Mpl Ligand (MGDF) Alone and in Combination with Stem Cell Factor (SCF) Promotes Proliferation and Survival of Human Megakaryocyte, Erythroid and Granulocyte/Macrophage Progenitors

Rasko, John E.J.; O’Flaherty, Elizabeth; Begley, C. Glenn

doi:10.1002/stem.150033

Cited by 42 publications

(12 citation statements)

References 55 publications

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“…Mpl ligand, the primary cytokine that drives megakaryopoiesis [Kaushansky, 1995], promotes differentiation, cessation of mitotic proliferation and polyploidization of megakaryocytes [Borge et al, 1996;Rasko et al, 1997;Yoshida et al, 1997]. These polyploid cells fragment into platelets in association with programmed cell death [Zauli et al, 1997].…”

Section: Discussionmentioning

confidence: 99%

Signaling by the Mpl receptor involves IKK and NF‐κB*

Zhang

Sun

Wang

et al. 2002

J of Cellular Biochemistry

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Binding of tumor necrosis factor-alpha (TNF-alpha) to its receptor activates IKK complex, which leads to inducement of NF-kappaB activity. Here we report that activation of Mpl ligand is also linked to IKK and NF-kappaB activity. Mpl ligand, also known as thrombopoietin (TPO) or megakaryocyte growth and development factor (MGDF), induces megakaryocyte differentiation and inhibition of mitotic proliferation, followed by induction of polyploidization and fragmentation into platelets. The latter process is often observed in megakaryocytes undergoing apoptosis. Treatment of a Mpl ligand-responding megakaryocytic cell line with this cytokine led to an immediate, transient increase in IKK activity followed by a profound decrease in this kinase activity over time. This decrease was not due to an effect on the levels of the IKK regulatory components IKKalpha and IKKbeta. Proliferating megakaryocytes displayed a constitutive DNA-binding activity of NF-kappaB p50 homodimers and of NF-kappaB p50-p65 heterodimers. As expected, reduced IKK activity in Mpl ligand-treated cells was associated with a significant reduction in NF-kappaB DNA binding activity and in the activity of a NF-kappaB-dependent promoter. Our study is thus the first to identify a constitutive NF-kappaB activity in proliferating megakaryocytes as well as to describe a link between Mpl receptor signaling and IKK and NF-kappaB activities. Since a variety of proliferation-promoting genes and anti-apoptotic mechanisms are activated by NF-kappaB, retaining its low levels would be one potential mechanism by which inhibition of mitotic proliferation is maintained and apoptosis is promoted during late megakaryopoiesis.

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Section: Discussionmentioning

confidence: 99%

Signaling by the Mpl receptor involves IKK and NF‐κB*

Zhang

Sun

Wang

et al. 2002

J of Cellular Biochemistry

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“…Progenitor cell assays. For megakaryocyte progenitor assays, we established an alkaline phosphatase anti-alkaline phosphatase (APAAP) method of staining whole agar cultures in situ (Rasko et al, 1997). Megakaryocyte cultures were stimulated with G-CSF (final concentration 500 U/ml), GM-CSF (100 ng/ml), SCF (100 ng/ml), IL-3 (100 ng/ml), IL-6 (100 ng/ml), erythropoietin (Epo, 4 U/ml), PEG-rHuMGDF (200 ng/ml; all cytokines supplied by Amgen, Thousand Oaks) and incubated for 10-12 d. Dried, fixed cultures were digested with b-agarose-1 (1 U/ml, 37ЊC, 1 h; Calbiochem), labelled with anti-CD41a (glycoprotein IIbIIIa; Biodesign) and anti-CD42b (glycoprotein Ib; Biodesign) and stained using the Dako APAAP Kit, according to the manufacturers' instructions.…”

Section: Methodsmentioning

confidence: 99%

Multilineage mobilization of peripheral blood progenitor cells in humans following administration of PEG‐rHuMGDF

et al. 1997

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Summary.The most important physiological regulator of megakaryocytopoiesis is the ligand for the c-mpl receptor (thrombopoietin/megakaryocyte growth and development factor, MGDF). We examined the effect of pegylatedrecombinant human MGDF (PEG-rHuMGDF): patients received PEG-rHuMGDF at doses of 0·03, 0·1, 0·3 or 1·0 mg/kg/d or placebo for 10 d maximum in a doubleblinded randomized study. There was a dose-dependent elevation in circulating platelet counts but no alteration in erythrocyte or total leucocyte counts. The number of bone marrow megakaryocytes was increased approximately 2-fold. The frequency of bone marrow progenitor cells was not altered. In contrast, both to the bone marrow results and to published pre-clinical data, there was a dose-dependent mobilization into the blood of progenitor cells of multiple cell lineages. Increased levels of Meg-CFC (maximum increase 30-fold), day 7 and day 14 GM-CFC and BFU-E were demonstrated at doses of 0·3 and 1·0 mg/kg/d PEG-rHuMGDF. At 0·1 mg/kg/d, mobilization of Meg-CFC alone occurred in two-thirds of patients. Maximum blood levels of progenitor cells occurred at day 12. Thus, administration of PEG-rHuMGDF to humans resulted in mobilization of progenitor cells of multiple lineages despite its 'lineage-specific' activity on mature cell development.

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“…20,62,63 In addition to acting as a potent megakaryocyte colony-stimulating factor, TPO has a synergistic effect on the growth of myeloid and erythroid precursors when combined with other hematopoietic growth factors such as erythropoietin or stem cell factor. [64][65][66] The role of TPO as the principal physiologic regulator of platelet production has been confirmed in studies of mutant mice lacking the ability to produce either TPO (TPO Ϫ/Ϫ ) or its receptor (c-Mpl Ϫ/Ϫ ). [67][68][69][70][71] Genetic elimination of TPO or c-Mpl results in an 85% to 95% reduction in the number of circulating platelets, megakaryocytes, and megakaryocyte progenitor cells.…”

Section: Tpo and Its Biology Isolation Of C-mpl Ligandmentioning

confidence: 99%

Recombinant human thrombopoietin: basic biology and evaluation of clinical studies

Kuter

Begley

2002

Blood

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338

236

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Thrombocytopenia is a common medical problem for which the main treatment is platelet transfusion. Given the increasing use of platelets and the declining donor population, identification of a safe and effective platelet growth factor could improve the management of thrombocytopenia. Thrombopoietin (TPO), the c-Mpl ligand, is the primary physiologic regulator of megakaryocyte and platelet development.

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Mpl Ligand (MGDF) Alone and in Combination with Stem Cell Factor (SCF) Promotes Proliferation and Survival of Human Megakaryocyte, Erythroid and Granulocyte/Macrophage Progenitors

Cited by 42 publications

References 55 publications

Signaling by the Mpl receptor involves IKK and NF‐κB*

Signaling by the Mpl receptor involves IKK and NF‐κB*

Multilineage mobilization of peripheral blood progenitor cells in humans following administration of PEG‐rHuMGDF

Recombinant human thrombopoietin: basic biology and evaluation of clinical studies

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