Differential role of Stat5 isoforms in effecting hematopoietic recovery induced by Mpl-ligand in lethally myelosuppressed mice.
OBJECTIVE
To determine the role of the c-terminal half of c-Mpl in Mpl-L-induced myeloprotection and the importance of Stat5 isoforms in the survival signaling pathways induced by Mpl ligand.


METHODS
Delta60-Mpl knockin mice, Stat5a(-/-)/b(-/-), Stat5a(-/-), and Stat5b(-/-) mice and wild-type (WT) controls were given a lethal myelosuppressive regimen: 80 mg/kg carboplatin intravenously followed by 7.5 or 6.5 Gy 137Cs total-body irradiation. A single dose of PEG-rmMGDF (65 microg/kg) was intravenously injected immediately after myelosuppression. Mice survival and blood counts were monitored for 22 days posttreatment.


RESULTS
Knockin Delta60-Mpl mice lacking the c-terminal half of the intracellular domain of c-Mpl show reduced ability of Mpl-L to prevent lethal myelosuppression and an impaired thrombopoietic response to exogenous c-Mpl ligand. The survival of Mpl-L-treated Stat5a(-/-)/b(-/-) mice exposed to the lethal myelosuppressive regimen was substantially compromised compared to that of WT mice. Reduced survival of Stat5a(-/-)/b(-/-) mice was due to more severe hematopoietic suppression. Deletion of Stat5a did not result in a defect in hematopoietic recovery. In contrast, Mpl-L-treated Stat5b-deficient mice demonstrated significantly delayed hematopoietic recovery compared to WT controls.


CONCLUSIONS
Myeloprotective signaling transduced by the terminal 60 amino acids of the intracellular domain of c-Mpl is essential for complete protection from lethal myelosuppression provided by Mpl-L. Our studies differentiate the functions of Stat5 isoforms in hematopoietic stress and reveal a pivotal role of Stat5b in Mpl-L-induced hematopoietic recovery in this lethal myelosuppression model.
Pestina
Tamara I
TI
Division of Experimental Hematology, Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA. tamara.pestina@stjude.org
Jackson
Carl W
CW
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006410:Hematopoiesis; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008894:Milk Proteins; D019653:Myeloablative Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D015513:Oncogene Proteins / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology*; D018121:Receptors, Cytokine / Q000235:genetics; D053628:Receptors, Thrombopoietin; D050799:STAT5 Transcription Factor; D017384:Sequence Deletion; D015398:Signal Transduction; D015996:Survival Rate; D013926:Thrombopoietin / Q000008:administration & dosage / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D008894:Milk Proteins; C481270:Mpl protein, mouse; D019653:Myeloablative Agonists; D015513:Oncogene Proteins; D020033:Protein Isoforms; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D013926:Thrombopoietin