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Blood ; 115(5): 1037-48, 2010 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-19996410

RESUMO

Constitutively active JAK2V617F and thrombopoietin receptor (TpoR) W515L/K mutants are major determinants of human myeloproliferative neoplasms (MPNs). We show that a TpoRW515 mutation (W515A), which we detected in 2 myelofibrosis patients, and the Delta5TpoR active mutant, where the juxtamembrane R/KW(515)QFP motif is deleted, induce a myeloproliferative phenotype in mouse bone marrow reconstitution experiments. This phenotype required cytosolic Y112 of the TpoR. Phosphotyrosine immunoprofiling detected phosphorylated cytosolic TpoR Y78 and Y112 in cells expressing TpoRW515A. Mutation of cytosolic Y112 to phenylalanine prevented establishment of the in vivo phenotype and decreased constitutive active signaling by Delta5TpoR and TpoRW515A, especially via the mitogen-activated protein (MAP)-kinase pathway, without decreasing Janus kinase 2 (JAK2) activation. In contrast, mutation of cytosolic Y78 to phenylalanine enhanced the myeloproliferative syndrome induced by the TpoRW515 mutants, by enhancing receptor-induced JAK2 activation. We propose that TpoR cytosolic phosphorylated Y112 and flanking sequences could become targets for pharmacologic inhibition in MPNs.


Assuntos
Mutação , Transtornos Mieloproliferativos/genética , Mielofibrose Primária/genética , Receptores de Trombopoetina/genética , Tirosina/genética , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea , Linhagem Celular , Proliferação de Células , Humanos , Immunoblotting , Janus Quinase 2/metabolismo , Camundongos , Transtornos Mieloproliferativos/metabolismo , Transtornos Mieloproliferativos/patologia , Fosfoproteínas/metabolismo , Fosforilação , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos B/metabolismo , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Receptores de Trombopoetina/metabolismo , Transfecção , Tirosina/metabolismo
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