1. ¹Laboratories of Cell Structure & Signal Integration, Van Andel Research Institute, Grand Rapids, MI, USA
2. ²Computational Biology, Van Andel Research Institute, Grand Rapids, MI, USA
3. ³Department of Biology, Calvin College, Grand Rapids, MI, USA
4. ⁴Translational Genomics Clinical Research Service, Scottsdale, AZ, USA

Correspondence: Dr AS Alberts, Laboratory of Cell Structure and Signal Integration, Van Andel Research Institute, 333 Bostwick Avenue, NE, Grand Rapids, MI 49503, USA. E-mail: art.alberts@vai.org

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

Received 7 March 2009; Revised 8 June 2009; Accepted 16 June 2009; Published online 13 July 2009.

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, -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.