Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients

Cabagnols, Xénia; Favale, Fabrizia; Pasquier, Florence; Messaoudi, Kahia; Defour, Jean‐Philippe; Ianotto, Jean‐Christophe; Marzac, Christophe; Couedic, J P Le; Droin, Nathalie; Chachoua, Ilyas; Favier, Rémi; Diop, M’Boyba; Ugo, Valérie; Casadevall, Nicole; Debili, Najet; Raslová, Hana; Bellanné‐Chantelot, Christine; Constantinescu, Stefan N.; Bluteau, Olivier; Plo, Isabelle; Vainchenker, William

doi:10.1182/blood-2015-07-661983

Cited by 161 publications

(145 citation statements)

References 49 publications

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“…These mutations were found to have a weak gain-of-function effect, either with a degree of thrombopoietin-independent growth or signaling, or thrombopoietin hypersensitivity. 36,37 Mutations in calreticulin (CALR) are also found in approximately 25-35% of patients with ET and 35-40% of those with MF ( Figure 2A). These are exclusively insertions/deletions (most commonly a 52 base pair deletion or 5 base pair insertion) in the final exon ( Figure 1B), and in all cases these result in a 1 base pair shift in the reading frame.…”

Section: Mutations In Mpl and Calrmentioning

confidence: 99%

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

2016

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Section: Mutations In Mpl and Calrmentioning

confidence: 99%

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

2016

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“…Two recent studies have indeed shown that a few triplenegative patients carry activating mutations of MPL outside exon 10, and that these noncanonical mutations may be either inherited or somatically acquired. 23,24 One study has also shown that some patients carry noncanonical, activating mutations of JAK2, which appear to be germ line in most instances. 23 Finally, some patients have evidence of polyclonal hematopoiesis, and most likely do not have a true MPN.…”

Section: How We Diagnose Etmentioning

confidence: 99%

“…Hereditary thrombocytosis may be associated with germ line mutations of THPO, the thrombopoietin gene, 63,64 or MPL, the thrombopoietin receptor gene. 23,24,65 Recent reports have described cases of hereditary thrombocytosis associated with noncanonical germ line mutations of JAK2. 23,[66][67][68][69] In familial ET, JAK2 (V617F) is always a somatically acquired event, as in the familial tree reported in Figure 2.…”

Section: Distinguishing Familial Et From Hereditary Thrombocytosismentioning

confidence: 99%

“…23 Finally, some patients have evidence of polyclonal hematopoiesis, and most likely do not have a true MPN. 23,24 Thus, the socalled triple-negative cases may include patients with ET associated with noncanonical mutations of MPL, individuals with hereditary thrombocytosis (see "Distinguishing familial ET from hereditary thrombocytosis"), and also subjects with nonclonal thrombocytosis (Figure 1). …”

Section: How We Diagnose Etmentioning

confidence: 99%

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How I treat essential thrombocythemia

Rumi

Cazzola

2016

Blood

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Essential thrombocythemia (ET) is an indolent myeloproliferative neoplasm that may be complicated by vascular events, including both thrombosis and bleeding. This disorder may also transform into more aggressive myeloid neoplasms, in particular into myelofibrosis. The identification of somatic mutations of JAK2, CALR, or MPL, found in about 90% of patients, has considerably improved the diagnostic approach to this disorder. Genomic profiling also holds the potential to improve prognostication and, more generally, clinical decision-making because the different driver mutations are associated with distinct clinical features. Prevention of vascular events has been so far the main objective of therapy, and continues to be extremely important in the management of patients with ET. Low-dose aspirin and cytoreductive drugs can be administered to this purpose, with cytoreductive treatment being primarily given to patients at high risk of vascular complications. Currently used cytoreductive drugs include hydroxyurea, mainly used in older patients, and interferon α, primarily given to younger patients. There is a need for disease-modifying drugs that can eradicate clonal hematopoiesis and/or prevent progression to more aggressive myeloid neoplasms, especially in younger patients. In this article, we use a case-based discussion format to illustrate our approach to diagnosis and treatment of ET.

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“…4,5 Recent work suggests that these patients may either have hereditary thrombocytosis or harbor as yet less well-described mutations in MPL or JAK2. [6][7][8] Patients with ET are commonly asymptomatic, but may throughout the course of the disease develop microvascular (headache, dizziness, erythromelalgia), thromboembolic or hemorrhagic complications. Disease progression to myelofibrosis (MF), termed post-ET myelofibrosis (PET-MF), in ET is thought to be uncommon particularly when strict interpretation of the WHO diagnostic criteria is applied, making the distinction between the so-called true ET and prefibrotic MF.…”

mentioning

confidence: 99%

Spotlight on anagrelide hydrochloride for the treatment of essential thrombocythemia

Sarma¹,

McLornan²,

Harrison³

2017

ODRR

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Anagrelide (ANA) hydrochloride is an oral imidazoquinazoline registered as an orphan drug in Europe. It is indicated as a second-line agent for the reduction of thrombocytosis in high-risk essential thrombocythemia (ET) in Europe and in any myeloproliferative neoplasmassociated thrombocytosis and for the amelioration of thrombo-hemorrhagic events in the context of myeloproliferative neoplasm in the USA and Japan. The compound has been in clinical use for almost two decades with approval in the European Union (EU) for over a decade. The licensed indication encompasses the apparently specific action of the drug to reduce the platelet count; however, the precise mode of action of ANA remains unclear. Here, we review the current data from two large phase 3 studies, PT-1 and ANAHDRET, and a phase 4 post-approval observational study EXELS. All of these studies were conducted in the EU and therefore pertain to ET as the only licensed indication. Data from these studies suggest that ANA is on the whole as effective as the most commonly used agent hydroxycarbamide (HC). Although ANA, when compared to HC, appears to be slightly less effective in preventing arterial thrombosis and myelofibrotic transformation, it is associated with lower risk of venous thrombosis. Since the initial data from the PT-1 study, a caution has been recommended for the combined use of ANA and aspirin as this may provoke excess hemorrhage. ET is a clinically and biologically heterogeneous condition, and these biological variations may in part explain some of the clinical differences observed in various studies in response to specific treatments. No new toxicities of ANA have emerged in the past decade, which means that clinicians and patients can be reassured about the efficacy and safety of this agent, which is of particular importance in a chronic condition such as ET.

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Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients

Cited by 161 publications

References 49 publications

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms

How I treat essential thrombocythemia

Spotlight on anagrelide hydrochloride for the treatment of essential thrombocythemia

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