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

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, R. J. D'Andrea

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17 Citations (Scopus)


The tumor suppressor Gadd45α was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45α 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 Gadd45α mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD+ cell line MV4;11. Knockdown of Gadd45α with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45α in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45α overexpression in FLT3-ITD+ AML cell lines also resulted in reduced growth associated with increased apoptosis and G1/S cell cycle arrest. Overexpression of Gadd45α in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45α downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45α by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML.

Original languageEnglish
Pages (from-to)729-738
Number of pages10
Issue number4
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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