Submitted December 24, 2008
Accepted February 17, 2009
Mutational inhibition of c-Myb or p300 ameliorates treatment-induced thrombocytopenia
Douglas J. Hilton, Benjamin T. Kile, and Warren S. Alexander*
Molecular Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
* Corresponding author; email: alexandw{at}wehi.edu.au.
The transcription factor c-Myb and co-regulator 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-MybPlt4 mutation on thrombocytopenia associated with reduced platelet lifespan in Bcl-XPlt20/Plt20 mice was assessed, as were responses in c-MybPlt4 and/or p300Plt6 mutant mice to thrombocytopenia associated with anti-platelet antibodies, chemotherapy or bone marrow transplantation. Homozygosity of the c-MybPlt4 allele ameliorated thrombocytopenia associated with reduced platelet lifespan and c-MybPlt4/+ mice exhibited more rapid than normal recovery from thrombocytopenia caused by anti-platelet serum or bone marrow transplantation. Recovery to pre-treatment platelet levels was unaltered in 5-FU-treated c-MybPlt4/+ mice relative to wild type controls, but enhanced platelet production during subsequent thrombocytosis was evident. More modest enhancement of platelet recovery following 5-FU or bone marrow transplantation was also evident in p300Plt6/+ animals. The data suggest potential utility of c-Myb/p300 as a target for therapeutic intervention in thrombocytopenia of diverse origins.
