Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/51001
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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
1476-5551
Statement of
Responsibility: 
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
Gadd45alpha
FLT3-ITD mutation
DOI: 10.1038/leu.2008.349
Published version: http://dx.doi.org/10.1038/leu.2008.349
Appears in Collections:Aurora harvest 5
Molecular and Biomedical Science publications

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