Mpl ligand prevents lethal myelosuppression by inhibiting p53-dependent apoptosis

Blood. 2001 Oct 1;98(7):2084-90. doi: 10.1182/blood.v98.7.2084.

Abstract

A single dose of Mpl ligand (Mpl-L) given immediately after lethal DNA-damaging regimens prevents the death of mice. However, the mechanism of this myeloprotection is unknown. The induction of p53-dependent apoptosis in response to DNA damage signals suggests that immediate administration of Mpl-L may inhibit p53-dependent apoptosis. This hypothesis was tested by administering a single injection of pegylated murine Megakaryocyte Growth and Development Factor (PEG-rmMGDF, a truncated recombinant Mpl-L) to p53(-/-) and wild-type mice immediately after carboplatin (80 mg/kg) and 7.5 Gy total body gamma-irradiation. PEG-rmMGDF was required to prevent the death of wild-type mice, whereas p53(-/-) mice survived with or without the exogenous cytokine. The degree of platelet depression and subsequent recovery was comparable in p53(-/-) mice to wild-type animals given PEG-rmMGDF. Hence, either Mpl-L administration or p53-deficiency protected multipotent hematopoietic progenitors and committed megakaryocyte precursors. The myelosuppressive regimen induced expression of p53 and the p53 target, p21(Cipl) in wild-type bone marrow, indicating that Mpl-L acts downstream of p53 to prevent apoptosis. Constitutive expression of the proapoptotic protein Bax, was not further increased. Bax(-/-) mice survived the lethal regimen only when given PEG-rmMGDF; however, these Bax(-/-) mice showed more rapid hematopoietic recovery than did identically-treated wild-type mice. Therefore, administration of Mpl-L immediately after myelosuppressive chemotherapy or preparatory regimens for autologous bone marrow transplantation should prevent p53-dependent apoptosis, decrease myelosuppression, and reduce the need for platelet transfusions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Ataxia Telangiectasia Mutated Proteins
  • Bone Marrow / drug effects*
  • Bone Marrow / physiology*
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / pathology
  • Bone Marrow Cells / radiation effects
  • Carboplatin / administration & dosage
  • Carboplatin / poisoning
  • Cell Cycle Proteins
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • DNA-Binding Proteins
  • Death
  • Hematopoiesis / drug effects
  • Mice
  • Mice, Knockout
  • Polyethylene Glycols / administration & dosage
  • Polyethylene Glycols / pharmacology
  • Protein Serine-Threonine Kinases / pharmacology
  • Proto-Oncogene Proteins / pharmacology
  • Proto-Oncogene Proteins c-bcl-2*
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Stem Cells / drug effects
  • Stem Cells / pathology
  • Stem Cells / radiation effects
  • Thrombopoietin / administration & dosage
  • Thrombopoietin / pharmacology*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / pharmacology*
  • Tumor Suppressor Proteins
  • Whole-Body Irradiation / adverse effects
  • bcl-2-Associated X Protein

Substances

  • Bax protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • bcl-2-Associated X Protein
  • polyethylene glycol-recombinant human megakaryocyte growth and development factor
  • Polyethylene Glycols
  • Thrombopoietin
  • Carboplatin
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein Serine-Threonine Kinases