Circulating megakaryocyte and platelet microvesicles correlate with response to ruxolitinib and distinct disease severity in patients with myelofibrosis

Barone, Martina; Ricci, Francesca; Sollazzo, Daria; Ottaviani, Emanuela; Romano, Marco; Auteri, Giuseppe; Bartoletti, Daniela; Reggiani, Maria Letizia Bacchi; Vianelli, Nicola; Tazzari, Pier Luigi; Cavo, Michèle; Forte, Dorian; Palandri, Francesca; Catani, Lucia

doi:10.1111/bjh.15682

Cited by 16 publications

(29 citation statements)

References 14 publications

(18 reference statements)

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“…These observations were immediately confirmed by an Italian study reporting small EVs released by megakaryocytes as a biomarker of thrombopoiesis in patients affected by MF (p < 0.001) [125]. In addition, the authors described, for the first time, a correlation between exosome numbers and myeloproliferative disorders, reporting the exosomes released by platelets to be increased in ET when compared to MF (p < 0.01) [125]. This last piece of evidence highlights the potential use of EVs and exosomes as disease markers as well as disease biomarker carriers, as stressed above.…”

Section: Small-ev Cargo As Disease Markerssupporting

confidence: 61%

“…Using enzymatic-, mass spectrometer-and absolute quantification-based approaches, Fel and colleagues detected high concentrations of procoagulant and proan-giogenic proteins in exosomes isolated from PV patients' plasma [124]. These observations were immediately confirmed by an Italian study reporting small EVs released by megakaryocytes as a biomarker of thrombopoiesis in patients affected by MF (p < 0.001) [125]. In addition, the authors described, for the first time, a correlation between exosome numbers and myeloproliferative disorders, reporting the exosomes released by platelets to be increased in ET when compared to MF (p < 0.01) [125].…”

Section: Small-ev Cargo As Disease Markersmentioning

confidence: 89%

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Exosomes and Extracellular Vesicles in Myeloid Neoplasia: The Multiple and Complex Roles Played by These “Magic Bullets”

Bernardi

Farina

2021

Biology

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Extracellular vesicles (exosomes, in particular) are essential in multicellular organisms because they mediate cell-to-cell communication via the transfer of secreted molecules. They are able to shuttle different cargo, from nucleic acids to proteins. The role of exosomes has been widely investigated in solid tumors, which gave us surprising results about their potential involvement in pathogenesis and created an opening for liquid biopsies. Less is known about exosomes in oncohematology, particularly concerning the malignancies deriving from myeloid lineage. In this review, we aim to present an overview of immunomodulation and the microenvironment alteration mediated by exosomes released by malicious myeloid cells. Afterwards, we review the studies reporting the use of exosomes as disease biomarkers and their influence in response to treatment, together with the recent experiences that have focused on the use of exosomes as therapeutic tools. The further development of new technologies and the increased knowledge of biological (exosomes) and clinical (myeloid neoplasia) aspects are expected to change the future approaches to these malignancies.

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Section: Small-ev Cargo As Disease Markerssupporting

confidence: 61%

Section: Small-ev Cargo As Disease Markersmentioning

confidence: 89%

Exosomes and Extracellular Vesicles in Myeloid Neoplasia: The Multiple and Complex Roles Played by These “Magic Bullets”

Bernardi

Farina

2021

Biology

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“…Similarly, despite the relevance of JAK2-dependent signaling in MPN cellular abnormalities and the fact that the JAK1/2 inhibitor ruxolitinib reduces the thrombotic risk (66), no decrease in platelet activation markers was shown in patients treated with this drug (67). In another study, normalization of circulating platelet-derived microvesicles was noted in ruxolitinib spleen-responders (68), pointing out that the impact of JAK2 inhibitors in hemostatic parameters deserves further evaluation.…”

Section: Role Of Platelets In Mpn Thrombosismentioning

confidence: 95%

Platelets as Mediators of Thromboinflammation in Chronic Myeloproliferative Neoplasms

Oyarzún

Heller

2019

Front. Immunol.

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Chronic myeloproliferative neoplasms (MPN) are stem cell disorders driven by mutations in JAK2, CALR , or MPL genes and characterized by myeloid proliferation and increased blood cell counts. They encompass three closely related conditions, including essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Elevated levels of cytokines released by clonal and non-clonal cells generate a chronic proinflammatory state that contributes to disease pathogenesis. Thrombosis represents the most common cause of morbidity and mortality in MPN, although paradoxically, patients may also present with a bleeding diathesis. The mechanisms leading to thrombosis are complex and multiple and include increased blood cells together with qualitative abnormalities of red cells, leukocytes, and platelets that favor a prothrombotic activated phenotype. The functional interplay between blood cells, the clotting cascade, and dysfunctional endothelium contributes to hypercoagulability and this process is perpetuated by the effect of inflammatory cytokines. In addition to their well-known function in hemostasis, platelets contribute to innate immunity and inflammation and play a key role in MPN thromboinflammatory state. In vivo platelet activation leads to platelet aggregate formation and exposure of adhesion molecules which favor their interaction with activated neutrophils and monocytes leading to circulating platelet-leukocyte heterotypic aggregates. Platelets are recruited to the activated endothelium further enhancing the reciprocal activation of both cell types. Crosstalk between activated cells drives cytokine production, further fuelling the self-reinforcing thromboinflammatory loop. In addition, MPN platelets provide a procoagulant scaffold which triggers the coagulation cascade and platelet-derived microparticles amplify this response. Markers of platelet, leukocyte, endothelial and coagulation activation are increased in MPN patients although prospective studies are required to determine the potential value of these parameters for identifying patients at increased thrombotic risk. Thrombosis remains the main complication of MPN patients, with a high risk of recurrence despite adequate cytoreductive and antithrombotic treatment. Deeper insight into the mechanism favoring thrombosis development in this setting may lead to novel therapeutic approaches for MPN thrombosis. Considering the critical role of inflammation in the vascular risk, concomitant targeting of inflammatory pathways could potentially impact on primary or secondary prevention strategies.

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“…35,36 High serum levels of EVs have been detected in hematological malignancies including myeloproliferative neoplasms (MPN) 37,38 and we recently described that circulating monocyte-derived EVs are increased in MF. 39 Despite a key role in regulating inflammation and immune response, the role of monocytes in the pathogenesis of MF needs to be fully addressed. Moreover, the impact of RUX inhibition on monocyte behavior has been poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The role of circulating monocytes and JAK inhibition in the infectious-driven inflammatory response of myelofibrosis

et al. 2020

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Myelofibrosis (MF) is characterized by chronic inflammation and hyper-activation of the JAK-STAT pathway. Infections are one of the main causes of morbidity/mortality. Therapy with Ruxolitinib (RUX), a JAK1/2 inhibitor, may further increase the infectious risk. Monocytes are critical players in inflammation/immunity through cytokine production and release of bioactive extracellular vesicles. However, the functional behavior of MF monocytes, particularly during RUX therapy, is still unclear. In this study, we found that monocytes from JAK2V617F-mutated MF patients show an altered expression of chemokine (CCR2, CXCR3, CCR5) and cytokine (TNF-α-R, IL10-R, IL1β-R, IL6-R) receptors. Furthermore, their ability to produce and secrete free and extracellular vesicles-linked cytokines (IL1β, TNF-α, IL6, IL10) under lipopolysaccharides (LPS) stimulation is severely impaired. Interestingly, monocytes from RUX-treated patients show normal level of chemokine, IL10, IL1β, and IL6 receptors together with a restored ability to produce intracellular and to secrete extracellular vesicles-linked cytokines after LPS stimulation. Conversely, RUX therapy does not normalize TNF-R1/2 receptors expression and the LPS-driven secretion of free pro/antiinflammatory cytokines. Accordingly, upon LPS stimulation, in vitro RUX treatment of monocytes from MF patients increases their secretion of extracellular vesicles-linked cytokines but inhibits the secretion of free pro/anti-inflammatory cytokines. In conclusion, we demonstrated that in MF the infection-driven response of circulating monocytes is defective. Importantly, RUX promotes their infection-driven cytokine production suggesting that infections following RUX therapy may not be due to monocyte failure. These findings contribute to better interpreting the immune vulnerability of MF and to envisaging strategies to improve the infection-driven immune response.

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Circulating megakaryocyte and platelet microvesicles correlate with response to ruxolitinib and distinct disease severity in patients with myelofibrosis

Cited by 16 publications

References 14 publications

Exosomes and Extracellular Vesicles in Myeloid Neoplasia: The Multiple and Complex Roles Played by These “Magic Bullets”

Exosomes and Extracellular Vesicles in Myeloid Neoplasia: The Multiple and Complex Roles Played by These “Magic Bullets”

Platelets as Mediators of Thromboinflammation in Chronic Myeloproliferative Neoplasms

The role of circulating monocytes and JAK inhibition in the infectious-driven inflammatory response of myelofibrosis

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