title: Ezrin is a target for oncogenic Kit mutants in murine erythroleukemia.
abstract: The model of erythroleukemia caused by Spi-1/PU.1 transgenesis in mice is a multistage disease. A preleukemic step is characterized by an acute proliferation of proerythroblasts due to the arrest of differentiation provoked by Spi-1/PU.1. Later on, a blastic crisis occurs associated with somatic oncogenic mutations in the stem cell factor (SCF) receptor kit. To gain insights into the mechanisms of the leukemic progression, we performed proteomic profiling analyses of proerythroblasts isolated at the 2 stages of the disease. Our results indicate that the level of ezrin, a membrane cytoskeletal crosslinker, is increased in the leukemic cells. We show that Kit oncogenic forms are responsible for ezrin phosphorylation and that phosphorylation rather than overexpression is essential in the leukemic proerythroblasts. Using expression of dominant-negative forms of ezrin, we show that phosphorylation of ezrin on residue Y353 participates in apoptosis resistance, whereas phosphorylation on residue Y145 promotes proliferation of the leukemic cells in vitro and in vivo. Another recurrent oncogenic form of tyrosine kinases (Flt3) most frequently involved in human myeloid leukemia was also able to phosphorylate ezrin. These findings point to a new role for ezrin as signaling player in the development of leukemia, being a downstream effector of oncogenic tyrosine kinases in leukemic blasts.
authors.affiliation: Inserm U830, Paris, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Monni
authors.forename: Lamya
authors.initials: L
authors.lastname: Haddaoui
authors.forename: Alexandra
authors.initials: A
authors.lastname: Naba
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gallais
authors.forename: Monique
authors.initials: M
authors.lastname: Arpin
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.forename: Françoise
authors.initials: F
authors.lastname: Moreau-Gachelin
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D036341:Intercellular Signaling Peptides and Proteins; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D000099149:Ezrin; C086597:lambda Spi-1