Mpl ligand prevents lethal myelosuppression by inhibiting p53-dependent apoptosis.
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.
Pestina
T I
TI
Division of Experimental Hematology and the Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Cleveland
J L
JL
Yang
C
C
Zambetti
G P
GP
Jackson
C W
CW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D001853:Bone Marrow / Q000187:drug effects* / Q000502:physiology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D016190:Carboplatin / Q000008:administration & dosage / Q000506:poisoning; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins; D003643:Death; D006410:Hematopoiesis / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D013926:Thrombopoietin / Q000008:administration & dosage / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins; D014916:Whole-Body Irradiation / Q000009:adverse effects; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C103117:polyethylene glycol-recombinant human megakaryocyte growth and development factor; D011092:Polyethylene Glycols; D013926:Thrombopoietin; D016190:Carboplatin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases