Mpl ligand prevents lethal myelosuppression by inhibiting p53-dependent apoptosis

A single dose of MpI ligand (MpI-L) given immediately after lethal DNA-dama ging regimens prevents the death of mice. However, the mechanism of this my elo-protection is unknown. The Induction of p53-dependent apoptosis in resp onse to DNA damage signals suggests that immediate administration of MpI-L may Inhibit p53-dependent apoptosis. This hypothesis was tested by administ ering a single injection of pegylated murine Megakaryocyte Growth and Devel opment Factor (PEG-rmMGDF, a truncated recombinant MpI-L) to p53(-/-), and wild-type mice immediately after carboplatin (80 mg/kg) and 7.5 Gy total bo dy gamma -irradiation. PEG-rmMGDF was required to prevent the death of wild -type mice, whereas p53(-/-) mice survived with or without the exogenous cy tokine. The degree of platelet depression and subsequent recovery was compa rable In p53(-/-) mice to wild-type animals given PEG-rmMGDF. Hence, either MpI-L administration or p53-deficiency protected multipotent hematopoietic progenitors and committed megakaryocyte precursors. The myelosuppressive r egimen induced expression of p53 and the p53 target, p21(Clpl) in wild-type bone marrow, indicating that MpI-L acts downstream of p53 to prevent apopt osis. Constitutive expression of the proapoptotic protein Bax, was not furt her Increased. Bax(-/-) mice survived the lethal regimen only when given PE G-rmMGDF; however, these Bax(-/-) mice showed more rapid hematopoietic reco very than did Identically-treated wild-type mice. Therefore, administration of MpI-L immediately after myelosuppressive chemotherapy or preparatory re gimens for autologous bone marrow tranplantation should prevent p53-depende nt apoptosis, decrease myelosuppression, and reduce the need for platelet t ransfusions. (C) 2001 by The American Society of Hematology.