Ezrin is a target for oncogenic Kit mutants in murine erythroleukemia

Blood
Richard MonniFrançoise Moreau-Gachelin

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 t...Continue Reading

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Citations

Aug 4, 2009·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Yu-Ching WeiHsuan-Ying Huang
Aug 30, 2008·The Journal of Biological Chemistry·Judith AustermannVolker Gerke
Feb 2, 2011·Leukemia & Lymphoma·Ming-Hua YangLi-Zhi Cao
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Jan 23, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Neetha ParameswaranNeetu Gupta
Apr 15, 2020·The American Journal of Pathology·Yuhua XueGeorge K Michalopoulos
Jul 2, 2021·Cellular Oncology (Dordrecht)·Jean Carlos Lipreri da SilvaJoão Agostinho Machado-Neto

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