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

Authors

K. M. Eisenmann, Van Andel Research InstituteFollow
K. J. Dykema, Van Andel Research Institute
Stephen F. Matheson, Van Andel Research InstituteFollow
N. F. Kent, Van Andel Research Institute

Document Type

Article

Publication Title

Oncogene

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. © 2009 Macmillan Publishers Limited All rights reserved.

First Page

3429

Last Page

3441

DOI

10.1038/onc.2009.207

Publication Date

10-1-2009

Recommended Citation

Eisenmann, K. M.; Dykema, K. J.; Matheson, Stephen F.; and Kent, N. F., "5q- myelodysplastic syndromes: Chromosome 5q genes direct a tumor-suppression network sensing actin dynamics" (2009). University Faculty Publications and Creative Works. 299.
https://digitalcommons.calvin.edu/calvin_facultypubs/299