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Repression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation

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dc.contributor.authorPerugini, M.
dc.contributor.authorKok, C.
dc.contributor.authorBrown, A.
dc.contributor.authorWilkinson, C.
dc.contributor.authorSalerno, D.
dc.contributor.authorYoung, S.
dc.contributor.authorDiakiw, S.
dc.contributor.authorLewis, I.
dc.contributor.authorGonda, T.
dc.contributor.authorD'Andrea, R.
dc.date.issued2009
dc.descriptionLink to a related website: https://www.nature.com/articles/leu2008349.pdf, Open Access via Unpaywall
dc.description.abstractThe 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.
dc.description.statementofresponsibilityM. 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
dc.identifier.citationLeukemia, 2009; 23(4):729-738
dc.identifier.doi10.1038/leu.2008.349
dc.identifier.issn0887-6924
dc.identifier.issn1476-5551
dc.identifier.orcidKok, C. [0000-0002-3181-7852]
dc.identifier.orcidBrown, A. [0000-0002-9023-0138]
dc.identifier.orcidGonda, T. [0000-0002-8792-3021]
dc.identifier.urihttp://hdl.handle.net/2440/51001
dc.language.isoen
dc.publisherNature Publishing Group
dc.rightsCopyright 2009 Macmillan
dc.source.urihttps://doi.org/10.1038/leu.2008.349
dc.subjectAML
dc.subjectFLT3 mutation
dc.subjectGadd45alpha
dc.subjectFLT3-ITD mutation
dc.titleRepression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation
dc.title.alternativeRepression of Gadd45alpha by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation
dc.typeJournal article
pubs.publication-statusPublished

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