Point mutation in the gene encoding p300 suppresses thrombocytopenia in Mpl-/- mice.
In an N-nitroso-N-ethylurea (ENU) mutagenesis screen using Mpl(-/-) mice, we isolated a semidominant suppressor of thrombocytopenia, termed Plt6. The gene mutated in Plt6 mice encodes the transcriptional coregulator p300, and the mutation, a tyrosine to asparagine substitution at amino acid 630 (Y630N), disrupts the interaction between p300 and c-Myb. Mpl(-/-) p300(Plt6/+) mice displayed elevated platelet counts relative to Mpl(-/-) p300(+/+) controls, whereas mice homozygous for the Plt6 mutation produced supraphysiological levels of circulating platelets. On a wild-type genetic background, mice homozygous for the p300(Plt6) mutation, or recipients of Mpl(+/+) p300(Plt6/Plt6) bone marrow, also exhibited thrombocytosis as well as deficiencies in B-lymphoid cells. Increased platelet numbers in Plt6 mutant mice were accompanied by significant increases in megakaryocyte progenitor cells within the bone marrow and spleen with concomitantly elevated numbers of megakaryocytes. The expansion of megakaryocytopoiesis and suppression of Mpl(-/-) thrombocytopenia in Plt6 mutants is highly reminiscent of that observed in mice with mutations affecting the p300 partner protein c-Myb, suggesting an indispensable repressive role for the c-Myb/p300 transcriptional regulatory complex in megakaryocyte development, the inhibition of which allows substantial thrombopoietin (TPO)-independent platelet production.
Kauppi
Maria
M
Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Murphy
James M
JM
de Graaf
Carolyn A
CA
Hyland
Craig D
CD
Greig
Kylie T
KT
Metcalf
Donald
D
Hilton
Adrienne A
AA
Nicola
Nicos A
NA
Kile
Benjamin T
BT
Hilton
Douglas J
DJ
Alexander
Warren S
WS
D000818:Animals; D001483:Base Sequence; D001792:Blood Platelets / Q000378:metabolism*; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000502:physiology*; D006720:Homozygote; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D017354:Point Mutation; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism / Q000502:physiology*; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D013921:Thrombocytopenia / Q000235:genetics*; D013926:Thrombopoietin / Q000378:metabolism
C481270:Mpl protein, mouse; D020598:Proto-Oncogene Proteins c-myb; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse