5q- myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics.
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, alpha-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.
Eisenmann
K M
KM
Laboratories of Cell Structure & Signal Integration, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Dykema
K J
KJ
Matheson
S F
SF
Kent
N F
NF
DeWard
A D
AD
West
R A
RA
Tibes
R
R
Furge
K A
KA
Alberts
A S
AS
D000199:Actins / Q000378:metabolism*; D000818:Animals; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000235:genetics*
D000199:Actins