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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2084-2090
HEMATOPOIESIS
Mpl ligand prevents lethal myelosuppression by inhibiting
p53-dependent apoptosis
Tamara I. Pestina,
John L. Cleveland,
Chunying Yang,
Gerard P. Zambetti, and
Carl W. Jackson
From the Division of Experimental Hematology and the
Department of Biochemistry, St Jude Children's Research Hospital,
Memphis, TN.
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  -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,
p21Cipl 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.
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