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Type: Journal article
Title: Repression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation
Other Titles: Repression of Gadd45alpha by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation
Author: Perugini, M.
Kok, C.
Brown, A.
Wilkinson, C.
Salerno, D.
Young, S.
Diakiw, S.
Lewis, I.
Gonda, T.
D'Andrea, R.
Citation: Leukemia, 2009; 23(4):729-738
Publisher: Nature Publishing Group
Issue Date: 2009
ISSN: 0887-6924
Statement of
M. Perugini, C. H. Kok, A. L. Brown, C. R. Wilkinson, D. G. Salerno, S. M. Young, S. M. Diakiw, I. D. Lewis, T. J. Gonda and R. J. D'Andrea
Abstract: The tumor suppressor Gadd45alpha was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45alpha as a downregulated gene in response to constitutive signaling from two FLT3 mutants (FLT3-ITD and FLT3-TKD) commonly found in AML, and a leukemogenic GM-CSF receptor trans-membrane mutant (GMR-V449E). GADD45A mRNA downregulation is also associated with FLT3-ITD(+) AML. Sustained ERK1/2 signaling contributes significantly to receptor-mediated downregulation of Gadd45alpha mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD(+) cell line MV4;11. Knockdown of Gadd45alpha with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45alpha in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45alpha overexpression in FLT3-ITD(+) AML cell lines also resulted in reduced growth associated with increased apoptosis and G(1)/S cell cycle arrest. Overexpression of Gadd45alpha in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45alpha downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45alpha by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML.
Keywords: AML
FLT3 mutation
FLT3-ITD mutation
DOI: 10.1038/leu.2008.349
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Appears in Collections:Aurora harvest 5
Molecular and Biomedical Science publications

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