Repression of Gadd45alpha by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation

Perugini, M., Kok, C. H., Brown, A. L., Wilkinson, C. R., Salerno, D. G., Young, S. M., Diakiw, S. M., Lewis, I. D., Gonda, T. J. and D'Andrea, R. J. (2009) Repression of Gadd45alpha by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation. Leukemia, 23 4: 729-738. doi:10.1038/leu.2008.349


Author Perugini, M.
Kok, C. H.
Brown, A. L.
Wilkinson, C. R.
Salerno, D. G.
Young, S. M.
Diakiw, S. M.
Lewis, I. D.
Gonda, T. J.
D'Andrea, R. J.
Title Repression of Gadd45alpha by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation
Journal name Leukemia   Check publisher's open access policy
ISSN 0887-6924
Publication date 2009-04-01
Year available 2009
Sub-type Article (original research)
DOI 10.1038/leu.2008.349
Volume 23
Issue 4
Start page 729
End page 738
Total pages 10
Editor Nicole Killman
Place of publication United Kingdom
Publisher Nature Publishing Group
Collection year 2010
Language eng
Subject C1
780105 Biological sciences
970106 Expanding Knowledge in the Biological Sciences
0601 Biochemistry and Cell Biology
Abstract The tumor suppressor Gadd45 alpha was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45 alpha 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 Gadd45 alpha mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD+ cell line MV4;11. Knockdown of Gadd45 alpha with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45 alpha in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45 alpha 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 Gadd45 alpha in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45 alpha downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45 alpha by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML.
Keyword Receptor
Mutants
Differentiation
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
UQ Diamantina Institute Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 11 times in Thomson Reuters Web of Science Article | Citations
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Created: Wed, 10 Mar 2010, 01:34:57 EST by Sarah Macaione on behalf of UQ Diamantina Institute