title: Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes.
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.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637;
authors.forename: Sriram
authors.initials: S
authors.lastname: Sundaravel
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637;
authors.forename: Ryan
authors.initials: R
authors.lastname: Duggan
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Tushar
authors.initials: T
authors.lastname: Bhagat
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637;
authors.forename: David L
authors.initials: DL
authors.lastname: Ebenezer
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637;
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Yiting
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Matthias
authors.initials: M
authors.lastname: Bartenstein
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Madhu
authors.initials: M
authors.lastname: Unnikrishnan
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637;
authors.forename: Subhradip
authors.initials: S
authors.lastname: Karmakar
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Ting-Chun
authors.initials: TC
authors.lastname: Liu
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Ingrid
authors.initials: I
authors.lastname: Torregroza
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Thomas
authors.initials: T
authors.lastname: Quenon
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637;
authors.forename: John
authors.initials: J
authors.lastname: Anastasi
authors.affiliation: Moffitt Cancer Center, Tampa, FL 33612;
authors.forename: Kathy L
authors.initials: KL
authors.lastname: McGraw
authors.affiliation: Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.affiliation: Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom;
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.affiliation: Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Vijay
authors.initials: V
authors.lastname: Yajnik
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637;
authors.forename: Andrew
authors.initials: A
authors.lastname: Artz
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637;
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.affiliation: Moffitt Cancer Center, Tampa, FL 33612;
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
authors.affiliation: Department of Surgery, Weill Cornell Medical College, New York, NY 10065; tre2003@med.cornell.edu amit.verma@einstein.yu.edu awickrem@medicine.bsd.uchicago.edu.
authors.forename: Todd
authors.initials: T
authors.lastname: Evans
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; tre2003@med.cornell.edu amit.verma@einstein.yu.edu awickrem@medicine.bsd.uchicago.edu.
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637; tre2003@med.cornell.edu amit.verma@einstein.yu.edu awickrem@medicine.bsd.uchicago.edu.
authors.forename: Amittha
authors.initials: A
authors.lastname: Wickrema
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004900:Erythroblasts / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020690:GTPase-Activating Proteins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D000099291:Adducins
chemical_list: D000199:Actins; D002148:Calmodulin-Binding Proteins; D020690:GTPase-Activating Proteins; D029961:Zebrafish Proteins; D020830:rac1 GTP-Binding Protein; D000099291:Adducins; C510122:DOCK4 protein, human; C107953:RAC1 protein, human
keywords: DOCK4; MDS; actin; erythroid; signaling