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Oncogenes, Fusion Genes and Tumor Suppressor Genes

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

Leukemia volume 23, pages 729–738 (2009)Cite this article

Abstract

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.

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Acknowledgements

We are grateful to Dr Jenny Hardingham for her assistance with obtaining AML sample information. We also thank Mrs Sylvia Nobbs and Mr Sandy McIntyre for their help with flow cytometry. MP and RJD wrote the paper. MP and CHK performed the experiments and analyzed the data. CRW performed the microarray comparisons and provided statistical support. DGS performed experiments. SMY, SMD and IDL provided the AML material and performed the FLT3-ITD screening. ALB and TJG were involved in data analysis and critical review of the paper. The study is supported by grants from the US National Institutes of Health (R01 HL60657) and from the National Health and Medical Research Council of Australia (ID no. 453408). RJD was supported by the Peter Nelson Leukemia Research Fellowship. ALB was supported by Fellowships from the Leukemia Foundation of Australia and the Cancer Council of SA.

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Author notes

  1. M Perugini and C H Kok: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Haematology, Institute of Medical and Veterinary Science, Hanson Institute, Adelaide, South Australia, Australia

    M Perugini, C H Kok, A L Brown, D G Salerno, S M Young, S M Diakiw, I D Lewis & R J D'Andrea

  2. Women's and Children's Health Research Institute, North Adelaide, South Australia, Australia

    M Perugini, C H Kok, A L Brown, D G Salerno, S M Diakiw & R J D'Andrea

  3. Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia

    C H Kok & R J D'Andrea

  4. School of Mathematical Sciences, The University of Adelaide, Adelaide, South Australia, Australia

    C R Wilkinson

  5. The Schools of Paediatrics and Reproductive Health and Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia

    C H Kok, S M Diakiw & R J D'Andrea

  6. Cancer Biology Program, Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia

    T J Gonda

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Perugini, M., Kok, C., Brown, A. et al. Repression of Gadd45α by activated FLT3 and GM-CSF receptor mutants contributes to growth, survival and blocked differentiation. Leukemia 23, 729–738 (2009). https://doi.org/10.1038/leu.2008.349

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