Project description:The aim of the study was to evaluate selected angiogenic factors in patients with essential thrombocythemia (ET) depending on JAK2V617F, calreticulin gene (CALR) and myeloproliferative leukemia virus oncogene (MPL) mutations. Sixty ET patients and 20 healthy volunteers were enrolled in the study. The following tests were performed: vascular endothelial growth factor- A (VEGF-A), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1),soluble vascular endothelial growth factor receptor-2 (sVEGFR-2), platelet-derived growth factor( PDGF-BB), and stromal-derived factor-1α (SDF-1α). We observed an increased PDGF-BB level in patients with ET compared to the controls. Patients with CALR mutation had significantly higher concentration of PDGF-BB and lower concentration of SDF-1α than patients with JAK2V617F mutation. High concentration of PDGF-BB and low concentration of SDF-1α in patients with CALR(+) ET may indicate a contribution of these chemokines in disturbed Ca2+ metabolism in platelets.

| S-EPMC6714737 | biostudies-literature

Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors.

Project description:Thrombopoietin (TPO) and the TPO-receptor (TPO-R, or c-MPL) are essential for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Agents that can modulate TPO-R signaling are highly desirable for both basic research and clinical utility. We developed a series of surrogate protein ligands for TPO-R, in the form of diabodies (DBs), that homodimerize TPO-R on the cell surface in geometries that are dictated by the DB receptor binding epitope, in effect "tuning" downstream signaling responses. These surrogate ligands exhibit diverse pharmacological properties, inducing graded signaling outputs, from full to partial TPO agonism, thus decoupling the dual functions of TPO/TPO-R. Using single-cell RNA sequencing and HSC self-renewal assays we find that partial agonistic diabodies preserved the stem-like properties of cultured HSCs, but also blocked oncogenic colony formation in essential thrombocythemia (ET) through inverse agonism. Our data suggest that dampening downstream TPO signaling is a powerful approach not only for HSC preservation in culture, but also for inhibiting oncogenic signaling through the TPO-R.

| S-EPMC7812794 | biostudies-literature

Familial Essential Thrombocythemia Associated with MPL W515L Mutation in Father and JAK2 V617F Mutation in Daughter.

Project description:Familial essential thrombocythemia features the acquisition of somatic mutations and an evolution similar to the sporadic form of the disease. Here we report two patients-father and daughter-with essential thrombocythemia who displayed a heterogeneous pattern of somatic mutations. The JAK2 V617F mutation was found in the daughter, while the father harbored the MPL W515L mutation. This case report may constitute further proof that in familial essential thrombocythemia there are other, still undefined, constitutional, inherited genetic factors predisposing to the acquisition of various somatic mutations (e.g., JAK2 V617F and MPL).

| S-EPMC4267161 | biostudies-literature

Ruxolitinib for essential thrombocythemia?

Project description: Not available

| S-EPMC5769968 | biostudies-literature

TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis.

Project description:High-throughput DNA sequence analysis was used to screen for TET2 mutations in bone marrow-derived DNA from 239 patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). Thirty-two mutations (19 frameshift, 10 nonsense, 3 missense; mostly involving exons 4 and 12) were identified for an overall mutational frequency of approximately 13%. Specific diagnoses included polycythemia vera (PV; n=89), essential thrombocythemia (ET; n=57), primary myelofibrosis (PMF; n=60), post-PV MF (n=14), post-ET MF (n=7) and blast phase PV/ET/MF (n=12); the corresponding mutational frequencies were approximately 16, 5, 17, 14, 14 and 17% (P=0.50). Mutant TET2 was detected in approximately 17 and approximately 7% of JAK2V617F-positive and -negative cases, respectively (P=0.04). However, this apparent clustering of the two mutations was accounted for by an independent association between mutant TET2 and advanced age; mutational frequency was approximately 23% in patients > or =60 years old versus approximately 4% in younger patients (P<0.0001). The presence of mutant TET2 did not affect survival, leukemic transformation or thrombosis in either PV or PMF; a correlation with hemoglobin <10 g per 100 ml in PMF was noted (P=0.05). We conclude that TET2 mutations occur in both JAK2V617F-positive and -negative MPN, are more prevalent in older patients, display similar frequencies across MPN subcategories and disease stages, and hold limited prognostic relevance.

| S-EPMC4654629 | biostudies-literature

Emerging treatments for essential thrombocythemia.

Project description:In 1934, Epstein and Goedel used the term hemorrhagic thrombocythemia to describe a disorder characterized by permanent elevation of a platelet count to more than three times normal, hyperplasia of megakaryocytes, and the tendency for venous thrombosis and spontaneous hemorrhage. Over the last 75 years, and particularly in the past 6 years, major progress has been made in our understanding of essential thrombocythemia (ET) and its pathogenesis with the identification of the highly prevalent JAK-2 V617F and other mutations. Current management of this condition is based upon historical data and with treatments that have not changed significantly for nearly two decades. This study discusses this and recent progress, highlighting exciting new data with old and new drugs, as well as which patients in particular should be evaluated for these new therapies.

| S-EPMC3262348 | biostudies-literature

ASXL1 mutations are prognostically significant in PMF, but not MF following essential thrombocythemia or polycythemia vera.

Project description: Not available

| S-EPMC9092422 | biostudies-literature

"Y appearance" infarction: caused by essential thrombocythemia.

Project description:Essential thrombocythemia (ET) is a myeloproliferative malignancy caused by the excessive proliferation of megakaryocytes in the bone marrow, resulting in the overproduction of peripheral platelets. ET can lead to thrombotic events, such as ischemic stroke (IS), though it is a rare cause of IS. Bilateral medial medullary infarction (BMMI), also known as "Y appearance" infarction due to its distinctive imaging morphology, is a rare clinical subtype of IS which typically has a poor prognosis and a high mortality rate. Herein, we report the case of a 43-year-old male with a history of ET. The patient's platelet count was poorly controlled, and he did not receive regular treatment. After developing symptoms such as dizziness, dysphagia, choking on water, slurred speech, blurred vision, and bilateral limb numbness. Head magnetic resonance imaging revealed a "Y appearance" infarction in the bilateral medial medulla. After admission, the patient was administered intravenous antiplatelet therapy with tirofiban. However, when he was switched to oral aspirin after three days, he experienced decreased muscle strength and worsening symptoms. Therefore, tirofiban was continued for 14 days. Upon discharge, the patient experienced residual limb numbness. His National Institutes of Health Stroke Scale score was 1, Modified Rankin Scale score was 0, and platelet count had decreased to the normal range. During the 9-month follow-up period after discharge, the patient still had only mild limb numbness. Our report presents a special case of "Y appearance" infarction due to ET. Owing to fluctuations in the patient's condition, he received long-term high-dose tirofiban, which ultimately led to a significant improvement in his symptoms.

| S-EPMC11460061 | biostudies-literature

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