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

Publication ,  Journal Article
Tiedt, R; Coers, J; Ziegler, S; Wiestner, A; Hao-Shen, H; Bornmann, C; Schenkel, J; Karakhanova, S; de Sauvage, FJ; Jackson, CW; Skoda, RC
Published in: Blood
February 19, 2009

We generated mice expressing a full-length Mpl transgene under the control of a 2-kb Mpl promoter in an Mpl(-/-) background, effectively obtaining mice that express full-length Mpl in the absence of other Mpl isoforms. These mice developed thrombocytosis with platelet levels approximately 5-fold higher than wild-type controls and markedly increased megakaryocyte numbers. The reintroduction of one wild-type Mpl allele restored normal platelet counts. We excluded the deletion of Mpl-tr, a dominant-negative isoform, as the underlying molecular cause for thrombocytosis. Instead, we found that transgene expression driven by the 2-kb Mpl promoter fragment was decreased during late megakaryocyte maturation, resulting in strongly diminished Mpl protein expression in platelets. Because platelets exert a negative feedback on thrombopoiesis by binding and consuming Tpo in the circulation through Mpl, we propose that the severe reduction of Mpl protein in platelets in Mpl-transgenic Mpl(-/-) mice shifts the equilibrium of this feedback loop, resulting in markedly elevated levels of megakaryocytes and platelets at steady state. Although the mechanism causing decreased expression of Mpl protein in platelets from patients with myeloproliferative disorders differs from this transgenic model, our results suggest that lowering Mpl protein in platelets could contribute to raising the platelet count.

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Published In

Blood

DOI

EISSN

1528-0020

Publication Date

February 19, 2009

Volume

113

Issue

8

Start / End Page

1768 / 1777

Location

United States

Related Subject Headings

  • Transgenes
  • Thrombopoietin
  • Thrombopoiesis
  • Thrombocytosis
  • Receptors, Thrombopoietin
  • Promoter Regions, Genetic
  • Platelet Count
  • Mice, Transgenic
  • Mice, Inbred Strains
  • Mice
 

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Tiedt, R., Coers, J., Ziegler, S., Wiestner, A., Hao-Shen, H., Bornmann, C., … Skoda, R. C. (2009). Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes. Blood, 113(8), 1768–1777. https://doi.org/10.1182/blood-2008-03-146084
Tiedt, Ralph, Jörn Coers, Sandra Ziegler, Adrian Wiestner, Hui Hao-Shen, Caroline Bornmann, Johannes Schenkel, et al. “Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes.Blood 113, no. 8 (February 19, 2009): 1768–77. https://doi.org/10.1182/blood-2008-03-146084.
Tiedt R, Coers J, Ziegler S, Wiestner A, Hao-Shen H, Bornmann C, et al. Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes. Blood. 2009 Feb 19;113(8):1768–77.
Tiedt, Ralph, et al. “Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes.Blood, vol. 113, no. 8, Feb. 2009, pp. 1768–77. Pubmed, doi:10.1182/blood-2008-03-146084.
Tiedt R, Coers J, Ziegler S, Wiestner A, Hao-Shen H, Bornmann C, Schenkel J, Karakhanova S, de Sauvage FJ, Jackson CW, Skoda RC. Pronounced thrombocytosis in transgenic mice expressing reduced levels of Mpl in platelets and terminally differentiated megakaryocytes. Blood. 2009 Feb 19;113(8):1768–1777.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

February 19, 2009

Volume

113

Issue

8

Start / End Page

1768 / 1777

Location

United States

Related Subject Headings

  • Transgenes
  • Thrombopoietin
  • Thrombopoiesis
  • Thrombocytosis
  • Receptors, Thrombopoietin
  • Promoter Regions, Genetic
  • Platelet Count
  • Mice, Transgenic
  • Mice, Inbred Strains
  • Mice