Screening for <i>MPL</i> mutations in essential thrombocythemia and primary myelofibrosis: normal Mpl expression and absence of constitutive STAT3 and STAT5 activation in <i>MPL</i>W515L‐positive platelets

Glembotsky, Ana Claudia; Korin, Laura; Lev, Paola Roxana; Chazarreta, Carlos D.; Marta, Rosana Fernanda; Molinas, Felisa C.; Heller, Paula G.

doi:10.1111/j.1600-0609.2010.01421.x

Cited by 5 publications

(4 citation statements)

References 43 publications

(83 reference statements)

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“…In any event, these results may explain the controversial reports of MPL expression in ET. [12][13][14][15][16] The mechanisms leading to an MPL expression decrease could depend on the disease as MPL mRNA expression was decreased in PMF whereas it was normal in ET, suggesting that a transcriptional mechanism could operate in PMF. The frequent mutations in epigenetic regulators identified in this disorder could participate in MPL deregulation.…”

Section: Discussionmentioning

confidence: 99%

“…9 In addition, MPL is downregulated in MKs and platelets of PMF patients, and this decrease is a more controversial issue in ET. [12][13][14][15][16] We have shown previously that TPO triggers MK proliferation arrest and promotes a differentiation-associated senescence through a strong mitogen-activated protein kinase (MAPK) signaling. 17 In the present study, we show that TPO-induced proliferation vs differentiation depends on JAK2 and MPL protein levels.…”

Section: Introductionmentioning

confidence: 99%

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JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation

Besancenot

Roos‐Weil

Tonetti

et al. 2014

Blood

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• We propose that megakaryopoiesis is regulated by the expression levels of the TPO receptor MPL and the associated tyrosine kinase JAK2.• This model could explain why suboptimal doses of JAK2 inhibitors can induce a paradoxical increase in platelet production.Megakaryopoiesis is a 2-step differentiation process, regulated by thrombopoietin (TPO), on binding to its cognate receptor myeloproliferative leukemia (MPL). This receptor associates with intracytoplasmic tyrosine kinases, essentially janus kinase 2 (JAK2), which regulates MPL stability and cell-surface expression, and mediates TPO-induced signal transduction. We demonstrate that JAK2 and MPL mediate TPO-induced proliferation arrest and megakaryocytic differentiation of the human megakaryoblastic leukemia cell line UT7-MPL. A decrease in JAK2 or MPL protein expression, and JAK2 chemical inhibition, suppress this antiproliferative action of TPO. The expression of JAK2 and MPL, which progressively increases along normal human megakaryopoiesis, is decreased in platelets of patients diagnosed with JAK2-or MPL-mutated essential thrombocytemia and primary myelofibrosis, 2 myeloproliferative neoplasms in which megakaryocytes (MKs) proliferate excessively. Finally, low doses of JAK2 chemical inhibitors are shown to induce a paradoxical increase in MK production, both in vitro and in vivo. We propose that JAK2 and MPL expression levels regulate megakaryocytic proliferation vs differentiation in both normal and pathological conditions, and that JAK2 chemical inhibitors could promote a paradoxical thrombocytosis when used at suboptimal doses. (Blood. 2014;124(13): 2104-2115

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation

Besancenot

Roos‐Weil

Tonetti

et al. 2014

Blood

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“… † Screening for JAK2 V617F, CALR and MPL mutations was perfomed as described525354. CALR and exon 10 MPL mutations were studied in JAK2 V617F-negative patients.…”

Section: Figurementioning

confidence: 99%

Neutrophil extracellular trap formation and circulating nucleosomes in patients with chronic myeloproliferative neoplasms

Oyarzún

Carestia

Lev

et al. 2016

Sci Rep

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The mechanisms underlying increased thrombotic risk in chronic myeloproliferative neoplasms (MPN) are incompletely understood. We assessed whether neutrophil extracellular traps (NETs), which promote thrombosis, contribute to the procoagulant state in essential thrombocythemia, polycythemia vera and myelofibrosis (MF) patients. Although MPN neutrophils showed increased basal reactive oxygen species (ROS), enhanced NETosis by unstimulated neutrophils was an infrequent finding, whereas PMA-triggered NETosis was impaired, particularly in MF, due to decreased PMA-triggered ROS production. Elevated circulating nucleosomes were a prominent finding and were higher in patients with advanced disease, which may have potential prognostic implication. Histone-MPO complexes, proposed as specific NET biomarker, were seldomly detected, suggesting NETs may not be the main source of nucleosomes in most patients, whereas their correlation with high LDH points to increased cell turn-over as a plausible origin. Lack of association of nucleosomes or NETs with thrombosis or activation markers does not support their use as predictors of thrombosis although prospective studies in a larger cohort may help define their potential contribution to MPN thrombosis. These results do not provide evidence for relevant in vivo NETosis in MPN patients under steady state conditions, although availability of standardized NET biomarkers may contribute to further research in this field.

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“…JAK2 V617F mutation was associated with significantly increased levels of phosphorylated STAT5 in hemopoietic cells, most marked in megakaryocytes, of patients with MPNs [11]. Abnormal nuclear megakaryocytic staining for p-STAT5 expression, previously associated with the JAK2 V617F mutation, was also associated with MPL W515L/K mutation [12].…”

Section: Introductionmentioning

confidence: 99%

Constitutive STAT5 phosphorylation in CD34+ cells of patients with primary myelofibrosis: Correlation with driver mutation status and disease severity

et al. 2019

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Primary Myelofibrosis (PMF) is a myeloproliferative disorder associated with JAK2 V617F, Calreticulin ( CALR ) indels, and MPL W515L/K mutations activating the tyrosine kinase JAK2 and its downstream signaling pathway. The nature of signaling abnormalities in primary cells from PMF patients is poorly understood, since most of the work has been performed in cell lines or animal models. By flow cytometry we measured constitutive and cytokine induced phosphorylation of STAT5, STAT3, and ERK1/2 in circulating CD34 + cells from 57 patients with PMF (20 with prefibrotic-PMF) and 13 healthy controls (CTRLs). Levels of constitutive and TPO induced p-STAT5, and IL6 induced p-STAT3 were higher in patients than in CTRLs. Constitutive p-STAT5 values were lower in CALR than homozygous JAK2 V617F mutated CD34 + cells from PMF patients. Moreover, constitutive p-STAT5 and IL6 induced p-STAT3 values correlated directly with circulating CD34 + cell number/L, and inversely with the frequency of circulating CD34 + cells expressing CXCR4. Constitutive p-STAT5 values of CD34 + cells were also inversely correlated with hemoglobin levels. When the patients were divided according with presence/absence of JAK2 V617F mutation, all the correlations described characterized the JAK2 V617F+ patients with prefibrotic-PMF (P-PMF). In conclusion, increased constitutive p-STAT5 and IL6 induced p-STAT3 values in circulating CD34 + cells characterize patients with PMF. Constitutive p-STAT5 and IL6 induced p-STAT3 values correlate with circulating CD34 + cell number/L, the frequency of circulating CD34 + cells expressing CXCR4 and hemoglobin levels within the prefibrotic JAK2 V617F + patient population. Our data point toward a complex activation of STAT5-dependent pathways in the stem/progenitor cell compartment, that characterize the phenotypic diversity of PMF.

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Screening for MPL mutations in essential thrombocythemia and primary myelofibrosis: normal Mpl expression and absence of constitutive STAT3 and STAT5 activation in MPLW515L‐positive platelets

Cited by 5 publications

References 43 publications

JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation

JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation

Neutrophil extracellular trap formation and circulating nucleosomes in patients with chronic myeloproliferative neoplasms

Constitutive STAT5 phosphorylation in CD34+ cells of patients with primary myelofibrosis: Correlation with driver mutation status and disease severity

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