title: Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q.
abstract: Myelodysplastic syndromes (MDS) are characterized by abnormal and dysplastic maturation of all blood lineages. Even though epigenetic alterations have been seen in MDS marrow progenitors, very little is known about the molecular alterations in dysplastic peripheral blood cells. We analyzed the methylome of MDS leukocytes by the HELP assay and determined that it was globally distinct from age-matched controls and was characterized by numerous novel, aberrant hypermethylated marks that were located mainly outside of CpG islands and preferentially affected GTPase regulators and other cancer-related pathways. Additionally, array comparative genomic hybridization revealed that novel as well as previously characterized deletions and amplifications could also be visualized in peripheral blood leukocytes, thus potentially reducing the need for bone marrow samples for future studies. Using integrative analysis, potentially pathogenic genes silenced by genetic deletions and aberrant hypermethylation in different patients were identified. DOCK4, a GTPase regulator located in the commonly deleted 7q31 region, was identified by this unbiased approach. Significant hypermethylation and reduced expression of DOCK4 in MDS bone marrow stem cells was observed in two large independent datasets, providing further validation of our findings. Finally, DOCK4 knockdown in primary marrow CD34(+) stem cells led to decreased erythroid colony formation and increased apoptosis, thus recapitulating the bone marrow failure seen in MDS. These findings reveal widespread novel epigenetic alterations in myelodysplastic leukocytes and implicate DOCK4 as a pathogenic gene located on the 7q chromosomal region.
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Joanna
authors.initials: J
authors.lastname: Opalinska
authors.forename: Davendra
authors.initials: D
authors.lastname: Sohal
authors.forename: Yiting
authors.initials: Y
authors.lastname: Yu
authors.forename: Yongkai
authors.initials: Y
authors.lastname: Mo
authors.forename: Tushar
authors.initials: T
authors.lastname: Bhagat
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Melissa
authors.initials: M
authors.lastname: Fazzari
authors.forename: Maria
authors.initials: M
authors.lastname: Figueroa
authors.forename: Cristina
authors.initials: C
authors.lastname: Alencar
authors.forename: Jinghang
authors.initials: J
authors.lastname: Zhang
authors.forename: Suman
authors.initials: S
authors.lastname: Kambhampati
authors.forename: Simrit
authors.initials: S
authors.lastname: Parmar
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Nischal
authors.forename: Christoph
authors.initials: C
authors.lastname: Hueck
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.forename: Ellen
authors.initials: E
authors.lastname: Freidman
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.forename: Yogen
authors.initials: Y
authors.lastname: Sauthararajah
authors.forename: Vijay
authors.initials: V
authors.lastname: Yajnik
authors.forename: Christine
authors.initials: C
authors.lastname: McMahon
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.forename: Ross
authors.initials: R
authors.lastname: Levine
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.forename: Amittha
authors.initials: A
authors.lastname: Wickrema
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.forename: Amit
authors.initials: A
authors.lastname: Verma
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics / Q000378:metabolism*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D020690:GTPase-Activating Proteins / Q000096:biosynthesis* / Q000235:genetics; D005819:Genetic Markers; D006801:Humans; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C510122:DOCK4 protein, human; D020690:GTPase-Activating Proteins; D005819:Genetic Markers