Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes

Sriram Sundaravel, Ryan Duggan, Tushar Bhagat, David L. Ebenezer, Hui Liu, Yiting Yu, Matthias Bartenstein, Madhu Unnikrishnan, Subhradip Karmakar, Ting Chun Liu, Ingrid Torregroza, Thomas Quenon, John Anastasi, Kathy L. McGraw, Andrea Pellagatti, Jacqueline Boultwood, Vijay Yajnik, Andrew Artz, Michelle M. Le Beau, Ulrich G. Steidl & 4 others Alan F. List, Todd Evans, Amit K. Verma, Amittha Wickrema

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E6359-E6368
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number46
DOIs
StatePublished - Nov 17 2015

Fingerprint

Cytokinesis
Myelodysplastic Syndromes
Actins
Erythroblasts
GTP Phosphohydrolases
Actin Cytoskeleton
rac1 GTP-Binding Protein
Genes
Erythroid Cells
Chromosomes, Human, Pair 7
Anemia
Erythrocytes
Bone Marrow
Phosphorylation
Survival

Keywords

  • Actin
  • DOCK4
  • Erythroid
  • MDS
  • Signaling

ASJC Scopus subject areas

  • General

Cite this

Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes. / Sundaravel, Sriram; Duggan, Ryan; Bhagat, Tushar; Ebenezer, David L.; Liu, Hui; Yu, Yiting; Bartenstein, Matthias; Unnikrishnan, Madhu; Karmakar, Subhradip; Liu, Ting Chun; Torregroza, Ingrid; Quenon, Thomas; Anastasi, John; McGraw, Kathy L.; Pellagatti, Andrea; Boultwood, Jacqueline; Yajnik, Vijay; Artz, Andrew; Le Beau, Michelle M.; Steidl, Ulrich G.; List, Alan F.; Evans, Todd; Verma, Amit K.; Wickrema, Amittha.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 46, 17.11.2015, p. E6359-E6368.

Research output: Contribution to journalArticle

Sundaravel, S, Duggan, R, Bhagat, T, Ebenezer, DL, Liu, H, Yu, Y, Bartenstein, M, Unnikrishnan, M, Karmakar, S, Liu, TC, Torregroza, I, Quenon, T, Anastasi, J, McGraw, KL, Pellagatti, A, Boultwood, J, Yajnik, V, Artz, A, Le Beau, MM, Steidl, UG, List, AF, Evans, T, Verma, AK & 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, vol. 112, no. 46, pp. E6359-E6368. https://doi.org/10.1073/pnas.1516394112
Sundaravel, Sriram ; Duggan, Ryan ; Bhagat, Tushar ; Ebenezer, David L. ; Liu, Hui ; Yu, Yiting ; Bartenstein, Matthias ; Unnikrishnan, Madhu ; Karmakar, Subhradip ; Liu, Ting Chun ; Torregroza, Ingrid ; Quenon, Thomas ; Anastasi, John ; McGraw, Kathy L. ; Pellagatti, Andrea ; Boultwood, Jacqueline ; Yajnik, Vijay ; Artz, Andrew ; Le Beau, Michelle M. ; Steidl, Ulrich G. ; List, Alan F. ; Evans, Todd ; Verma, Amit K. ; Wickrema, Amittha. / Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 46. pp. E6359-E6368.
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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.",
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AU - Yu, Yiting

AU - Bartenstein, Matthias

AU - Unnikrishnan, Madhu

AU - Karmakar, Subhradip

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AU - McGraw, Kathy L.

AU - Pellagatti, Andrea

AU - Boultwood, Jacqueline

AU - Yajnik, Vijay

AU - Artz, Andrew

AU - Le Beau, Michelle M.

AU - Steidl, Ulrich G.

AU - List, Alan F.

AU - Evans, Todd

AU - Verma, Amit K.

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