title: A point mutation of zebrafish c-cbl gene in the ring finger domain produces a phenotype mimicking human myeloproliferative disease.
abstract: Controlled self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs) are critical for vertebrate development and survival. These processes are tightly regulated by the transcription factors, signaling molecules and epigenetic factors. Impaired regulations of their function could result in hematological malignancies. Using a large-scale zebrafish N-ethyl-N-nitrosourea mutagenesis screening, we identified a line named LDD731, which presented significantly increased HSPCs in hematopoietic organs. Further analysis revealed that the cells of erythroid/myeloid lineages in definitive hematopoiesis were increased while the primitive hematopoiesis was not affected. The homozygous mutation was lethal with a median survival time around 14-15 days post fertilization. The causal mutation was located by positional cloning in the c-cbl gene, the human ortholog of which, c-CBL, is found frequently mutated in myeloproliferative neoplasms (MPN) or acute leukemia. Sequence analysis showed the mutation in LDD731 caused a histidine-to-tyrosine substitution of the amino acid codon 382 within the RING finger domain of c-Cbl. Moreover, the myeloproliferative phenotype in zebrafish seemed dependent on the Flt3 (fms-like tyrosine kinase 3) signaling, consistent with that observed in both mice and humans. Our study may shed new light on the pathogenesis of MPN and provide a useful in vivo vertebrate model of this syndrome for screening drugs.
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Peng
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Dong
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.|Shanghai Center for Systems Biomedicine, Ministry of Education Key Laboratory of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: X-E
authors.initials: XE
authors.lastname: Jia
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Mao
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Jin
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Gao
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: K
authors.initials: K
authors.lastname: Ma
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
authors.forename: T
authors.initials: T
authors.lastname: Du
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Jin
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
authors.forename: K
authors.initials: K
authors.lastname: Li
authors.affiliation: Stem Cell Program at Boston Children's Hospital, Hematology/Oncology Program at Children's Hospital and Dana Faber Cancer Institute, Harvard Medical School, Boston, MA, USA.|Howard Hughes Medical Institute, Boston, MA, USA.
authors.forename: L I
authors.initials: LI
authors.lastname: Zon
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.|Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Deng
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate University, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Xi
authors.affiliation: Stem Cell Program at Boston Children's Hospital, Hematology/Oncology Program at Children's Hospital and Dana Faber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University (SJTU) School of Medicine, and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
authors.forename: S
authors.initials: S
authors.lastname: Chen
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D009196:Myeloproliferative Disorders / Q000209:etiology / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D050721:Proto-Oncogene Proteins c-cbl / Q000737:chemistry / Q000235:genetics*; D015027:Zebrafish
chemical_list: D050721:Proto-Oncogene Proteins c-cbl