Aberrant Epigenetic and Genetic Marks Are Seen in Myelodysplastic Leukocytes and Reveal Dock4 as a Candidate Pathogenic Gene on Chromosome 7q

Zhou, Li; Opalinska, Joanna; Sohal, Davendra; Yu, Yiting; Mo, Yongkai; Bhagat, Tushar D.; Abdel-Wahab, Omar; Fazzari, Melissa; Figueroa, María E.; Alencar, Cristina; Zhang, Jinghang; Kambhampati, Suman; Parmar, Simrit; Nischal, Sangeeta; Hueck, Christoph J.; Suzuki, Masako; Freidman, Ellen; Pellagatti, Andrea; Boultwood, Jacqueline; Steidl, Ulrich; Sauthararajah, Yogen; Yajnik, Vijay; McMahon, Christine M.; Gore, Steven D.; Platanias, Leonidas C.; Levine, Ross L.; Melnick, Ari; Wickrema, Amittha; Greally, John M.; Vermaa, Amit

doi:10.1074/jbc.m111.235028

Cited by 43 publications

(42 citation statements)

References 44 publications

(27 reference statements)

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“…S5J). Our earlier work had shown that DOCK4 can also be epigenetically silenced by aberrant DNA methylation in MDS (8). We examined MDS bone marrow samples without deletion of chromosome 7 and determined that reduced expression of DOCK4 can be seen in some samples and that this result correlates with actin filament disruption seen in erythroid cells generated from these samples (SI Appendix, Fig.…”

Section: Dock4 Knockdown In Primary Human Erythroblasts Results Inmentioning

confidence: 99%

“…In a previous study (8), we had observed that numerous 7q genes, including dedicator of cytokinesis 4 (DOCK4), were deleted or epigenetically silenced in MDS, thus prompting an examination of its role in erythropoiesis in the present study. DOCK4 belongs to a large family of proteins (CED5/DOCK180/MYOBLAST CITY class) that is well conserved in mammals (9)(10)(11).…”

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confidence: 99%

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Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes

Sundaravel

Duggan

Bhagat

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.yelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders that are characterized by cytopenias caused by ineffective hematopoiesis (1-3). Even though MDS may transform to acute leukemia in one-third of patients who have MDS, cytopenias drive morbidity for most patients (4). Most of the morbidity experienced by these patients is due to low red blood cell (RBC) counts; therefore, studies on the molecular pathogenesis of dysplastic erythropoiesis are critically needed. Cytogenetic studies have shown that stem and progenitor cells in MDS contain deletions in chromosomes 5, 7, 20, and others (5). Deletions of the chromosomal 7q region are seen in 10% of cases and are associated with significantly worse survival (6). These genomic deletions are usually large, and even though some candidate pathogenic genes have been postulated (7), it is not clear which of the deleted genes contribute to the pathogenesis of ineffective erythropoiesis and dysplasia in MDS.In a previous study (8), we had observed that numerous 7q genes, including dedicator of cytokinesis 4 (DOCK4), were deleted or epigenetically silenced in MDS, thus prompting an examination of its role in erythropoiesis in the present study. DOCK4 belongs to a large family of proteins (CED5/DOCK180/MYOBLAST CITY class) that is well conserved in mammals (9-11). They are large proteins (>200 kb) that act as signaling intermediates and provide docking sites for many other signaling molecules. One of the welldescribed functions of DOCK4 is its ability to activate GTPases, such as ras-related C3 botulinum toxin substrate 1 (RAC1) and RAP1, in man...

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Section: Dock4 Knockdown In Primary Human Erythroblasts Results Inmentioning

confidence: 99%

mentioning

confidence: 99%

Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes

Sundaravel

Duggan

Bhagat

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Methylation analysis by the HELP assay (22,(57)(58)(59) and a modified protocol to successfully work with low genomic DNA yield from low numbers of sorted stem and progenitor cells have been described (24,25). Integrity of genomic DNA of high molecular weight was assured by electrophoresis for all samples used.…”

Section: Methodsmentioning

confidence: 99%

HSC commitment–associated epigenetic signature is prognostic in acute myeloid leukemia

Bartholdy¹,

Christopeit

Will³

et al. 2014

J. Clin. Invest.

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Acute myeloid leukemia (AML) is characterized by disruption of HSC and progenitor cell differentiation.Frequently, AML is associated with mutations in genes encoding epigenetic modifiers. We hypothesized that analysis of alterations in DNA methylation patterns during healthy HSC commitment and differentiation would yield epigenetic signatures that could be used to identify stage-specific prognostic subgroups of AML. We performed a nano HpaII-tiny-fragment-enrichment-by-ligation-mediated-PCR (nanoHELP) assay to compare genome-wide cytosine methylation profiles between highly purified human long-term HSC, short-term HSC, common myeloid progenitors, and megakaryocyte-erythrocyte progenitors. We observed that the most striking epigenetic changes occurred during the commitment of short-term HSC to common myeloid progenitors and these alterations were predominantly characterized by loss of methylation. We developed a metric of the HSC commitment-associated methylation pattern that proved to be highly prognostic of overall survival in 3 independent large AML patient cohorts, regardless of patient treatment and epigenetic mutations. Application of the epigenetic signature metric for AML prognosis was superior to evaluation of commitment-based gene expression signatures. Together, our data define a stem cell commitment-associated methylome that is independently prognostic of poorer overall survival in AML.

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“…[12][13][14][15][16][17][18][19][20][21][22] In an early study of ours, we identified disease-specific dysregulated genes and pathways using GeneChip analysis of bulk CD34 1 hematopoietic stem (HSCs) and progenitor cells (HSPCs) from patients with MDS with monosomy 7. 20 However, the absence of specific cell-membrane markers to separate cytogenetically normal and abnormal cells hindered further analysis of dysregulated molecular mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Single-cell RNA-seq reveals a distinct transcriptome signature of aneuploid hematopoietic cells

Zhao

Gao

et al. 2017

Blood

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Aberrant Epigenetic and Genetic Marks Are Seen in Myelodysplastic Leukocytes and Reveal Dock4 as a Candidate Pathogenic Gene on Chromosome 7q

Cited by 43 publications

References 44 publications

Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes

Reduced DOCK4 expression leads to erythroid dysplasia in myelodysplastic syndromes

HSC commitment–associated epigenetic signature is prognostic in acute myeloid leukemia

Single-cell RNA-seq reveals a distinct transcriptome signature of aneuploid hematopoietic cells

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