The molecular mechanisms that control thrombopoiesis

Kaushansky, Kenneth

doi:10.1172/jci26674

Cited by 497 publications

(471 citation statements)

References 106 publications

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“…20 In the present in-vitro study, we demonstrated that mRNA and protein expression of Mcl-1 was also upregulated via TPO/Jak signaling in megakaryoblastic cells as well as Bcl-xL. Among its known downstream pathways including Stat5, Akt, Erk and p38, 21 we found that TPO administration phosphorylated Erk as well as Stat5; the phosphorylation of both was blocked by Jak inhibition. Thus, these pathways might be involved in the downstream portion of TPO/Jak signaling regulating these anti-apoptotic protein expression.…”

Section: Discussionsupporting

confidence: 52%

“…These findings demonstrated that TPO/Jak signaling regulated Mcl-1 expression as well as Bcl-xL in megakaryoblastic cells. While several pathways including Stat5, ERK, p38 and Akt were previously reported as being downstream of TPO/Jak signaling, 21 TPO induced phosphorylation of Stat5 and ERK in these cells, both of which were prevented by the Jak inhibitor (Figure 5h). Pharmacological inhibition of the Jak signaling was found to cause caspase activation, demonstrated by the appearance of a cleaved form of caspase-3, and impaired cell survival with downregulation of both Mcl-1 and Bcl-xL expression (Figures 5h and i), suggesting the involvement of Jak signaling in the survival of these cells.…”

Section: Resultsmentioning

confidence: 62%

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Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

et al. 2012

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Section: Discussionsupporting

confidence: 52%

Section: Resultsmentioning

confidence: 62%

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

et al. 2012

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“…Reciprocal decreases in MK size, ploidy and volume occur with experimentally induced thrombocytosis (Burstein et al, 1979;Jackson et al, 1984). These alterations, found in both experimental animals and human subjects, are primarily mediated by thrombopoietin (TPO) (Kaushansky, 2005a).…”

Section: Megakaryocyte Maturationmentioning

confidence: 99%

Megakaryocyte development and platelet production

2006

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SummaryMegakaryocytopoiesis involves the commitment of haematopoietic stem cells, and the proliferation, maturation and terminal differentiation of the megakaryocytic progenitors. Circulating levels of thrombopoietin (TPO), the primary growth-factor for the megakaryocyte (MK) lineage, induce concentration-dependent proliferation and maturation of MK progenitors by binding to the c-Mpl receptor and signalling induction. Decreased platelet turnover rates results in increased concentration of free TPO, enabling the compensatory response of marrow MKs to increased platelet production. C-Mpl activity is orchestrated by a complex cascade of signalling molecules that induces the action of specific transcription factors to drive MK proliferation and maturation. Mature MKs form proplatelet projections that are fragmented into circulating particles. Newly developed thrombopoietic agents operating via c-Mpl receptor may prove useful in supporting platelet production in thrombocytopenic state. Herein, we review the regulation of megakaryocytopoiesis and platelet production in normal and disease state, and the new approaches to thrombopoietic therapy.

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“…1 In a steady state, platelet production is tightly regulated by the hormone thrombopoietin (TPO), which is primarily synthesized in the liver, with some contribution by the kidney. 2 The receptor for TPO, c-Mpl, is expressed mainly on megakaryocytic and platelet membranes. The amount of TPO made available to megakaryocytes in the bone marrow for their proliferation and maturation is controlled by clearance of the hormone through binding to c-Mpl on circulating platelets.…”

mentioning

confidence: 99%

Thrombocytosis and Thrombosis

Vannucchi¹,

Barbui²

2007

Hematology

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The aim of this review is to discuss current diagnostic approaches to, and classification of, patients presenting with thrombocytosis, in light of novel information derived from the discovery of specific molecular abnormalities in chronic myeloproliferative disorders (CMPD), which represent the most common cause of primary thrombocytosis. The JAK2V617F and the MPLW515L/K mutations have been found in patients with essential thrombocythemia, polycythemia vera, and primary myelofibrosis, and less frequently in other myeloproliferative disorders complicated by thrombocytosis. However, neither mutation is disease specific nor is it universally present in patients with elevated platelet counts due to a CMPD; therefore, distinguishing between reactive and primary forms of thrombocytosis, as well as among the different clinical entities that constitute the CMPD, still requires a multifaceted diagnostic approach that includes as a key step the accurate evaluation of bone marrow histology. The role of elevated platelet counts in thrombosis, which represent the predominant complication of CMPD,significantly affecting prognosis and quality of life as well as, paradoxically, in the pathogenesis of the hemorrhagic manifestations, will be discussed. Established and novel potential risk factors for thrombosis, including the clinical relevance of the JAK2V617F mutation, and current management strategies for thrombocytosis are also briefly discussed.

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The molecular mechanisms that control thrombopoiesis

Cited by 497 publications

References 106 publications

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages

Megakaryocyte development and platelet production

Thrombocytosis and Thrombosis

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