MPN: The Molecular Drivers of Disease Initiation, Progression and Transformation and their Effect on Treatment

Grabek, Julian; Straube, Jasmin; Bywater, Megan J.; Lane, Steven

doi:10.3390/cells9081901

Cited by 36 publications

(48 citation statements)

References 215 publications

(304 reference statements)

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“…The classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are a group of closely-related stem cell disorders, characterized by excessive proliferation and abnormal differentiation of one or more myeloid cell lineages, coupled with varying degrees of bone marrow fibrosis, altered peripheral blood cells count, extramedullary hematopoiesis, and organomegaly [11]. Classical MPN categories include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), which in turn is divided into a pre-fibrotic (prePMF) and overt stage (overtPMF) [12].…”

Section: Mpns As a Model Of Onco-inflammatory Disordersmentioning

confidence: 99%

Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

Masselli

Pozzi

Gobbi

et al. 2020

Cells

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Among hematologic malignancies, the classic Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are considered a model of inflammation-related cancer development. In this context, the use of immune-modulating agents has recently expanded the MPN therapeutic scenario. Cytokines are key mediators of an auto-amplifying, detrimental cross-talk between the MPN clone and the tumor microenvironment represented by immune, stromal, and endothelial cells. This review focuses on recent advances in cytokine-profiling of MPN patients, analyzing different expression patterns among the three main Philadelphia-negative (Ph-negative) MPNs, as well as correlations with disease molecular profile, phenotype, progression, and outcome. The role of the megakaryocytic clone as the main source of cytokines, particularly in myelofibrosis, is also reviewed. Finally, we report emerging intriguing evidence on the contribution of host genetic variants to the chronic pro-inflammatory state that typifies MPNs.

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Section: Mpns As a Model Of Onco-inflammatory Disordersmentioning

confidence: 99%

Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

Masselli

Pozzi

Gobbi

et al. 2020

Cells

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“…All these clonal markers are formally integrated into the WHO diagnostic criteria for PV (98% JAK2 mutational frequency), ET (60% JAK2, 22% CALR and 3% MPL) and PMF (58% JAK2, 25% CALR and 7% MPL); about 10–15% of patients with PMF or ET lack all the three driver mutations and are generally referred to as “triple negative” [ 7 , 17 ]. Almost one third of the patients with MPNs harbor non-driver molecular lesions that might cooperate with the driver mutations in fostering disease progression [ 18 , 19 ]. The genes involved are those relevant to epigenetic (e.g., TET2, ASXL1, IDH1, IDH2, DNMT3A, EZH2), RNA splicing (e.g., SF3B1, SRSF2, U2AF1) or transcriptional (e.g., IKZF1, TP53, NF-E2, CUX1) regulation, some of which carry prognostic information, especially in PMF [ 7 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

Nasillo

Riva

Paolini

et al. 2021

IJMS

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The Philadelphia-negative myeloproliferative neoplasms (MPNs) are malignancies of the hematopoietic stem cell (HSC) arising as a consequence of clonal proliferation driven by somatically acquired driver mutations in discrete genes (JAK2, CALR, MPL). In recent years, along with the advances in molecular characterization, the role of immune dysregulation has been achieving increasing relevance in the pathogenesis and evolution of MPNs. In particular, a growing number of studies have shown that MPNs are often associated with detrimental cytokine milieu, expansion of the monocyte/macrophage compartment and myeloid-derived suppressor cells, as well as altered functions of T cells, dendritic cells and NK cells. Moreover, akin to solid tumors and other hematological malignancies, MPNs are able to evade T cell immune surveillance by engaging the PD-1/PD-L1 axis, whose pharmacological blockade with checkpoint inhibitors can successfully restore effective antitumor responses. A further interesting cue is provided by the recent discovery of the high immunogenic potential of JAK2V617F and CALR exon 9 mutations, that could be harnessed as intriguing targets for innovative adoptive immunotherapies. This review focuses on the recent insights in the immunological dysfunctions contributing to the pathogenesis of MPNs and outlines the potential impact of related immunotherapeutic approaches.

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“…Additionally, mutations in disease-modifying genes that seem to increase the risk of leukemic transformation or progression from ET to myelofibrosis have also been identified [ 73 , 74 , 75 ]. The products encoded by these genes are involved in epigenetic modification, tumor suppression, transcription regulation, splicing, and some other signaling pathways [ 76 , 77 ]. Other factors, such as genetic predisposition, age or environment have also been shown to influence the heterogeneity of MPN phenotypes [ 78 ].…”

Section: Introductionmentioning

confidence: 99%

A Broad Overview of Signaling in Ph-Negative Classic Myeloproliferative Neoplasms

Guijarro-Hernández

Vizmanos

2021

Cancers

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Ph-negative myeloproliferative neoplasms (polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)) are infrequent blood cancers characterized by signaling aberrations. Shortly after the discovery of the somatic mutations in JAK2, MPL, and CALR that cause these diseases, researchers extensively studied the aberrant functions of their mutant products. In all three cases, the main pathogenic mechanism appears to be the constitutive activation of JAK2/STAT signaling and JAK2-related pathways (MAPK/ERK, PI3K/AKT). However, some other non-canonical aberrant mechanisms derived from mutant JAK2 and CALR have also been described. Moreover, additional somatic mutations have been identified in other genes that affect epigenetic regulation, tumor suppression, transcription regulation, splicing and other signaling pathways, leading to the modification of some disease features and adding a layer of complexity to their molecular pathogenesis. All of these factors have highlighted the wide variety of cellular processes and pathways involved in the pathogenesis of MPNs. This review presents an overview of the complex signaling behind these diseases which could explain, at least in part, their phenotypic heterogeneity.

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MPN: The Molecular Drivers of Disease Initiation, Progression and Transformation and their Effect on Treatment

Cited by 36 publications

References 215 publications

Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

Cytokine Profiling in Myeloproliferative Neoplasms: Overview on Phenotype Correlation, Outcome Prediction, and Role of Genetic Variants

Inflammatory Microenvironment and Specific T Cells in Myeloproliferative Neoplasms: Immunopathogenesis and Novel Immunotherapies

A Broad Overview of Signaling in Ph-Negative Classic Myeloproliferative Neoplasms

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