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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3163-3172. Prepublished online as a Blood First Edition Paper on January 8, 2008; DOI 10.1182/blood-2007-09-110510. This Article Full Text Full Text (PDF) Supplemental Tables and Figure All Versions of this Article: blood-2007-09-110510v1 111/6/3163    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Monni, R. Articles by Moreau-Gachelin, F. Search for Related Content PubMed PubMed Citation Articles by Monni, R. Articles by Moreau-Gachelin, F. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Ezrin is a target for oncogenic Kit mutants in murine erythroleukemia Richard Monni1,2, Lamya Haddaoui3,4, Alexandra Naba5, Isabelle Gallais1,2, Monique Arpin5, Patrick Mayeux3,4, and Françoise Moreau-Gachelin1,2 1 Inserm U830, Paris; 2 Institut Curie, Paris; 3 Inserm U567, Paris; 4 Institut Cochin, Université Descartes, Centre National de la Recherche Scientifique (CNRS) (Unités mixte de recherche [UMR] 8104), Paris; 5 Institut Curie, UMR 144 CNRS, Paris, France 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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