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Journal of Cellular and Molecular... Sep 2017A decade on from the description of JAK2 V617F, the MPNs are circumscribed by an increasingly intricate landscape. There is now evidence that they are likely the result... (Review)
Review
A decade on from the description of JAK2 V617F, the MPNs are circumscribed by an increasingly intricate landscape. There is now evidence that they are likely the result of combined genetic dysregulation, with several mutated genes involved in the regulation of epigenetic mechanisms. Epigenetic changes are not due to a change in the DNA sequence but are reversible modifications that dictate the way in which genes may be expressed (or silenced). Among the epigenetic mechanisms, DNA methylation is probably the best described. Currently known MPN-associated mutations now include JAK2, MPL, LNK, CBL, CALR, TET2, ASXL1, IDH1, IDH2, IKZF1 and EZH2. Enhancing our knowledge about the mutation profile of patients may allow them to be stratified into risk groups which would aid clinical decision making. Ongoing work will answer whether the use of epigenetic therapies as alterative pathway targets in combination with JAK inhibitors may be more effective than single agent treatment.
Topics: Chromatin; DNA Methylation; Epigenesis, Genetic; Humans; MicroRNAs; Mutation; Myeloproliferative Disorders
PubMed: 28677265
DOI: 10.1111/jcmm.13095 -
Leukemia Research Apr 2022Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare hematologic malignancy belonging to the category... (Review)
Review
Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare hematologic malignancy belonging to the category of myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes. While certain clinical features, including anemia and thrombocytosis, are common to both the MDS and MPN disease components, the biologic consequences of the spliceosome mutation SF3B1 results in notable clinical exceptions. Importantly, both overall and leukemia free survival are shorter for MDS/MPN-RS-T when compared to essential thrombocythemia (ET). In the case of MDS/MPN-RS-T, thrombotic risk is not associated with the presence of JAK2V617F, nor history of prior thrombosis, but is associated with the presence of the mutated spliceosome gene SF3B1. In this review, we highlight the biology, pathology, risk stratification, and treatment approach to MDS/MPN-RS-T. In particular, we focus on clinical management concepts, which are largely borrowed from MDS and MPN, including the use of cytoreduction, bone marrow stimulating agents, and the role of allogeneic stem cell transplantation. We end by highlighting unmet needs and future research priorities in MDS/MPN-RS-T.
Topics: Anemia, Sideroblastic; Hematologic Neoplasms; Humans; Mutation; Myelodysplastic-Myeloproliferative Diseases; Myeloproliferative Disorders; RNA Splicing Factors; Syndrome; Thrombocytosis
PubMed: 35279478
DOI: 10.1016/j.leukres.2022.106820 -
Expert Review of Hematology Aug 2015Patients with the classical Philadelphia chromosome-negative chronic myeloproliferative neoplasms including essential thrombocythemia, polycythemia vera and primary... (Meta-Analysis)
Meta-Analysis Review
Patients with the classical Philadelphia chromosome-negative chronic myeloproliferative neoplasms including essential thrombocythemia, polycythemia vera and primary myelofibrosis often suffer from comorbidities, in particular, cardiovascular diseases and thrombotic events. Apparently, there is also an increased risk of osteoporotic fractures among these patients. However, the true prevalence, mechanisms involved and therapeutic implications are not well described. In this review, we summarize what is currently known about possible associations between bone disease and chronic myeloproliferative neoplasms. Chronic inflammation has been suggested to explain the initiation of clonal development and progression in chronic myeloproliferative neoplasms. Decreased bone mineral density and enhanced fracture risk are well-known manifestations of many chronic systemic inflammatory diseases. As opposed to systemic mastocytosis (SM) where pathogenic mechanisms for bone manifestations probably involve effects of mast cell mediators on bone metabolism, the mechanisms responsible for increased fracture risk in other chronic myeloproliferative neoplasms are not known.
Topics: Bone Density; Bone Diseases; Chronic Disease; Humans; Myeloproliferative Disorders; Treatment Outcome
PubMed: 26036168
DOI: 10.1586/17474086.2015.1053456 -
Blood Cancer Journal Nov 2018Prefibrotic myelofibrosis (pre-PMF) is a distinct entity among chronic myeloproliferative neoplasm diagnosed according to the revised 2016 WHO classification. The... (Review)
Review
Prefibrotic myelofibrosis (pre-PMF) is a distinct entity among chronic myeloproliferative neoplasm diagnosed according to the revised 2016 WHO classification. The clinical picture is heterogeneous, ranging from isolated thrombocytosis, mimicking essential thrombocythemia (ET), to symptoms of high-risk PMF. Retrospective studies showed that survival of patients with pre-PMF is worse than that of ET and better than overt PMF. Whilst a specific prognostic score is lacking, the International Prognostic Scoring System is able to predict survival in pre-PMF patients, yet failing to separate intermediate-1 and -2 groups, and can be used in clinical practice. Each patient should be evaluated for, and interventions adapted to, both life-expectancy and the risk of bleeding and thrombosis. In low-risk patients with expected long survival, observation only is recommended; in cumulated intermediate-1 and -2 risk cases, whose median survival is projected at more than 10 years, treatment is based on symptoms; in high risk cases, with median survival lower than 5 years, intensive management is required. A pragmatic approach to address the risk of bleeding and thrombosis includes: no treatment or low-dose aspirin in asymptomatic patients; aspirin or oral anticoagulation if previous arterial or venous thrombosis, and hydroxyurea as first-line cytoreduction in case of thrombocytosis or leukocytosis.
Topics: Algorithms; Animals; Biomarkers; Disease Management; Female; Humans; Male; Mutation; Myeloproliferative Disorders; Outcome Assessment, Health Care; Phenotype; Primary Myelofibrosis; Risk Assessment; Risk Factors; Thrombocythemia, Essential
PubMed: 30405096
DOI: 10.1038/s41408-018-0142-z -
American Journal of Hematology Apr 2023
Topics: Humans; Blast Crisis; Myeloproliferative Disorders; Hematopoietic Stem Cell Transplantation
PubMed: 36655312
DOI: 10.1002/ajh.26849 -
Blood Dec 2017Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago... (Review)
Review
Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.
Topics: Animals; Cell Transformation, Neoplastic; Clonal Evolution; Disease Progression; Epistasis, Genetic; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Janus Kinases; Mutation; Myeloproliferative Disorders; Phenotype; STAT Transcription Factors; Signal Transduction
PubMed: 29212804
DOI: 10.1182/blood-2017-06-782037 -
British Journal of Hospital Medicine... Oct 2017Elevated platelet counts are frequently encountered in hospital medicine and arise from both physiological and pathological mechanisms. Thrombocytosis may be secondary,... (Review)
Review
Elevated platelet counts are frequently encountered in hospital medicine and arise from both physiological and pathological mechanisms. Thrombocytosis may be secondary, reflecting an inflammatory state, iron deficiency, recent surgery or point towards an underlying neoplasm. Thrombocytosis may be the presenting sign of solid tumours and haematological conditions. The discovery of the activating mutations affecting thrombopoiesis led to greater understanding of the pathobiology of essential thrombocythaemia and other myeloproliferative neoplasms. The investigation of suspected primary thrombocytosis has evolved to include testing for these disease-associated mutations. Therapy for patients with essential thrombocythaemia aims to reduce their risk of thrombotic complications by addressing cardiovascular risk factors, and using antiplatelet agents and, in selected patients, cytoreductive therapy. This article provides a logical approach to distinguishing reactive or secondary thrombocytosis from thrombocytosis associated with an underlying myeloproliferative neoplasm and gives an overview of the management of essential thrombocythaemia.
Topics: Blood Platelets; Diagnosis, Differential; Disease Management; Humans; Myeloproliferative Disorders; Platelet Count; Risk Factors; Thrombocytosis
PubMed: 29019736
DOI: 10.12968/hmed.2017.78.10.558 -
British Journal of Haematology May 2022Myeloproliferative neoplasm (MPN)-unclassifiable (MPN-U) or not otherwise specified represents a rare, poorly defined and heterogeneous group of MPNs. Disease incidence... (Review)
Review
Myeloproliferative neoplasm (MPN)-unclassifiable (MPN-U) or not otherwise specified represents a rare, poorly defined and heterogeneous group of MPNs. Disease incidence is difficult to define but likely represents close to 5% of all MPNs when strict World Health Organisation (WHO) criteria are applied. Dynamic review over time is required to assess if the disease can be re-classified into another MPN entity. A diagnosis of MPN-U leads to many challenges for both the patient and physician alike including lack of agreed monitoring and therapeutic guidelines, validated prognostic markers and licenced therapies coupled with exclusion from clinical trials. MPN-U has an inherent risk of an aggressive clinical course and transformation in some but who, and when to treat in the chronic phase, including identifying who may require more aggressive therapy at an earlier stage, remains elusive. Moreover, despite the significant thrombotic risk, there is no agreement on systematic primary thromboprophylaxis. We hereby provide a contemporary overview of MPN-U in addition to four illustrative cases providing our collective suggested approaches to clinical challenges.
Topics: Anticoagulants; Humans; Myeloproliferative Disorders; Neoplasms; Venous Thromboembolism
PubMed: 35191542
DOI: 10.1111/bjh.18087 -
Hematology. American Society of... Dec 2017Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago... (Review)
Review
Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.
Topics: Animals; DNA Mutational Analysis; Hematologic Neoplasms; Humans; Janus Kinase 2; Mutation; Myelopoiesis; Myeloproliferative Disorders; Protein Kinase Inhibitors
PubMed: 29222295
DOI: 10.1182/asheducation-2017.1.470 -
International Journal of Molecular... Mar 2021mutations are a revolutionary discovery and represent an important hallmark of myeloproliferative neoplasms (MPN), especially essential thrombocythemia and primary... (Review)
Review
mutations are a revolutionary discovery and represent an important hallmark of myeloproliferative neoplasms (MPN), especially essential thrombocythemia and primary myelofibrosis. To date, several mutations were identified, with only frameshift mutations linked to the diseased phenotype. It is of diagnostic and prognostic importance to properly define the type of mutation and subclassify it according to its structural similarities to the classical mutations, a 52-bp deletion (type 1 mutation) and a 5-bp insertion (type 2 mutation), using a statistical approximation algorithm (AGADIR). Today, the knowledge on the pathogenesis of -positive MPN is expanding and several cellular mechanisms have been recognized that finally cause a clonal hematopoietic expansion. In this review, we discuss the current basis of the cellular effects of mutants and the understanding of its implementation in the current diagnostic laboratorial and medical practice. Different methods of detection are explained and a diagnostic algorithm is shown that aids in the approach to -positive MPN. Finally, contemporary methods joining artificial intelligence in accordance with molecular-genetic biomarkers in the approach to MPN are presented.
Topics: Algorithms; Animals; Artificial Intelligence; Biomarkers; Calreticulin; DNA Mutational Analysis; Gene Deletion; Hematology; Humans; Ligands; Machine Learning; Molecular Chaperones; Mutation; Myeloproliferative Disorders; Phenotype; Prognosis; Signal Transduction; Thrombocytosis
PubMed: 33806036
DOI: 10.3390/ijms22073371