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Pleiotrophin mediates hematopoietic regeneration via activation of RAS.

Publication ,  Journal Article
Himburg, HA; Yan, X; Doan, PL; Quarmyne, M; Micewicz, E; McBride, W; Chao, NJ; Slamon, DJ; Chute, JP
Published in: J Clin Invest
November 2014

Hematopoietic stem cells (HSCs) are highly susceptible to ionizing radiation-mediated death via induction of ROS, DNA double-strand breaks, and apoptotic pathways. The development of therapeutics capable of mitigating ionizing radiation-induced hematopoietic toxicity could benefit both victims of acute radiation sickness and patients undergoing hematopoietic cell transplantation. Unfortunately, therapies capable of accelerating hematopoietic reconstitution following lethal radiation exposure have remained elusive. Here, we found that systemic administration of pleiotrophin (PTN), a protein that is secreted by BM-derived endothelial cells, substantially increased the survival of mice following radiation exposure and after myeloablative BM transplantation. In both models, PTN increased survival by accelerating the recovery of BM hematopoietic stem and progenitor cells in vivo. PTN treatment promoted HSC regeneration via activation of the RAS pathway in mice that expressed protein tyrosine phosphatase receptor-zeta (PTPRZ), whereas PTN treatment did not induce RAS signaling in PTPRZ-deficient mice, suggesting that PTN-mediated activation of RAS was dependent upon signaling through PTPRZ. PTN strongly inhibited HSC cycling following irradiation, whereas RAS inhibition abrogated PTN-mediated induction of HSC quiescence, blocked PTN-mediated recovery of hematopoietic stem and progenitor cells, and abolished PTN-mediated survival of irradiated mice. These studies demonstrate the therapeutic potential of PTN to improve survival after myeloablation and suggest that PTN-mediated hematopoietic regeneration occurs in a RAS-dependent manner.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

November 2014

Volume

124

Issue

11

Start / End Page

4753 / 4758

Location

United States

Related Subject Headings

  • ras Proteins
  • Signal Transduction
  • Regeneration
  • Radiation Injuries, Experimental
  • Mice
  • Immunology
  • Hematopoiesis
  • Cytokines
  • Cells, Cultured
  • Carrier Proteins
 

Citation

APA
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MLA
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Himburg, H. A., Yan, X., Doan, P. L., Quarmyne, M., Micewicz, E., McBride, W., … Chute, J. P. (2014). Pleiotrophin mediates hematopoietic regeneration via activation of RAS. J Clin Invest, 124(11), 4753–4758. https://doi.org/10.1172/JCI76838
Himburg, Heather A., Xiao Yan, Phuong L. Doan, Mamle Quarmyne, Eva Micewicz, William McBride, Nelson J. Chao, Dennis J. Slamon, and John P. Chute. “Pleiotrophin mediates hematopoietic regeneration via activation of RAS.J Clin Invest 124, no. 11 (November 2014): 4753–58. https://doi.org/10.1172/JCI76838.
Himburg HA, Yan X, Doan PL, Quarmyne M, Micewicz E, McBride W, et al. Pleiotrophin mediates hematopoietic regeneration via activation of RAS. J Clin Invest. 2014 Nov;124(11):4753–8.
Himburg, Heather A., et al. “Pleiotrophin mediates hematopoietic regeneration via activation of RAS.J Clin Invest, vol. 124, no. 11, Nov. 2014, pp. 4753–58. Pubmed, doi:10.1172/JCI76838.
Himburg HA, Yan X, Doan PL, Quarmyne M, Micewicz E, McBride W, Chao NJ, Slamon DJ, Chute JP. Pleiotrophin mediates hematopoietic regeneration via activation of RAS. J Clin Invest. 2014 Nov;124(11):4753–4758.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

November 2014

Volume

124

Issue

11

Start / End Page

4753 / 4758

Location

United States

Related Subject Headings

  • ras Proteins
  • Signal Transduction
  • Regeneration
  • Radiation Injuries, Experimental
  • Mice
  • Immunology
  • Hematopoiesis
  • Cytokines
  • Cells, Cultured
  • Carrier Proteins