Perugini, M.Kok, C.Brown, A.Wilkinson, C.Salerno, D.Young, S.Diakiw, S.Lewis, I.Gonda, T.D'Andrea, R.2009-09-222009-09-222009Leukemia, 2009; 23(4):729-7380887-69241476-5551http://hdl.handle.net/2440/51001Link to a related website: https://www.nature.com/articles/leu2008349.pdf, Open Access via UnpaywallThe 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.enCopyright 2009 MacmillanAMLFLT3 mutationGadd45alphaFLT3-ITD mutationJournal article002009053710.1038/leu.2008.3490002652208000142-s2.0-6484910095239009Kok, C. [0000-0002-3181-7852]Brown, A. [0000-0002-9023-0138]Gonda, T. [0000-0002-8792-3021]