title: A Zebrafish Model of 5q-Syndrome Using CRISPR/Cas9 Targeting RPS14 Reveals a p53-Independent and p53-Dependent Mechanism of Erythroid Failure.
abstract: 5q-syndrome is a distinct form of myelodysplastic syndrome (MDS) where a deletion on chromosome 5 is the underlying cause. MDS is characterized by bone marrow failures, including macrocytic anemia. Genetic mapping and studies using various models support the notion that ribosomal protein S14 (RPS14) is the candidate gene for the erythroid failure. Targeted disruption of RPS14 causes an increase in p53 activity and p53-mediated apoptosis, similar to what is observed with other ribosomal proteins. However, due to the higher risk for cancer development in patients with ribosome deficiency, targeting the p53 pathway is not a viable treatment option. To better understand the pathology of RPS14 deficiency in 5q-deletion, we generated a zebrafish model harboring a mutation in the RPS14 gene. This model mirrors the anemic phenotype seen in 5q-syndrome. Moreover, the anemia is due to a late-stage erythropoietic defect, where the erythropoietic defect is initially p53-independent and then becomes p53-dependent. Finally, we demonstrate the versatility of this model to test various pharmacological agents, such as RAP-011, L-leucine, and dexamethasone in order to identify molecules that can reverse the anemic phenotype.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Ear
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hsueh
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Melinda
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: QingHua
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Celgene Corporation, San Francisco 94158, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Sung
authors.affiliation: Celgene Corporation, Summit, NJ 07901, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Chopra
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94304, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Sakamoto
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA. Electronic address: shuolin@ucla.edu.
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
mesh_terms: D000740:Anemia / Q000150:complications; D000748:Anemia, Macrocytic / Q000097:blood / Q000150:complications / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D064113:CRISPR-Cas Systems / Q000235:genetics*; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D004195:Disease Models, Animal; D041905:Erythroid Cells / Q000378:metabolism*; D000072669:Gene Editing; D009154:Mutation; D012269:Ribosomal Proteins / Q000172:deficiency / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C039747:ribosomal protein S14
keywords: 5q-syndrome; Myelodysplastic syndrome; RPS14; Ribosomopathy