Mutational inhibition of c-Myb or p300 ameliorates treatment-induced thrombocytopenia.
The transcription factor c-Myb and coregulator p300 have a key role in maintaining production of controlled numbers of megakaryocytes and platelets. In mice, mutations in c-Myb or p300 cause thrombocytosis in otherwise wild-type animals and can ameliorate the thrombocytopenia in mice lacking the thrombopoietin receptor, c-Mpl, a model for human congenital amegakaryocytic thrombocytopenia. To examine whether inhibition of c-Myb/p300 is effective in other models of thrombocytopenia, the effect of the c-Myb(Plt4) mutation on thrombocytopenia associated with reduced platelet life span in Bcl-X(Plt20/Plt20) mice was assessed, as were responses in c-Myb(Plt4) and/or p300(Plt6) mutant mice to thrombocytopenia associated with antiplatelet antibodies, chemotherapy, or bone marrow transplantation. Homozygosity of the c-Myb(Plt4) allele ameliorated thrombocytopenia associated with reduced platelet life span, and c-Myb(Plt4/+) mice exhibited more rapid than normal recovery from thrombocytopenia caused by antiplatelet serum or bone marrow transplantation. Recovery to pretreatment platelet levels was unaltered in 5-fluorouracil-treated c-Myb(Plt4/+) mice relative to wild-type controls, but enhanced platelet production during subsequent thrombocytosis was evident. More modest enhancement of platelet recovery after 5-fluorouracil or bone marrow transplantation was also evident in p300(Plt6/+) animals. The data suggest potential utility of c-Myb/p300 as a target for therapeutic intervention in thrombocytopenia of diverse origins.
Hilton
Douglas J
DJ
Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Kile
Benjamin T
BT
Alexander
Warren S
WS
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000534:rehabilitation; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000502:physiology; D050881:E1A-Associated p300 Protein / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology; D020570:Genes, myb; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D053628:Receptors, Thrombopoietin / Q000235:genetics; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000235:genetics / Q000534:rehabilitation; D051020:bcl-X Protein / Q000235:genetics
D000970:Antineoplastic Agents; C481270:Mpl protein, mouse; D010975:Platelet Aggregation Inhibitors; D053628:Receptors, Thrombopoietin; D051020:bcl-X Protein; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D005472:Fluorouracil