Molecular basis and clonal evolution of myeloproliferative neoplasms

Cleary, Ciara; Královics, Róbert

doi:10.1515/cclm-2013-0135

Cited by 8 publications

(5 citation statements)

References 75 publications

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“…Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classified among the 2016 WHO-defined myeloproliferative neoplasms 1 (MPN) and are referred to as Philadelphia-chromosome negative MPN. They are clonal stem cell diseases 2,3 which share a set of mutually exclusive somatic mutations 4 in the JAK2, MPL and CalR genes. In 45% of cases these driver gene mutations are the sole mutations 5 .…”

Section: Introductionmentioning

confidence: 99%

Increased levels of NETosis in myeloproliferative neoplasms are not linked to thrombotic events

et al. 2021

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Morbidity and mortality of Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) are mainly determined by thromboembolic complications. Thrombus formation is facilitated by a neutrophil-specific form of cell death linked to Neutrophil Extracellular Trap (NET) formation (NETosis). Pre-clinical and clinical data suggested a potential link between NETosis and thrombosis in MPN. In this study we aimed at defining the impact of NETosis on clinical endpoints in a large MPN cohort. NETosis was induced in vitro by Ionomycin and quantified by ELISA-based nucleosome release assays as well as fluorescent staining of free DNA in 103 samples from MPN patients and 28 healthy donors. NETosis rate was correlated to a broad set of clinical data, such as MPN subtype, mutational status, laboratory variables, history of thrombotic events and treatment types. Triggered NETosis levels were clearly higher in MPN patients when compared to healthy donors. Both, positivity for JAK2 V617F or exon 12 as well as CalR mutations correlate with increased NET formation. However, neither JAK2 allelic burden nor history of thromboembolic complication nor the presence of other risk factors for thrombosis (e.g. leukocytosis) were associated with the rate of NETosis. In addition, none of the analyzed laboratory parameters nor the type of treatment significantly impacted the rate of NETosis formation. MPN biology impacts NET formation as genetic driver mutations favor NETosis induction. However, this seems not to translate into important clinical endpoints such as thromboembolic complications. Therefore, NETosis may play a role in facilitating thrombosis but is not a sole causative determinant in MPN-associated thrombophilia.

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Section: Introductionmentioning

confidence: 99%

Increased levels of NETosis in myeloproliferative neoplasms are not linked to thrombotic events

et al. 2021

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“…Therefore, additional mutations at the HSC level are necessary before MPNs can develop. This may involve regulators of the JAK-STAT pathway or gene expression via epigenetic modifications or transcription factor mutations [37]. As reviewed by several authors, additional mutations might affect cytokine signaling, splicing machinery, transcription factors, and epigenetic modifiers [38][39][40].…”

Section: Molecular Biology Of Ph-negative Myeloproliferative Neoplasms and Predictive/prognostic Implicationsmentioning

confidence: 99%

The Role of Neutrophilic Granulocytes in Philadelphia Chromosome Negative Myeloproliferative Neoplasms

Kiem

Wagner

Magnes

et al. 2021

IJMS

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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.

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“…These latter mutations are almost always detected in both the primary MPN and the secondary AML, with a prevalence of around 20%. Interestingly, the prevalence of ASXL1 represents 22% of MF patients, but only 5% in PV and ET patients [66]. The frequencies of TET2 and IDH1/2 mutations in secondary AML are around 25% and 10% respectively [63] and an even higher frequency (45.5%) of TP53 mutations has been observed in post-MPN AML [67].…”

Section: Molecular Characterization Of Mpnsmentioning

confidence: 99%

“…One certain requirement for all MPNs is that the initial clone must expand relative to other clones within a patient and generally this is thought to occur through the acquisition of a mutation or series of mutations in HSCs that give the mutant clone a self-renewal advantage over time. This process can eventually lead to monoclonal hematopoiesis, which is a well-documented phenomenon in hematological malignancies [66,101]. The reduced clonal diversity with age may alter the competitive ability of endogenous HSCs, thereby permitting (or restricting) the expansion capabilities of a clone that acquires a JAK2 mutation.…”

Section: Clonal Evolution Of Mpnsmentioning

confidence: 99%

Clonal heterogeneity as a driver of disease variability in the evolution of myeloproliferative neoplasms

Prick

Haan

Green

et al. 2014

Experimental Hematology

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Myeloproliferative neoplasms (MPNs) are clonal hematological diseases in which cells of the myelo-erythroid lineage are overproduced and patients are predisposed to leukemic transformation. Hematopoietic stem cells are the suspected disease-initiating cells, and these cells must acquire a clonal advantage relative to nonmutant hematopoietic stem cells to perpetuate disease. In 2005, several groups identified a single gain-of-function point mutation in JAK2 that associated with the majority of MPNs, and subsequent studies have led to a comprehensive understanding of the mutational landscape in MPNs. However, confusion still exists as to how a single genetic aberration can be associated with multiple distinct disease entities. Many explanations have been proposed, including JAK2V617F homozygosity, individual patient heterogeneity, and the differential regulation of downstream JAK2 signaling pathways. Several groups have made knock-in mouse models expressing JAK2V617F and have observed divergent phenotypes, each recapitulating some aspects of disease. Intriguingly, most of these models do not observe a strong hematopoietic stem cell self-renewal advantage compared with wild-type littermate controls, raising the question of how a clonal advantage is established in patients with MPNs. This review summarizes the current molecular understanding of MPNs and the diversity of disease phenotypes and proposes that the increased proliferation induced by JAK2V617F applies a selection pressure on the mutant clone that results in highly diverse clonal evolution in individuals.

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Molecular basis and clonal evolution of myeloproliferative neoplasms

Cited by 8 publications

References 75 publications

Increased levels of NETosis in myeloproliferative neoplasms are not linked to thrombotic events

Increased levels of NETosis in myeloproliferative neoplasms are not linked to thrombotic events

The Role of Neutrophilic Granulocytes in Philadelphia Chromosome Negative Myeloproliferative Neoplasms

Clonal heterogeneity as a driver of disease variability in the evolution of myeloproliferative neoplasms

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