title: Functional evidence implicating chromosome 7q22 haploinsufficiency in myelodysplastic syndrome pathogenesis.
abstract: Chromosome 7 deletions are highly prevalent in myelodysplastic syndrome (MDS) and likely contribute to aberrant growth through haploinsufficiency. We generated mice with a heterozygous germ line deletion of a 2-Mb interval of chromosome band 5A3 syntenic to a commonly deleted segment of human 7q22 and show that mutant hematopoietic cells exhibit cardinal features of MDS. Specifically, the long-term hematopoietic stem cell (HSC) compartment is expanded in 5A3(+/del) mice, and the distribution of myeloid progenitors is altered. 5A3(+/del) HSCs are defective for lymphoid repopulating potential and show a myeloid lineage output bias. These cell autonomous abnormalities are exacerbated by physiologic aging and upon serial transplantation. The 5A3 deletion partially rescues defective repopulation in Gata2 mutant mice. 5A3(+/del) hematopoietic cells exhibit decreased expression of oxidative phosphorylation genes, increased levels of reactive oxygen species, and perturbed oxygen consumption. These studies provide the first functional data linking 7q22 deletions to MDS pathogenesis.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, United States.
authors.forename: Jasmine C
authors.initials: JC
authors.lastname: Wong
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, United States.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Weinfurtner
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, United States.
authors.forename: Maria Del Pilar
authors.initials: Mdel P
authors.lastname: Alzamora
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, San Francisco, United States.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Burgess
authors.affiliation: Unit of Hematopoietic Stem Cell and Transgenic Animal Models, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Joy
authors.initials: J
authors.lastname: Nakitandwe
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: Shann-Ching
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Theodore T
authors.initials: TT
authors.lastname: Ho
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Johanna
authors.initials: J
authors.lastname: Flach
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Damien
authors.initials: D
authors.lastname: Reynaud
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, University of California, San Francisco, San Francisco, United States.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States.
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
mesh_terms: D000818:Animals; D002897:Chromosomes, Human, Pair 7; D004195:Disease Models, Animal; D056426:Genetic Loci; D057895:Haploinsufficiency; D006801:Humans; D008810:Mice, Inbred C57BL; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D017382:Reactive Oxygen Species; D010100:Oxygen
keywords: chromosome engineering; haploinsufficiency; hematopoietic stem cells; human biology; medicine; monosomy 7; mouse; myelodysplastic syndrome; oxidative phosphorylation