Platelet c‐mpl expression is dysregulated in patients with essential thrombocythaemia but this is not of diagnostic value

Abstract

Summary. Essential thrombocythaemia (ET) can be dif®cult to discriminate from an occult case of reactive thrombocytosis (RT). Since thrombopoietin (TPO) is the primary regulator of thrombopoiesis, we have investigated whether levels of TPO and/or its receptor, c-mpl, are of value in the differential diagnosis of ET. Plasma TPO levels in patients with ET, RT and other myeloproliferative disorders (MPDs) did not differ signi®cantly from normal controls. However, surface c-mpl expression was signi®cantly reduced in platelets from 18 ET patients, 0±65´5% of controls (P < 0´001). Immunoblots on ®ve of these and ®ve additional patients were consistent with absent or reduced c-mpl protein levels. The surface c-mpl expression results were signi®cantly different from those in eight RT patients (21´3±95´5%, P 0´0015), but there was considerable overlap between the two groups and a reduced level was not restricted to ET. Furthermore, c-mpl expression in ET patients was not different from eight patients with other MPDs (0±87´6%, P 0´06), nor could it differentiate between ET patients with monoclonal and polyclonal haemopoiesis. Although a low or absent c-mpl level is suggestive of a primary rather than a secondary thrombocytosis, it is insuf®ciently discriminatory to be used as a diagnostic marker for ET.

Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes

“…[50][51][52] Loss of Mpl protein was also observed in megakaryocytes from patients with MPD, 49,53,54 but it is currently unclear whether this specifically affects late megakaryocytes, as we observed in our mice. Recently, a correlation between decreased expression of Mpl and mutant JAK2-V617F was noted.…”

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

“…Accordingly, a thrombocytosis is observed in transgenic mice expressing reduced levels of MPL, 29,30 and a decrease in MPL expression was observed in platelets and MKs of patients with MPNs, with either PMF or ET. [13][14][15] This decrease in MPL expression was obvious in patients harboring a JAK2 V617F or a MPL W515 mutation, whereas MPL expression was increased in ET patients without any of these mutations. As we were not able to evaluate reliably the cell-surface expression of MPL in these patients, we cannot exclude a decreased expression in their MK progenitors related to a trafficking defect.…”

“…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.…”

“…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.…”

JAK2V617F mutation in essential thrombocythaemia: clinical associations and long‐term prognostic relevance

“…ET shares both bone marrow histological (dysmorphic megakaryocyte proliferation with clustering) and clinical (increased risk of thrombohaemorrhagic events) phenotype with PV (Michiels & Thiele, 2002;Elliott & Tefferi, 2005). Similarly, a substantial number of patients with ET display PV-characteristic biological features including clonal myelopoiesis (Fialkow et al, 1981), in vitro growth factor independence/hypersensitivity of both erythroid and megakaryocyte progenitor cells (Juvonen et al, 1993;Axelrad et al, 2000), low serum erythropoietin level (Messinezy et al, 2002), altered megakaryocyte/platelet Mpl expression (Harrison et al, 1999a;Yoon et al, 2000), increased neutrophil PRV-1 expression (Passamonti et al, 2004b;Tefferi et al, 2004a), and decreased platelet serotonin content (Koch et al, 2004). Furthermore, another shared molecular phenotype between ET, PV, and several other MPD has recently been reported and involves an activating JAK2 tyrosine kinase mutation (JAK2 V617F ) (Baxter et al, 2005;James et al, 2005; Summary Clinical correlates and long-term prognostic relevance of the JAK2 V617F mutation was studied in 150 patients with essential thrombocythaemia (ET) from a single institution and followed for a median of 11AE4 years.…”