PUBLICATION
Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes
- Authors
- Sundaravel, S., Duggan, R., Bhagat, T., Ebenezer, D.L., Liu, H., Yu, Y., Bartenstein, M., Unnikrishnan, M., Karmakar, S., Liu, T.C., Torregroza, I., Quenon, T., Anastasi, J., McGraw, K.L., Pellagatti, A., Boultwood, J., Yajnik, V., Artz, A., Le Beau, M.M., Steidl, U., List, A.F., Evans, T., Verma, A., Wickrema, A.
- ID
- ZDB-PUB-170214-78
- Date
- 2015
- Source
- Proceedings of the National Academy of Sciences of the United States of America 112: E6359-68 (Journal)
- Registered Authors
- Evans, Todd
- Keywords
- DOCK4, MDS, actin, erythroid, signaling
- MeSH Terms
-
- Male
- Zebrafish/genetics
- Zebrafish/metabolism
- Female
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- GTPase-Activating Proteins/biosynthesis*
- GTPase-Activating Proteins/genetics
- Actins/genetics
- Actins/metabolism
- Animals
- Erythroblasts/metabolism*
- Erythroblasts/pathology
- Gene Expression Regulation*
- rac1 GTP-Binding Protein/genetics
- rac1 GTP-Binding Protein/metabolism
- Humans
- Calmodulin-Binding Proteins/genetics
- Calmodulin-Binding Proteins/metabolism
- Myelodysplastic Syndromes/genetics
- Myelodysplastic Syndromes/metabolism*
- Myelodysplastic Syndromes/pathology
- PubMed
- 26578796 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Sundaravel, S., Duggan, R., Bhagat, T., Ebenezer, D.L., Liu, H., Yu, Y., Bartenstein, M., Unnikrishnan, M., Karmakar, S., Liu, T.C., Torregroza, I., Quenon, T., Anastasi, J., McGraw, K.L., Pellagatti, A., Boultwood, J., Yajnik, V., Artz, A., Le Beau, M.M., Steidl, U., List, A.F., Evans, T., Verma, A., Wickrema, A. (2015) Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes. Proceedings of the National Academy of Sciences of the United States of America. 112:E6359-68.
Abstract
Anemia is the predominant clinical manifestation of myelodysplastic syndromes (MDS). Loss or deletion of chromosome 7 is commonly seen in MDS and leads to a poor prognosis. However, the identity of functionally relevant, dysplasia-causing, genes on 7q remains unclear. Dedicator of cytokinesis 4 (DOCK4) is a GTPase exchange factor, and its gene maps to the commonly deleted 7q region. We demonstrate that DOCK4 is underexpressed in MDS bone marrow samples and that the reduced expression is associated with decreased overall survival in patients. We show that depletion of DOCK4 levels leads to erythroid cells with dysplastic morphology both in vivo and in vitro. We established a novel single-cell assay to quantify disrupted F-actin filament network in erythroblasts and demonstrate that reduced expression of DOCK4 leads to disruption of the actin filaments, resulting in erythroid dysplasia that phenocopies the red blood cell (RBC) defects seen in samples from MDS patients. Reexpression of DOCK4 in -7q MDS patient erythroblasts resulted in significant erythropoietic improvements. Mechanisms underlying F-actin disruption revealed that DOCK4 knockdown reduces ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase activation, leading to increased phosphorylation of the actin-stabilizing protein ADDUCIN in MDS samples. These data identify DOCK4 as a putative 7q gene whose reduced expression can lead to erythroid dysplasia.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping