Oxford Specialist Handbook: Myeloproliferative Neoplasms

2020 ◽  
Keyword(s):  
State Of The Art ◽  
Myeloproliferative Neoplasms ◽  
Myeloid Cell ◽  
Primary Myelofibrosis ◽  
Polycythaemia Vera ◽  
Clinical Knowledge ◽  
Cell Lineages ◽  
The Past ◽  
Accessible Format ◽  
Excessive Accumulation

Our understanding of myeloproliferative neoplasms (MPN) disorders, a group of clonal haematological malignancies characterized by excessive accumulation of one or more myeloid cell lineages, has grown considerably over the past four decades. Even more importantly is the speed at which many of these findings were translated to accord survival benefits to our patients with MPN, in particular chronic myeloid leukaemia (CML), polycythaemia vera (PV), essential thrombocythaemia (ET), and primary myelofibrosis (PMF). This text offers a detailed evidence-based guide to MPN in an easily accessible format, structure to facilitate learning specialist information presenting core information in ‘bite size’ chunks. Each chapter summarizes the state-of-the art preclinical and clinical knowledge, and its impact on the clinical management of patients with MPN.

Leukaemic Transformation of Philadelphia-chromosome-negative Myeloproliferative Neoplasms — A Review of the Molecular Background

2011 ◽  
Vol 07 (01) ◽  
pp. 59
Author(s):  
Nils H Thoennissen ◽  
H Phillip Koeffler ◽  
◽  
Keyword(s):  
Chromosomal Abnormalities ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myeloid Cell ◽  
Primary Myelofibrosis ◽  
Haematopoietic Stem Cell ◽  
Polycythaemia Vera ◽  
Causative Role ◽  
Blast Phase

Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), including polycythaemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythaemia (ET), are clonal haematopoietic stem cell disorders characterised by proliferation of one or more myeloid cell lineages. They are closely associated with theJAK2V617F mutation, whose detection is used as a clonal marker in the differential diagnosis of MPN. Despite recent improvements in the molecular diagnosis and therapeutic regimen of these chronic disorders, haematological evolution to blast phase remains a major cause of long-term mortality. The mechanism of MPN transformation is still a matter of some controversy because of insufficient insights into the underlying molecular pathogenesis. The purpose of this article is to summarise the increasing data concerning the mechanism of leukaemic evolution of patients diagnosed with chronic MPN. Chromosomal abnormalities and genes that have been shown to play a potential causative role in chronic-phase acceleration are discussed, as are aberrations that may serve as prognostic markers in the blast phase of MPN.

scholarly journals The Role of Neutrophilic Granulocytes in Philadelphia Chromosome Negative Myeloproliferative Neoplasms

2021 ◽  
Vol 22 (17) ◽  
pp. 9555
Author(s):  
Dominik Kiem ◽  
Sandro Wagner ◽  
Teresa Magnes ◽  
Alexander Egle ◽  
Richard Greil ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Myeloid Cell ◽  
Primary Myelofibrosis ◽  
Neutrophilic Granulocytes ◽  
Essential Thrombocytosis ◽  
Cell Lineages ◽  
Hemorrhagic Events ◽  
Venous Thromboembolic

Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are composed of polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF). The clinical picture is determined by constitutional symptoms and complications, including arterial and venous thromboembolic or hemorrhagic events. MPNs are characterized by mutations in JAK2, MPL, or CALR, with additional mutations leading to an expansion of myeloid cell lineages and, in PMF, to marrow fibrosis and cytopenias. Chronic inflammation impacting the initiation and expansion of disease in a major way has been described. Neutrophilic granulocytes play a major role in the pathogenesis of thromboembolic events via the secretion of inflammatory markers, as well as via interaction with thrombocytes and the endothelium. In this review, we discuss the molecular biology underlying myeloproliferative neoplasms and point out the central role of leukocytosis and, specifically, neutrophilic granulocytes in this group of disorders.

Haematopathology of classic myeloproliferative neoplasms

2020 ◽  
pp. 45-62
Author(s):  
Hans Michael Kvasnicka ◽  
Jürgen Thiele
Keyword(s):  
Continuous Improvement ◽  
Who Classification ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
World Health ◽  
Polycythaemia Vera ◽  
The World ◽  
Health Organization ◽  
Diagnostic Importance

The classification of the World Health Organization (WHO) continues to advocate the diagnostic importance of bone marrow (BM) morphology in the diagnostic workup of myeloproliferative neoplasms (MPN). In this regard, distinctive histological BM patterns characterize specific subtypes of MPN and are the key to a meaningful clinical and molecular-defined risk stratification of patients. In this regard, the morphological denominator includes a characteristic megakaryocytic proliferation along with variable changes in the granulopoiesis and erythropoiesis. Importantly, diagnosis of MPN requires absence of relevant dysgranulopoiesis or dyserythropoiesis. In terms of clinical practice, the concept of precursor stages provides the possibility of an early intervention by appropriate therapeutic regimens that might prevent fatal complications like thrombosis and haemorrhage, especially in early stages of polycythaemia vera or in primary myelofibrosis. However, the WHO classification is not aimed to capture all biological true cases of MPN or guarantee a complete diagnostic specificity and thus might be in need of continuous improvement following clinical experience.

scholarly journals Genomics of Myeloproliferative Neoplasms

2017 ◽  
Vol 35 (9) ◽  
pp. 947-954 ◽  
Author(s):  
Katerina Zoi ◽  
Nicholas C.P. Cross
Keyword(s):  
Clinical Laboratory ◽  
Myeloproliferative Neoplasms ◽  
Genomic Analysis ◽  
Myeloid Cell ◽  
Scoring Systems ◽  
Driver Mutations ◽  
Cell Lineages ◽  
Disease Definition ◽  
Genetic Complexity ◽  
Multiple Abnormalities

Myeloproliferative neoplasms (MPNs) are a group of related clonal hematologic disorders characterized by excess accumulation of one or more myeloid cell lineages and a tendency to transform to acute myeloid leukemia. Deregulated JAK2 signaling has emerged as the central phenotypic driver of BCR -ABL1–negative MPNs and a unifying therapeutic target. In addition, MPNs show unexpected layers of genetic complexity, with multiple abnormalities associated with disease progression, interactions between inherited factors and phenotype driver mutations, and effects related to the order in which mutations are acquired. Although morphology and clinical laboratory analysis continue to play an important role in defining these conditions, genomic analysis is providing a platform for better disease definition, more accurate diagnosis, direction of therapy, and refined prognostication. There is an emerging consensus with regard to many prognostic factors, but there is a clear need to synthesize genomic findings into robust, clinically actionable and widely accepted scoring systems as well as the need to standardize the laboratory methodologies that are used.

scholarly journals JAK2-V617F mutation in patients with myeloproliferative neoplasms: Association with FLT3-ITD mutation

2010 ◽  
Vol 138 (9-10) ◽  
pp. 614-618
Author(s):  
Vesna Spasovski ◽  
Natasa Tosic ◽  
Tatjana Kostic ◽  
Sonja Pavlovic ◽  
Milica Colovic
Keyword(s):  
Cell Proliferation ◽  
Myeloproliferative Neoplasms ◽  
Myeloid Cell ◽  
Jak2 V617f ◽  
Signalling Pathway ◽  
Janus Kinase ◽  
Jak2 V617f Mutation ◽  
Polycythaemia Vera ◽  
Jak2 Mutation ◽  
V617f Mutation

Introduction. An acquired somatic mutation V617F in Janus kinase 2 gene (JAK2) is the cause of uncontrolled proliferation in patients with myeloproliferative neoplasms. It is known that uncontrolled myeloid cell proliferation is also provoked by alteration in other genes, e.g. mutations in receptor tyrosine kinase FLT3 gene. FLT3 represents the most frequently mutated gene in acute myeloid leukaemia. Interestingly, mutated FLT3- ITD (internal tandem duplication) protein is a member of the same signalling pathway as JAK2 protein, the STAT5 signalling pathway. STAT5 activation is recognized as important for selfrenewal of haematopoetic stem cells. Objective. The aim of this study was the detection of JAK2- V617F mutation in patients with myeloproliferative neoplasms. Additionally, we investigated the presence of FLT3-ITD mutation in JAK2-V617F-positive patients in order to shed the light on the hypothesis of a similar role of these two molecular markers in haematological malignancies. Methods. Using allele-specific PCR, 61 patients with known or suspected diagnosis of myeloproliferative neoplasms were tested for the presence of JAK2-V617F mutation. Samples that were positive for JAK2 mutation were subsequently tested for the presence of FLT3-ITD mutation by PCR. Results. Eighteen of 61 analysed patients were positive for JAK2-V617F mutation. Among them, 8/18 samples were diagnosed as polycythaemia vera, and 10/18 as essential thrombocythaemia. None of JAK2-V617F-positive patient was positive for FLT3-ITD mutation. Conclusion. This study suggests that one activating mutation is sufficient for aberrant cell proliferation leading to malignant transformation of haematopoetic stem cell.

JAK-2 V617F mutation increases heparanase procoagulant activity

2016 ◽  
Vol 115 (01) ◽  
pp. 73-80 ◽  
Author(s):  
Inna Kogan ◽  
Dafna Chap ◽  
Ron Hoffman ◽  
Elena Axelman ◽  
Benjamin Brenner ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Erythropoietin Receptor ◽  
Procoagulant Activity ◽  
Coagulation System ◽  
Polycythaemia Vera ◽  
Bone Marrow Biopsies ◽  
Increased Risk ◽  
V617f Mutation ◽  
Mcf 7

SummaryPatients with polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are at increased risk of arterial and venous thrombosis. In patients with ET a positive correlation was observed between JAK-2 V617F mutation, that facilitates erythropoietin receptor signalling, and thrombotic events, although the mechanism involved is not clear. We previously demonstrated that heparanase protein forms a complex and enhances the activity of the blood coagulation initiator tissue factor (TF) which leads to increased factor Xa production and subsequent activation of the coagulation system. The present study was aimed to evaluate heparanase procoagulant activity in myeloproliferative neoplasms. Forty bone marrow biopsies of patients with ET, PV, PMF and chronic myelogenous leukaemia (CML) were immunostained to heparanase, TF and TF pathway inhibitor (TFPI). Erythropoietin receptor positive cell lines U87 human glioma and MCF-7 human breast carcinoma were studied. Heparanase and TFPI staining were more prominent in ET, PV and PMF compared to CML. The strongest staining was in JAK-2 positive ET biopsies. Heparanase level and procoagulant activity were higher in U87 cells transfected to over express JAK-2 V617F mutation compared to control and the effect was reversed using JAK-2 inhibitors (Ruxolitinib, VZ3) and hydroxyurea, although the latter drug did not inhibit JAK-2 phosphorylation. Erythropoietin increased while JAK-2 inhibitors decreased the heparanase level and procoagulant activity in U87 and MCF-7 parental cells. In conclusion, JAK-2 is involved in heparanase up-regulation via the erythropoietin receptor. The present findings may potentially point to a new mechanism of thrombosis in JAK-2 positive ET patients.

scholarly journals Renal post-mortem findings in myeloproliferative and myelodysplastic/myeloproliferative neoplasms

2021 ◽  
Author(s):  
Fermin Person ◽  
Sara C. Meyer ◽  
Helmut Hopfer ◽  
Thomas Menter
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Renal Involvement ◽  
Primary Myelofibrosis ◽  
Extramedullary Hematopoiesis ◽  
Glomerular Sclerosis ◽  
Polycythaemia Vera ◽  
Post Mortem ◽  
Hypertensive Nephropathy ◽  
Hematological Disorders ◽  
Tumor Involvement

AbstractMyeloproliferative neoplasms (MPN) are a heterogeneous group of hematological disorders presenting with an increased proliferation in one or several hematological cell lines. Renal manifestations of MPN have not been fully characterized so far. To morphologically assess the potential renal involvement in MPN patients, we analyzed histomorphological findings of a post-mortem cohort (n = 57) with a disease history of Philadelphia-negative MPN including polycythaemia vera, primary myelofibrosis, essential thrombocythemia, or chronic myelomonocytic leukemia (CMML). Seven (12.2%) patients presented with a pattern of diffuse glomerulosclerosis not attributable to diabetic or hypertensive nephropathy. Weak C4d staining suggestive for chronic thrombotic microangiopathy (TMA) was observed in 4/7 cases. Glomerulonephritis was excluded by light microscopy and immunohistochemistry. Patients with a pattern of diffuse glomerulosclerosis did not differ from the rest of the cohort regarding MPN subtype, disease duration, age, or sex. No significant proteinuria had been observed before death. Further findings attributed to MPNs were extramedullary hematopoiesis (n = 5; 8.8%) and tumor involvement in advanced disease (n = 4; 7.0%). Other common findings included arteriolosclerosis (n = 18; 31.6%) and signs of shock (n = 8; 14.0%). To our knowledge, this study is so far the largest investigating renal findings in MPN patients. There may be a causal relationship between idiopathic diffuse glomerular sclerosis and MPN, although its clinical significance and pathophysiology remain uncertain with TMA probably being relevant in a subgroup of cases. Our findings demonstrate the spectrum of renal findings in MPN from early to terminal disease of which hematologists should be aware of in daily clinical practice.

Monitoring efforts in myeloproliferative neoplasms

2020 ◽  
pp. 234-248
Author(s):  
Daniel Egan ◽  
Jerald P. Radich
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Polycythaemia Vera ◽  
Mrna Levels ◽  
Tyrosine Kinase Inhibitor Therapy

Targeted therapy with tyrosine kinase inhibitors (TKI) has transformed the therapy of chronic myeloid leukaemia (CML), and is increasingly playing a role in the management of the myeloproliferative neoplasms (MPN), as a whole. In CML, the Philadelphia chromosome drives disease pathogenesis, and is the basis of both therapy (aimed at the BCR-ABL protein) and monitoring (the BCR-ABL chimeric mRNA). The efficacy of tyrosine kinase inhibitor therapy in CML is now accessed by reaching treatment milestones based on the BCR-ABL mRNA levels. In MPN, the landscape of genetic mutations associated with essential thrombocytosis (ET), polycythaemia vera (PV), and primary myelofibrosis (PMF) is ongoing. However, the recent discoveries of the JAK2 V617F and calreticulin mutations (for example) have a similar potential for disease targeting and monitoring as in CML.

Myeloproliferative neoplasms

2015 ◽  
Author(s):  
Drew Provan ◽  
Trevor Baglin ◽  
Inderjeet Dokal ◽  
Johannes de Vos
Keyword(s):  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Polycythaemia Vera ◽  
Essential Thrombocythaemia ◽  
Cell Disease ◽  
Reactive Thrombocytosis ◽  
History Of ◽  
Mast Cell Disease ◽  
Idiopathic Erythrocytosis

Myeloproliferative neoplasms (MPNs) - Pathogenesis of the MPNs - Polycythaemia vera (PV) - Natural history of PV - Management of PV - Secondary erythrocytosis - Relative erythrocytosis - Idiopathic erythrocytosis - Essential thrombocythaemia - Reactive thrombocytosis - Primary myelofibrosis - Chronic neutrophilic leukaemia - Eosinophilic syndromes and neoplasms - Mastocytosis (mast cell disease) - Systemic mastocytosis - MPN—unclassifiable

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