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5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

Oncogene volume 28, pages 3429–3441 (2009)Cite this article

Abstract

Complete loss or interstitial deletions of chromosome 5 are the most common karyotypic abnormality in myelodysplastic syndromes (MDSs). Isolated del(5q)/5q– MDS patients have a more favorable prognosis than those with additional karyotypic defects, who tend to develop myeloproliferative neoplasms (MPNs) and acute myeloid leukemia. The frequency of unbalanced chromosome 5 deletions has led to the idea that 5q harbors one or more tumor-suppressor genes that have fundamental roles in the growth control of hematopoietic stem/progenitor cells (HSCs/HPCs). Cytogenetic mapping of commonly deleted regions (CDRs) centered on 5q31 and 5q32 identified candidate tumor-suppressor genes, including the ribosomal subunit RPS14, the transcription factor Egr1/Krox20 and the cytoskeletal remodeling protein, α-catenin. Although each acts as a tumor suppressor, alone or in combination, no molecular mechanism accounts for how defects in individual 5q candidates may act as a lesion driving MDS or contributing to malignant progression in MPN. One candidate gene that resides between the conventional del(5q)/5q– MDS-associated CDRs is DIAPH1 (5q31.3). DIAPH1 encodes the mammalian Diaphanous-related formin, mDia1. mDia1 has critical roles in actin remodeling in cell division and in response to adhesive and migratory stimuli. This review examines evidence, with a focus on mouse gene-targeting experiments, that mDia1 acts as a node in a tumor-suppressor network that involves multiple 5q gene products. The network has the potential to sense dynamic changes in actin assembly. At the root of the network is a transcriptional response mechanism mediated by the MADS-box transcription factor, serum response factor (SRF), its actin-binding myocardin family coactivator, MAL, and the SRF-target 5q gene, EGR1, which regulate the expression of PTEN and p53-family tumor-suppressor proteins. We hypothesize that the network provides a homeostatic mechanism balancing HPC/HSC growth control and differentiation decisions in response to microenvironment and other external stimuli.

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Acknowledgements

ASA and RAW were supported by the Van Andel Foundation, the JP McCarthy Foundation and the American Cancer Society (RSG-05-033-01-CSM). We are grateful to David Nadziejka for vigilant editing as well as Nick Duesbery, Cindy Miranti and Jeff Mackeigan for their thoughtful discussion.

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Author notes

  1. K M Eisenmann

    Present address: 5Current address: Department of Biochemistry and Cancer Biology, The University of Toledo, 3000 Arlington Avenue, Toledo, OH 43614-2598 USA.,

Authors and Affiliations

  1. Laboratories of Cell Structure & Signal Integration, Van Andel Research Institute, Grand Rapids, MI, USA

    K M Eisenmann, S F Matheson, N F Kent, A D DeWard, R A West & A S Alberts

  2. Computational Biology, Van Andel Research Institute, Grand Rapids, MI, USA

    K J Dykema & K A Furge

  3. Department of Biology, Calvin College, Grand Rapids, MI, USA

    S F Matheson

  4. Translational Genomics Clinical Research Service, Scottsdale, AZ, USA

    R Tibes

Authors
  1. K M Eisenmann
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  2. K J Dykema
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  3. S F Matheson
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  4. N F Kent
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  5. A D DeWard
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  6. R A West
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  7. R Tibes
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  8. K A Furge
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  9. A S Alberts
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Corresponding author

Correspondence to A S Alberts.

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Eisenmann, K., Dykema, K., Matheson, S. et al. 5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics. Oncogene 28, 3429–3441 (2009). https://doi.org/10.1038/onc.2009.207

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  • DOI: https://doi.org/10.1038/onc.2009.207

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