Human thrombopoiesis depends on Protein kinase C /protein kinase C  functional couple

Carubbi, Cecilia; Masselli, Elena; Martini, Silvia; Galli, Daniela; Aversa, Franco; Mirandola, Prisco; Italiano, Joseph E.; Gobbi, Giuliana; Vitale, Marco

doi:10.3324/haematol.2015.137984

Cited by 13 publications

(10 citation statements)

References 50 publications

(80 reference statements)

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“…While this may seem problematic, data collected using CD34+ human cells from patients with either primary myelofibrosis (PMF) or essential thrombocythemia (ET) appears consistent with findings reported in this manuscript. CD34+ cells from patients with PMF cultured to induce megakaryocyte differentiation have heightened PKCε expression, while CD34+ cells from patients with ET cultured to induce megakaryocyte differentiation have reduced PKCε expression compared to control [ 29 ]. This is consistent with our murine data in that cultures from PMF patients (high PKCε expression) have reduced megakaryocyte differentiation, while cultures from ET patients (low PKCε expression) have robust megakaryocyte differentiation [ 25 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis

2017

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BackgroundIt has long been postulated that Protein Kinase C (PKC) is an important regulator of megakaryopoiesis. Recent contributions to the literature have outlined the functions of several individual PKC isoforms with regard to megakaryocyte differentiation and platelet production. However, the exact role of PKCε remains elusive.ObjectiveTo delineate the role of PKCε in megakaryopoiesis.Approach and resultsWe used a PKCε knockout mouse model to examine the effect of PKCε deficiency on platelet mass, megakaryocyte mass, and bone marrow progenitor cell distribution. We also investigated platelet recovery in PKCε null mice and TPO-mediated signaling in PKCε null megakaryocytes. PKCε null mice have higher platelet counts due to increased platelet production compared to WT littermate controls (p<0.05, n = 8). Furthermore, PKCε null mice have more bone marrow megakaryocyte progenitor cells than WT littermate control mice. Additionally, thrombopoietin-mediated signaling is perturbed in PKCε null mice as Akt and ERK1/2 phosphorylation are enhanced in PKCε null megakaryocytes stimulated with thrombopoietin. Finally, in response to immune-induced thrombocytopenia, PKCε null mice recovered faster and had higher rebound thrombocytosis than WT littermate control mice.ConclusionsEnhanced platelet recovery could be due to an increase in megakaryocyte progenitor cells found in PKCε null mice as well as enhanced thrombopoietin-mediated signaling observed in PKCε deficient megakaryocytes. These data suggest that PKCε is a negative regulator of megakaryopoiesis.

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Section: Discussionmentioning

confidence: 99%

PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis

2017

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“…Our publications pinpoint to PKCepsilon as relevant modulator of hematopoietic progenitors' differentiation pathways, since its over-expression has been linked to a significant impairment of MK differentiation up to a complete block of maturation, as described in acute myeloid leukemia blasts (9)(10)(11)(12)(13). More in details, we recently demonstrated that PKCepsilon plays a crucial role in PMF aberrant megakaryocytopoiesis.…”

Section: Introductionmentioning

confidence: 63%

“…The oncoprotein PKCepsilon has a key role in MF aberrant megakaryocytopoiesis, as we proved to be overexpressed in MF MK and that its levels correlate with high risk disease (13,14). On these bases, and given the assumption that platelets "inherit" mRNA and proteins from their MK progenitors, here we assessed whether circulating platelets from MF patients displayed the same aberrant expression of PKCepsilon as their precursors.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, it is known that in human normal platelets, PKC epsilon is nearly absent (25,26). This kinetic of expression can be altered during malignant megakaryopoiesis, as we showed that PKCepsilon is over-expressed in PMF MKs accounting for enhanced proliferation and impaired differentiation (13,14). Since platelets are anucleated cells that retain mRNA and proteins from their MK precursors, we tested whether MF platelets could inherit higher PKCepsilon levels from MF MK.…”

Section: Mf Platelets Are Characterized By Higher Levels Of Pkcepsilonmentioning

confidence: 96%

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Platelet expression of PKCepsilon oncoprotein in myelofibrosis is associated with disease severity and thrombotic risk

Masselli¹,

Carubbi²,

Pozzi³

et al. 2017

Ann. Transl. Med.

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Background: Myelofibrosis (MF) is the most aggressive Philadelphia-negative chronic myeloproliferative neoplasm (MPN) with high morbidity and mortality due to thrombo-hemorrhagic complications and leukemic transformation. MF is characterized by profound alterations of megakaryocytopoiesis, with consequent abnormalities in platelet number and function. We recently showed that the overexpression of the oncoprotein PKCepsilon plays a key role in the aberrant differentiation of MF megakaryocyte clone and that its levels correlate with disease burden. Moreover, our group previously demonstrated that PKCepsilon is over-expressed in platelets from patients with acute myocardial infarction (MI) and accounts for their increased reactivity. On these bases, we investigated here the activation state and PKCepsilon expression of MF platelets, testing potential correlations with thrombotic risk and disease aggressiveness.Methods: Platelets were isolated from peripheral blood samples of MF patients and healthy donors (HDs).Patients were stratified according to the IPSS/DIPSS risk category and history of cardiovascular events.Platelet activation was assessed by flow cytometry. PKCepsilon mRNA and protein levels were determined by real time-PCR and western blot.Results: MF platelets circulate in an activated status and display significantly higher levels of PKCepsilon compared to HDs. In MF patients, PKCepsilon platelet levels were associated with high-risk disease as well as with a positive history of major cardiovascular events.Conclusions: PKCepsilon is configuring as the common denominator of neoplastic transformation and thrombus formation in MF. Overall, our data pinpoint PKCepsilon as a potential novel biomarker of disease aggressiveness and thrombotic risk in this hematologic neoplasm.

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“…Among the three MPNs, MF is predominantly characterized by profound alterations of megakaryocytopoiesis, such as MK hyper-proliferation coupled with impaired differentiation [42,43,46,47]. As a result, MF patients display alterations in both platelet number (increased or decreased), morphology (presence of giant platelets), and function (reduced ADP-dependent maximal platelet aggregation) [48,49] that may recall inherited platelet disorders [50].…”

Section: Role Of the Megakaryocytic Clone In Cytokine Production In Mpnsmentioning

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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Human thrombopoiesis depends on Protein kinase C /protein kinase C functional couple

Cited by 13 publications

References 50 publications

PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis

PKC-epsilon deficiency alters progenitor cell populations in favor of megakaryopoiesis

Platelet expression of PKCepsilon oncoprotein in myelofibrosis is associated with disease severity and thrombotic risk

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

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