is a highly heterogeneous hematologic tumor that includes three subtypes, namely polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). Despite having the same JAK2 mutation, the clinical manifestations of these three subtypes of MPN differ significantly, which suggests that the bone marrow (BM) immune microenvironment may also play an important role. In recent years, several studies have shown that peripheral blood monocytes play an important role in promoting MPN. However, to date, the role of BM monocytes/macrophages in MPN and their transcriptomic alterations remain incompletely understood. The purpose of this study was to clarify the role of BM monocytes/macrophages in MPN patients with the JAK2 mutation. MPN patients with the JAK2 mutation were enrolled in this study. We investigated the roles of monocytes/macrophages in the BM of MPN patients, using flow cytometry, monocyte/macrophage enrichment sorting, cytospins and Giemsa-Wright staining, and RNA-seq. Pearson correlation coefficient analysis was also used to detect the correlation between BM monocytes/macrophages and the MPN phenotype. In the present study, the proportion of CD163 monocytes/macrophages increased significantly in all three subtypes of MPN. Interestingly, the percentages of CD163 monocytes/macrophages are positively correlated with HGB in PV patients and PLT in ET patients. In contrast, the percentages of CD163 monocytes/macrophages are negatively correlated with HGB and PLT in PMF patients. It was also found that CD14CD16 monocytes/macrophages increased and correlated with MPN clinical phenotypes. RNA-seq analyses demonstrated that the transcriptional expressions of monocytes/macrophages in MPN patients are relatively distinct. Gene expression profiles of BM monocytes/macrophages suggest a specialized function in support of megakaryopoiesis in ET patients. In contrast, BM monocytes/macrophages yielded a heterogeneous status in the support or inhibition of erythropoiesis. Significantly, BM monocytes/macrophages shaped an inflammatory microenvironment, which, in turn, promotes myelofibrosis. Thus, we characterized the roles of increased monocytes/macrophages in the occurrence and progression of MPNs. Our findings of the comprehensive transcriptomic characterization of BM monocytes/macrophages provide important resources to serve as a basis for future studies and future targets for the treatment of MPN patients.
Topics: Humans; Bone Marrow; Monocytes; Myeloproliferative Disorders; Polycythemia Vera; Mutation; Bone Marrow Neoplasms; Thrombocythemia, Essential; Janus Kinase 2; Tumor Microenvironment
PubMed: 37233774
DOI: 10.1007/s00277-023-05284-5 -
British Journal of Haematology Nov 2022Myeloproliferative neoplasms can be associated with bleeding manifestations which can cause significant morbidities. Although haematologists are aware of the likelihood... (Review)
Review
Myeloproliferative neoplasms can be associated with bleeding manifestations which can cause significant morbidities. Although haematologists are aware of the likelihood of this complication in the setting of myeloproliferative neoplasms, it may often be overlooked especially in patients with no extreme elevation of blood counts and those with myelofibrosis. Acquired von Willebrand syndrome and platelet dysfunction are the two common diagnoses to be considered in this regard. In this review article, we discuss the mechanisms for the development of these rare bleeding disorders, their diagnosis and practical management.
Topics: Humans; von Willebrand Factor; Neoplasms; Myeloproliferative Disorders; von Willebrand Diseases; Primary Myelofibrosis; Hemorrhage
PubMed: 35724983
DOI: 10.1111/bjh.18322 -
Virchows Archiv : An International... Oct 2022The first section of the bone marrow workshop of the European Association of Haematopathology (EAHP) 2020 Virtual Meeting was dedicated to pediatric myeloid neoplasms....
The first section of the bone marrow workshop of the European Association of Haematopathology (EAHP) 2020 Virtual Meeting was dedicated to pediatric myeloid neoplasms. The section covered the whole spectrum of myeloid neoplasms, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia (AML). The workshop cases are hereby presented, preceded by an introduction on these overall rare diseases in this age group. Very rare entities such as primary myelofibrosis, pediatric MDS with fibrosis, and MDS/MPN with JMML-like features and t(4;17)(q12;q21); FIP1L1::RARA fusion, are described in more detail.
Topics: Bone Marrow; Child; Humans; Myelodysplastic Syndromes; Myelodysplastic-Myeloproliferative Diseases; Myeloproliferative Disorders; Neoplasms
PubMed: 35819517
DOI: 10.1007/s00428-022-03375-8 -
Cell Chemical Biology Jun 2023Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and other hematologic malignancies. Currently available...
Recurrent JAK2 alterations are observed in myeloproliferative neoplasms, B-cell acute lymphoblastic leukemia, and other hematologic malignancies. Currently available type I JAK2 inhibitors have limited activity in these diseases. Preclinical data support the improved efficacy of type II JAK2 inhibitors, which lock the kinase in the inactive conformation. By screening small molecule libraries, we identified a lead compound with JAK2 selectivity. We highlight analogs with on-target biochemical and cellular activity and demonstrate in vivo activity using a mouse model of polycythemia vera. We present a co-crystal structure that confirms the type II binding mode of our compounds with the "DFG-out" conformation of the JAK2 activation loop. Finally, we identify a JAK2 G993A mutation that confers resistance to the type II JAK2 inhibitor CHZ868 but not to our analogs. These data provide a template for identifying novel type II kinase inhibitors and inform further development of agents targeting JAK2 that overcome resistance.
Topics: Humans; Mutation; Myeloproliferative Disorders; Janus Kinase 2
PubMed: 37290440
DOI: 10.1016/j.chembiol.2023.05.007 -
Current Hematologic Malignancy Reports Oct 2021Coronavirus disease 2019 (COVID-19) is associated with a high rate of respiratory failure, thromboembolism, bleeding, and death. Patients with myeloproliferative... (Review)
Review
PURPOSE OF REVIEW
Coronavirus disease 2019 (COVID-19) is associated with a high rate of respiratory failure, thromboembolism, bleeding, and death. Patients with myeloproliferative neoplasms (MPNs) are prone to both thrombosis and bleeding, calling for special care during COVID-19. We reviewed the clinical features of MPN patients with COVID-19, suggesting guidance for treatment.
RECENT FINDINGS
One study by the European LeukemiaNet collected 175 MPN patients with COVID-19 during the first wave of the pandemic, from February to May 2020. Patients with primary myelofibrosis (PMF) were at higher risk of mortality (48%) in comparison with essential thrombocythemia (ET) (25%) and polycythemia vera (19%); the risk of death was higher in those patients who abruptly discontinued ruxolitinib. In patients followed at home, in regular wards, or in ICU, the thrombosis rate was 1.0%, 2.8%, and 18.4%, respectively. Independent risk factors for thrombosis were ET phenotype, transfer to ICU, and neutrophil/lymphocyte ratio; major bleeding occurred in 4.3% of patients, particularly those with PMF. MPN patients with non-severe COVID-19 treated at home should continue their primary or secondary antithrombotic prophylaxis with aspirin or oral anticoagulants. In the case of hospitalization, patients assuming aspirin should add low molecular weight heparin (LMWH) at standard doses. In contrast, LMWH at intermediate/therapeutic doses should replace oral anticoagulants prescribed for atrial fibrillation or previous venous thromboembolism. Intermediate/high doses of LMWH can also be considered in ICU patients with ET, particularly in the case of a rapid decline in the number of platelets and progressive respiratory failure.
Topics: Anticoagulants; COVID-19; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; Myeloproliferative Disorders; Pandemics; SARS-CoV-2; Thrombosis
PubMed: 34586561
DOI: 10.1007/s11899-021-00647-z -
Blood Jun 2022Leukemic transformation (LT) of myeloproliferative neoplasm (MPN) has a dismal prognosis and is largely fatal. Mutational inactivation of TP53 is the most common somatic...
Leukemic transformation (LT) of myeloproliferative neoplasm (MPN) has a dismal prognosis and is largely fatal. Mutational inactivation of TP53 is the most common somatic event in LT; however, the mechanisms by which TP53 mutations promote LT remain unresolved. Using an allelic series of mouse models of Jak2/Trp53 mutant MPN, we identify that only biallelic inactivation of Trp53 results in LT (to a pure erythroleukemia [PEL]). This PEL arises from the megakaryocyte-erythroid progenitor population. Importantly, the bone morphogenetic protein 2/SMAD pathway is aberrantly activated during LT and results in abnormal self-renewal of megakaryocyte-erythroid progenitors. Finally, we identify that Jak2/Trp53 mutant PEL is characterized by recurrent copy number alterations and DNA damage. Using a synthetic lethality strategy, by targeting active DNA repair pathways, we show that this PEL is highly sensitive to combination WEE1 and poly(ADP-ribose) polymerase inhibition. These observations yield new mechanistic insights into the process of p53 mutant LT and offer new, clinically translatable therapeutic approaches.
Topics: Animals; Bone Morphogenetic Protein 2; Janus Kinase 2; Megakaryocyte-Erythroid Progenitor Cells; Megakaryocytes; Mice; Mutation; Myeloproliferative Disorders; Tumor Suppressor Protein p53
PubMed: 35421216
DOI: 10.1182/blood.2021014465 -
International Journal of Molecular... Aug 2023V617F is the predominant driver mutation in patients with Philadelphia-negative myeloproliferative neoplasms (MPN). mutations are also frequent in clonal hematopoiesis... (Review)
Review
V617F is the predominant driver mutation in patients with Philadelphia-negative myeloproliferative neoplasms (MPN). 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 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 -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.
Topics: Humans; Early Detection of Cancer; Genome-Wide Association Study; Germ-Line Mutation; Myeloproliferative Disorders; Neoplasms
PubMed: 37628880
DOI: 10.3390/ijms241612700 -
Current Hematologic Malignancy Reports Apr 2020Myeloproliferative neoplasms are traditionally seen in older adults, making them poorly understood in younger patients. Clinical presentation, genetic landscape,... (Review)
Review
PURPOSE OF REVIEW
Myeloproliferative neoplasms are traditionally seen in older adults, making them poorly understood in younger patients. Clinical presentation, genetic landscape, outcomes, and best management practices are inadequately described in this group. Over the past decade, more research has focused on younger patients, and this paper seeks to review and describe the current status of the field.
RECENT FINDINGS
A recent review analyzed the available pediatric MPN literature and highlighted the paucity of published data. Pediatric patients showed lower rates of the common mutations found in adults, thrombotic events, and disease transformation to myelofibrosis and acute leukemia. A number of centers have recently shared their experience with young adult patients. Better survival outcomes were confirmed for young adult patients compared to older patients. There is still much to learn about myeloproliferative neoplasms in pediatric and young adult patients, but currently available data showing better outcomes is reassuring.
Topics: Adolescent; Adult; Age of Onset; Biomarkers, Tumor; Child; Child, Preschool; Genetic Predisposition to Disease; Humans; Infant; Myeloproliferative Disorders; Phenotype; Risk Factors; Treatment Outcome; Young Adult
PubMed: 32172359
DOI: 10.1007/s11899-020-00571-8 -
Nature Communications Sep 2022Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including...
Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including myeloproliferative neoplasms (MPNs). Here we show that IL-1β serum levels and expression of IL-1 receptors on hematopoietic progenitors and stem cells correlate with JAK2-V617F mutant allele fraction in peripheral blood of patients with MPN. We show that the source of IL-1β overproduction in a mouse model of MPN are JAK2-V617F expressing hematopoietic cells. Knockout of IL-1β in hematopoietic cells of JAK2-V617F mice reduces inflammatory cytokines, prevents damage to nestin-positive niche cells and reduces megakaryopoiesis, resulting in decrease of myelofibrosis and osteosclerosis. Inhibition of IL-1β in JAK2-V617F mutant mice by anti-IL-1β antibody also reduces myelofibrosis and osteosclerosis and shows additive effects with ruxolitinib. These results suggest that inhibition of IL-1β with anti-IL-1β antibody alone or in combination with ruxolitinib could have beneficial effects on the clinical course in patients with myelofibrosis.
Topics: Animals; Interleukin-1beta; Janus Kinase 2; Mice; Mice, Knockout; Myeloproliferative Disorders; Neoplasms; Nitriles; Osteosclerosis; Primary Myelofibrosis; Pyrazoles; Pyrimidines
PubMed: 36100613
DOI: 10.1038/s41467-022-32927-4 -
Advances in Therapy May 2020Patients with myeloproliferative neoplasms (MPNs), a group of rare haematological conditions including polycythaemia vera, essential thrombocythaemia, and myelofibrosis,... (Review)
Review
Patients with myeloproliferative neoplasms (MPNs), a group of rare haematological conditions including polycythaemia vera, essential thrombocythaemia, and myelofibrosis, often experience a range of symptoms which can significantly impact their quality of life (QoL). Although symptom burden is highest in myelofibrosis and high-risk patients, lower-risk patients also report symptoms impacting their daily life and ability to work. In addition to physical symptoms, MPNs affect emotional well-being, with anxiety and depression frequently reported by patients. Despite significant advances in treatment options, such as the introduction of JAK1/JAK2 inhibitors, therapy for MPNs is often palliative; therefore, reduction of symptoms and improvement of QoL should be considered as major treatment goals. One of the main issues impacting MPN treatment is the discord between patient and physician perceptions of symptom burden, treatment goals, and expectations. New technologies, such as app-based reporting, can aid this communication, but are still not widely implemented. Additionally, regional variation further affects the psychosocial burden of MPNs on patients and their associates, as treatments and access to clinical trials are options for patients living in some areas, but not others. Overcoming some of the challenges in patient-physician communication and treatment access are key to improving disease management and QoL, as well as giving the patient greater input in treatment decisions.
Topics: Antineoplastic Agents; Disease Management; Female; Hematologic Neoplasms; Humans; Janus Kinase 1; Janus Kinase 2; Male; Myeloproliferative Disorders; Physician-Patient Relations; Protein Kinase Inhibitors; Quality of Life; Severity of Illness Index
PubMed: 32329011
DOI: 10.1007/s12325-020-01314-0